New Drug Relieves Back Pain, But Safety Issues Remain

By Pat Anson, PNN Editor

An experimental non-opioid pain reliever gives long-term relief for chronic low back pain, but questions remain about joint damage and other side effects from the drug, according to a large new study.

Tanezumab is a humanized monoclonal antibody that targets nerve growth factor (NGF), a protein in the blood that heightens pain sensitivity. Tanezumab binds to NGF and inhibits pain signals from reaching the brain.

In a Phase III study of over 1,800 patients with difficult-to-treat low back pain, participants given an injection of tanezumab once every two months had significantly more pain relief than those given tramadol or a placebo. The study was funded by Pfizer and Eli Lilly, which have spent nearly a decade jointly developing tanezumab as an alternative to opioid medication.

"This demonstration of efficacy is a major breakthrough in the global search to develop non-opioid treatments for chronic pain," said lead author John Markman, MD, director of the Translational Pain Research Program at the University of Rochester Medical Center. "There were also improvements in function linked to the reduction in pain severity."

But this “major breakthrough” is tainted by the fact that about 10% of patients given 10mg of tanezumab had joint pain or other side effects. Seven of them needed total joint replacement surgery. Patients who received 5mg injections of tanezumab had fewer side effects, but less relief from back pain.

NGF inhibitors have previously been linked to a rapidly progressive form of osteoarthritis. But researchers say other methods of treating back pain, such as opioids, non-steroidal anti-inflammatory drugs (NSAIDs) and surgery, have their own safety risks.

"In the future, clinicians may have to weigh the different risks of lumbar fusion surgery, chronic opioid use, or NSAIDs against the unique risks of a rare but rapidly progressive form of joint problem associated with blocking nerve growth factor," said Markman. "I expect that that the tradeoffs between benefit and risk will be different for osteoarthritis than for chronic low back pain."

Tanezumab is currently under review by the Food and Drug Administration as a treatment for moderate-to-severe osteoarthritis (OA), with a decision expected late this year. In a 2019 study of osteoarthritis patients taking a 5mg dose of tanezumab, there was significant improvement in their pain and physical function. But about 6% experienced rapidly progressive osteoarthritis.

Pfizer and Eli Lilly are not currently pursuing tanezumab as a treatment for chronic low back pain (CLBP).  

“Pfizer and Lilly made the decision to prioritize OA based on an assessment of the totality of SC tanezumab data and an initial discussion with the FDA,” a Pfizer spokesman said in an email to PNN. “At this time, regulatory submissions are not planned for tanezumab in patients with moderate-to-severe CLBP. Additional data analyses, and potentially further clinical study, may be required to more fully characterize tanezumab in CLBP patients.”

The new study was published in the journal Pain. Some of its findings had previously been released by Pfizer and Lilly.

Most Patients Say Cannabis Effective for Musculoskeletal Pain

By Pat Anson, PNN Editor

The vast majority of people with musculoskeletal pain who have tried medical cannabis say it is an effective pain reliever and over half believe it works better than other pain medications, according to a new study released by the American Academy of Orthopaedic Surgeons.  

Researchers surveyed 629 patients being treated at orthopaedic clinics to see how widely cannabis is being used for chronic muscle and joint pain that can be caused by arthritis, fibromyalgia, osteoporosis and many other conditions.

“Over time, we’ve certainly seen an increase in the use of cannabis to manage musculoskeletal (MSK) pain,” said lead author Timothy Leroux, MD, an orthopaedic surgeon and assistant professor at the University of Toronto.

“There is definite interest to see if cannabis can be used to manage chronic MSK pain, as opposed to other conventional treatments such as anti-inflammatories and opioids. With this study, we wanted to get a lay of the land as to who is using it, what proportion are using and what they perceive the efficacy to be.”

One in five of the patients surveyed said they are currently using or have tried cannabis to manage their MSK pain. Of those, 90% said cannabis was effective, 57% believe it works better than other pain medications, and 40% said it decreased their use of other drugs.

Patients who used cannabis for MSK pain were more likely to have multiple conditions, including depression, back pain, chronic pelvic pain and chronic neck pain. They were also more likely to use muscle relaxants and opioids for pain relief.

The most common form of cannabis used was cannabidiol (39%) and the most common route of ingestion was CBD oil (60%). Over a third of patients said they spent at least $200 per month on cannabis products.

Among the cannabis users, only 26% received a recommendation from a physician. Most said they tried cannabis at the urging of a friend or family member.

“Most doctors, especially orthopaedic surgeons, don’t have prescribing power for cannabis, so there is minimal physician oversight when it comes to cannabis use to manage chronic MSK pain,” said Leroux. “To complicate things, it’s a little bit of a Wild West in the cannabis industry in terms of what you get in a product, namely actual vs. labelled composition, and consistency.

“Another challenge is that we don’t fully know what products, formulations, dosages, and routes of administration are best to manage chronic MSK pain. Given the high rate of use observed in this study and little physician oversight, there’s an impetus for us as a medical community to try to understand what role, if any, cannabis may serve in the management of chronic MSK pain.”

Even among non-users, there was a fair amount of interest in cannabis. Sixty-five percent reported an interest in trying cannabis for MSK pain. Common barriers to using cannabis were stigma and lack of knowledge about its efficacy, doses and routes of administration.

“We tend to associate cannabis with a younger age due to recreational use, but in our study, age was not a significant factor influencing use for the management of chronic MSK pain,” said Leroux. “Patients reported use well into their 80’s, many whom we assumed would want to use more conventional products.

“We’d like to repeat this study in the next few years to see how use and demographics change as people become more comfortable with the idea of cannabis as the norm as well as what role state legalization plays in patients’ attitudes towards its use.”

Prescriptions for Hydroxychloroquine Surge, But Drop for Hydrocodone

By Pat Anson, PNN Editor

Prescriptions for the antimalarial drugs hydroxychloroquine and chloroquine surged dramatically over the last few months, likely due to their off-label use for treating COVID-19, according to a new analysis published in JAMA. The study also found a significant decline in prescriptions for the opioid painkiller Vicodin and other hydrocodone/acetaminophen combinations.  

Researchers at Brigham and Women's Hospital studied prescription drug data from over 58,000 chain, independent and mail-order pharmacies in the U.S. from February 16 to April 25, and compared them to prescriptions over the same period in 2019.

Prescriptions for hydroxychloroquine and chloroquine spiked in mid-March – rising over 2,000 percent in one week -- soon after President Trump began touting the drugs as a possible treatment for the coronavirus. Brigham researchers estimate there were close to half a million additional prescriptions filled for hydroxychloroquine/chloroquine in 2020 compared to the year before.

SOURCE: JAMA

Hydroxychloroquine is only approved by the Food and Drug Administration to treat autoimmune diseases such as lupus and rheumatoid arthritis. Increased demand for the drug and government stockpiling soon led to spot shortages of hydroxychloroquine.

"There have been indications that hydroxychloroquine (HCQ) prescribing had increased and shortages had been reported, but this study puts a spotlight on the extent to which excess hydroxychloroquine/chloroquine prescriptions were filled nationally," said corresponding author Haider Warraich, MD, an associate physician in the Division of Cardiovascular Medicine at the Brigham.

"This analysis doesn't include patients who were prescribed HCQ in a hospital setting -- this means that patients could have been taking the drugs at home, without supervision or monitoring for side effects."

Last month President Trump took hydroxychloroquine for about two weeks with a doctor’s permission, even though the FDA warned that hydroxychloroquine should not be used as a treatment for COVID-19 outside of a hospital or clinical study because it could aggravate heart problems. The drug has been linked to at least 48 deaths in the U.S. so far this year, according to an FDA database.

On Sunday, the White House announced the U.S. supplied Brazil with 2 million doses of hydroxychloroquine. Brazil reported a record 33,274 new cases of the coronavirus over the weekend. Its death toll now ranks only below the United States, Britain and Italy.

Other Drugs Impacted by Pandemic

Brigham researchers say prescriptions for hydrocodone/acetaminophen fell by nearly 22 percent over the study period. There were also notable declines in prescriptions for the antibiotics amoxicillin and azithromycin, the blood pressure drug lisinopril, and the nerve drug gabapentin. Researchers said there are a variety of reasons why the drugs are being prescribed less often.

“The modest decline for most common long-term therapies after peak could represent reduced contact with prescribing clinicians, restricted access to pharmacies, pharmacist rationing, loss of insurance from unemployment, or replete supplies from early stockpiling,” researchers said. “Steep declines for amoxicillin and azithromycin appeared out of proportion to expected seasonal declines and could represent fewer outpatient prescriptions for upper respiratory tract infection symptoms.”

The pandemic appears to be taking a toll on the nation’s mental health. In the early stages of the outbreak, pharmacy benefit manager Express Scripts reported a surge in prescriptions for anti-anxiety medications such as Xanax and Valium, as well as antidepressants and anti-insomnia drugs.

A recent survey by the Kaiser Family Foundation found that nearly half of Americans said that they or a family member had cancelled or postponed medical care because of the pandemic. About one in every ten said the person’s medical condition worsened as a result of the delayed care.

Study Debunks Use of Hydroxychloroquine for COVID-19

By Pat Anson, PNN Editor

A large international study on the use of hydroxychloroquine and chloroquine for treating COVID-19 has found the antimalarial drugs offer no benefit for hospitalized coronavirus patients and appear to significantly raise the risk of death, particularly when taken with antibiotics.

The study, published in the peer-reviewed journal The Lancet, looked at data from nearly 15,000 patients with COVID-19 who received hydroxychloroquine or chloroquine, with or without the use of antibiotics. They were compared to a control group of over 81,000 patients who did not take the drugs. The study included patients being treated at 671 hospitals in North America, Europe, Asia, Africa, South America and Australia.

(Update: On June 4, The Lancet retracted this study after the authors said were unable to complete an independent audit of their research and concluded they “can no longer vouch for the veracity of the primary data sources.”)

“We found no evidence of benefit of hydroxychloroquine or chloroquine when used either alone or with a macrolide (antibiotic),” researchers said. “Our study included a large number of patients across multiple geographic regions and provides the most robust real-world evidence to date on the usefulness of these treatment regimens. Although observational studies cannot fully account for unmeasured confounding factors, our findings suggest not only an absence of therapeutic benefit but also potential harm.”

The study found that 9.3% of patients in the control group died in the hospital. Of those treated with chloroquine or hydroxychloroquine alone, 16.4% died. The outcomes were even worse for patients who used chloroquine with an antibiotic (22.2%) or hydroxychloroquine with an antibiotic (23.8%).

Researchers also found that serious cardiac arrhythmias, which cause the lower chamber of the heart to beat rapidly and irregularly, were more common in the groups that took hydroxychloroquine or chloroquine.

“This is the first large scale study to find statistically robust evidence that treatment with chloroquine or hydroxychloroquine does not benefit patients with COVID-19. Instead, our findings suggest it may be associated with an increased risk of serious heart problems and increased risk of death,” said lead author Mandeep Mehra, MD, Executive Director of the Brigham and Women’s Hospital Center for Advanced Heart Disease.

“Randomised clinical trials are essential to confirm any harms or benefits associated with these agents. In the meantime, we suggest these drugs should not be used as treatments for COVID-19 outside of clinical trials.”

President Trump disclosed this week that he has been taking hydroxychloroquine as a preventative treatment for COVID-19, even though there is only anecdotal evidence the drug may work against the virus. The president said he was prescribed the drug by his physician after two White House staff members were diagnosed with the virus. Trump said he would only take hydroxychloroquine for about two weeks.

The Food and Drug Administration has said hydroxychloroquine or chloroquine should not be used as frontline treatments for COVID-19 outside of hospitals and clinical trials.

The FDA has only approved chloroquine to treat malaria and hydroxychloquine as a treatment for lupus and rheumatoid arthritis. Both drugs have good safety profiles for those conditions.

Chloroquine and hydroxychloquine have been shown to have antiviral effects in laboratory tests, which has sparked interest in their use as potential treatments for COVID-19. Some countries have been stockpiling the drugs. In March, the FDA added hydroxychloquine and chloroquine to its list of drug shortages. Chloroquine was recently taken off the list.

“Several countries have advocated use of chloroquine and hydroxychloroquine, either alone or in combination, as potential treatments for COVID-19,” said co-author Frank Ruschitzka, MD, Director of the Heart Center at University Hospital Zurich.

“Justification for repurposing these medicines in this way is based on a small number of anecdotal experiences that suggest they may have beneficial effects for people infected with the SARS-CoV-2 virus. However, previous small-scale studies have failed to identify robust evidence of a benefit and larger, randomised controlled trials are not yet completed. However, we now know from our study that the chance that these medications improve outcomes in COVID-19 is quite low.”

In addition to their findings on chloroquine and hydroxychloroquine, researchers also noted that obesity, heart disease, diabetes and smoking raise the risk of death for hospitalized COVID-19 patients. Interestingly, patients being treated with statins or ACE inhibitors for high blood pressure had a lower risk of mortality, suggesting that medications that stabilize the cardiovascular system may be beneficial.

Controversy Grows Over Trump's Use of Hydroxychloroquine

By Pat Anson, PNN Editor

President Trump on Tuesday defended his use of hydroxychloroquine (Plaquenil) as a preventative treatment for COVID-19, even though there is only anecdotal evidence the drug may work against the virus and it may be harmful to some patients. Hydroxychloroquine has been linked to at least 48 deaths in the U.S. so far this year, according to an FDA database.

The president first disclosed his use of hydroxychloquine on Monday, claiming that White House physician Sean Conley said it was okay for him to take the drug.

“I asked him, ‘What do you think?’ He said, ‘Well, if you’d like it.’ I said, ‘Yeah, I’d like it. I’d like to take it,’” Trump said.

Dr. Conley confirmed that account in a statement.

“After numerous discussions (Trump) and I had regarding the evidence for and against the use of hydroxychloroquine, we concluded the potential benefit from treatment outweighed the relative risk," Conley said.

The Food and Drug Administration has only approved hydroxychloquine for the treatment of malaria, lupus and rheumatoid arthritis. However, nothing prevents a doctor from prescribing a drug "off-label" to treat another condition.

In recent months, Trump has touted hydroxychloquine as a possible "game changer" in the treatment of COVID-19. He said he started taking the drug as a preventative measure a week and a half ago, at about the same time two White House staff members tested positive for coronavirus.

“I’m not going to get hurt by it. It’s been around for 40 years,” Trump said. “For malaria, for lupus, for other things. I take it. Front-line workers take it. A lot of doctors take it."

Last month, the FDA warned against using hydroxychloroquine as a treatment for COVID-19 outside of a hospital or clinical study because of “serious and potentially life-threatening heart rhythm problems.” Patients with heart and kidney disease are especially at risk, the agency said.

The FDA's Adverse Events Reporting System lists over 10,000 reported cases involving hydroxychloroquine in the past decade, most of them serious, life threatening or resulting in hospitalizations. Nearly 600 people have died since 2010, including 48 deaths so far this year.

The number of adverse events involving hydroxychloroquine has soared in recent years, from less than a hundred cases in 2010 to over 4,500 in 2019

SOURCE: FDA ADVERSE EVENTS REPORTING SYSTEM

'Reckless Action'

"President Trump’s use of hydroxychloroquine to prevent Covid-19 infection without any clinical evidence of its utility is dangerous and will cause untoward toxicities, likely including death, in some people following his lead," Dr. Michael Polis, a fellow at the Infectious Diseases Society of America, told The New York Times.

"He needs to be strongly criticized by the medical community for this reckless action."

A recent study funded by the National Institutes of Health looked at patients at VA hospitals who were given hydroxychloroquine to treat COVID-19. They concluded the drug was ineffective and raised the risk of patients dying.

“In this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone. These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs,” researchers found.

Trump dismissed the research as a "phony study" by his political enemies.

“There was a false study done where they gave it to very sick people, extremely sick people, people that were ready to die,” he said Tuesday. “It was given by obviously not friends of the administration.” 

Several patients who are prescribed hydroxychloroquine for rheumatoid arthritis or lupus have told PNN they are worried about possible shortages due to Trump's touting of the drug.

“I have been on hydroxychloroquine for five years for my autoimmune disease and had never had an issue getting the medication until the virus. In March, I had to check 3 different pharmacies before I found one that had any in stock,” one patient said. “My usual pharmacy said that not a single one of their local chains had it in stock and that they were back-ordered. The pharmacy that did have it, was only able to do a partial refill.” 

“I am currently on Plaquenil for lupus and having Trump declare it is the cure for COVID-19 has limited my access to my medication. I am worried there won’t be enough,” another patient said.  

“I am in a horrible RA flare at this moment. I have no doubt that the stress of being concerned about getting my needed medication has helped to bring this flare on," said another. "I am really concerned about being able to get my much-needed hydroxychloroquine. There is no reasonable explanation for drug shortages in this country other than ignorance.” 

Former Vice-President Joe Biden said Trump was “absolutely irresponsible” for taking hydroxychloroquine, which could encourage others to take it to prevent COVID-19 infections.

"It's like saying maybe if you injected Clorox into your blood, maybe it'll cure you. What is he doing? What in God's name is he doing?" said the presumptive Democratic 2020 nominee. “Look, this is absolutely irresponsible. There's no serious medical personnel out there saying to use that drug. It's counterproductive. It's not going to help."

Prescriptions for Anti-Anxiety Meds Surge Due to Coronavirus

By Pat Anson, PNN Editor

After weeks of isolation and the uncertainty of dealing with the coronavirus outbreak, it’s no surprise that many Americans are feeling depressed, anxious and not sleeping well.

“The trauma of a loved one being in the ICU, alone and not knowing if you'll ever see them again is horrific. It also adds to personal health anxiety,” one patient told us in our recent survey on the coronavirus.

“This is an extremely scary time. My anxiety is through the roof for many reasons,” another patient said. “I’m extremely worried I won’t pull through this or my husband and daughter won’t pull through this if they contract the virus! We’ve already lost my aunt and best friend both to coronavirus. One was 34, the other 62.”

“I feel more depressed and find my anxiety level is up. I worry most about getting my medications,” said another. 

New research from pharmacy benefit manager Express Scripts shows the stress is having a significant impact on the nation’s mental health. 

From February 16 to March 15, the number of prescriptions filled in the U.S. for anti-anxiety medications rose by a third (34.1%), along with antidepressants (18.6%) and anti-insomnia drugs (14.8%).

More than three quarters (78%) of the prescriptions were new – meaning they weren’t refills.

“As COVID-19 began to significantly impact the U.S., we observed an increase in the use of prescription drugs that treat mental health conditions, particularly commonly used anti-anxiety medications known as benzodiazepines,” Express Script said in a new report called “America’s State of Mind.”

SOURCE: EXPRESS SCRIPTS

The increased use of benzodiazepines such as Xanax and Valium is striking, because the drugs had fallen out of favor in recent years in large part due to fears that they raise the risk of respiratory depression and overdose when used with opioids.

Prescriptions for anti-anxiety medication rose more for women (39.6%) than men (22.7%) between February 16 and March 15, according to Express Scripts.

Hydroxychloroquine Shortages

Some patients with rheumatoid arthritis, lupus and other autoimmune diseases say their stress levels are up because they worry about losing access hydroxychloroquine (Plaquenil), a drug repeatedly touted by President Trump as a possible treatment for COVID-19.

“I am currently on Plaquenil for lupus and having Trump declare it is the cure for COVID-19 has limited my access to my medication. I am worried there won’t be enough,” a patient said.  

“No chronic pain patient should have to sit and have the anxiety from concerns on being able to have access to medication needed to treat their illness,” a rheumatoid arthritis sufferer said. “I am in a horrible RA flare at this moment. I have no doubt that the stress of being concerned about getting my needed medication has helped to bring this flare on. I am really concerned about being able to get my much-needed hydroxychloroquine. There is no reasonable explanation for drug shortages in this country other than ignorance.” 

“I have been on hydroxychloroquine for five years for my autoimmune disease and had never had an issue getting the medication until the virus. In March, I had to check 3 different pharmacies before I found one that had any in stock,” another patient said. “My usual pharmacy said that not a single one of their local chains had it in stock and that they were back-ordered. The pharmacy that did have it, was only able to do a partial refill.” 

When she told her doctor what happened, he agreed to write a 3-month prescription for hydroxychloroquine to make sure she’d have an adequate supply. Her insurance company, however, refused to pay for more than a month’s supply. 

“Not only do I worry about running out of medication, but each time I have to go to the pharmacy for various medications, I am exposing myself to others which could cause me to get the virus. As someone who has a compromised immune system, I want to leave the house as little as possible to avoid exposure,” the patient said.

On Friday, the Food and Drug Administration warned against using hydroxychloroquine or chloroquine as a treatment for COVID-19 outside a hospital or clinical study because of “serious and potentially life-threatening heart rhythm problems.” Patients with heart and kidney disease are especially at risk.

The FDA said patients taking the drugs for approved reasons, including malaria and autoimmune conditions like lupus, should continue taking them as prescribed.

Stem Cell Trial Significantly Reduced Osteoarthritis Knee Pain

By A. Rahman Ford, PNN Columnist

A small clinical trial has shown that a single injection of autologous stem cells derived from a patient’s own body fat can significantly reduce osteoarthritis knee pain for up to a year with no serious side effects, according to findings published in the American Journal of Sports Medicine.

A total of 39 osteoarthritis patients participated in the Phase 2 placebo-controlled trial. Some participants received injections into their knees of stromal vascular fraction (SVF) cells derived from adipose fat tissue, while others received placebo injections.

"Our randomized, controlled clinical trial is the first cellular therapy study for osteoarthritis to meet study endpoints using autologous adipose stromal cells for a point-of-care therapy. Eighty-eight percent of subjects responded greater than placebo at one year and reported a median 87% improvement in pain, stiffness and function," said William Cimino, PhD, CEO of GID BIO, which funded the study. GID BIO develops cellular therapies for degenerative musculoskeletal, dermal and other chronic diseases.

SVF therapy is controversial because it is not yet FDA-approved. Some stem cell clinics currently using SVF therapy are in the crosshairs of the FDA, with ongoing federal litigation in Florida and California. That’s what makes the new study findings significant.

"Publishing this data signifies real science and a breakthrough in regenerative medicine. We've completed a prior safety trial, an FDA-approved Phase 2b trial, and are now beginning a Phase 3 pivotal trial. Physicians will be able to use the SVF-2 technology to provide a cellular therapy option for patients," said principal investigator Jaime Garza, MD, Professor of Orthopedic Surgery at Tulane University School of Medicine.

Interestingly, Garza is a former star football player at Tulane whose fledgling NFL career was cut short by nagging knee injuries. As PNN has reported, regenerative cell therapies are increasing in popularity among NFL players and other professional athletes, who often have chronic pain from lingering injuries.

Knee osteoarthritis (OA) is the most prevalent joint disease in the United States, affecting nearly 1 in 5 Americans aged 45 years and older. Since the mid-20th century, knee OA has doubled in prevalence, due primarily to age and obesity. Women are more likely than men to have knee OA and have more severe pain.

Total knee arthroplasty – a procedure that attempts to restore function by resurfacing the knee joint – is the only surgical intervention for knee OA. Other treatments include anti-inflammatory medications, physical therapy and steroid injections.  The FDA is also considering a new drug application for tanezumab, a biologic drug that blocks pain signals from reaching the brain.

“While current nonoperative modalities can offer symptomatic relief, these treatment modalities often fail, ultimately leading to knee arthroplasty. There is a need for more effective nonoperative knee OA treatment modalities, especially ones that may arrest or even reverse disease progression,” wrote Garza.

A. Rahman Ford, PhD, is a lawyer and research professional. He is a graduate of Rutgers University and the Howard University School of Law, where he served as Editor-in-Chief of the Howard Law Journal. Rahman lives with chronic inflammation in his digestive tract and is unable to eat solid food. He has received stem cell treatment in China.

FDA Reviewing New Osteoarthritis Drug

By Pat Anson, PNN Editor

A decade long effort to bring a new non-opioid pain reliever on the market is a step closer to reality – although lingering questions remain over the safety of the drug.

Pfizer and Eli Lilly have announced that the U.S. Food and Drug Administration has accepted for review a Biologics License Application for tanezumab as a treatment of chronic pain due to moderate-to-severe osteoarthritis (OA). The FDA set December 2020 as a goal for making a decision on the application.

Tanezumab is a humanized monoclonal antibody that targets nerve growth factor (NGF), a protein that increases in the body because of injury, inflammation or chronic pain. Tanezumab binds to NGF and inhibits pain signals from muscles, skin and organs from reaching the brain.

"The FDA acceptance of the tanezumab application represents a significant milestone, and the breadth of our regulatory submission reflects the extensive clinical data we have gathered for tanezumab over the course of its development," Ken Verburg, Pfizer’s tanezumab development team leader, said in a statement.

"There is an urgent need for innovation in the treatment of osteoarthritis, as there have been no new classes of medicines available for this debilitating condition in more than a decade. If approved, tanezumab would be a first-in-class treatment for patients suffering from chronic pain due to moderate-to-severe osteoarthritis who have experienced inadequate pain relief with other analgesics."

Pfizer and Eli Lilly are jointly developing tanezumab, which was given “fast track” designation by the FDA in 2017 to help speed its development. The companies submitted data to the FDA from 39 clinical studies evaluating the safety and efficacy of tanezumab on more than 18,000 patients.

A Phase 3 clinical study in 2018 found that osteoarthritis patients who were given two injections of tanezumab had significant improvement in their pain and physical function compared to a placebo.

Not all of the studies have been positive, however. Another Phase 3 study last year found that over 6% of osteoarthritis patients taking a 5 mg dose of tanezumab experienced rapidly progressive OA in their joints. There was significant improvement in their pain and physical function, but the patients’ overall assessment of their condition was no better than those treated with non-steroidal anti-inflammatory drugs (NSAIDs).

Patients in the same study taking a lower 2.5 mg dose of tanezumab did not have any significant improvement in their pain, quality of life or overall condition. And 3.2% experienced rapidly progressive osteoarthritis. The license application accepted by the FDA is for that smaller 2.5 mg dose.

In 2010, Pfizer reported some osteoarthritis patients taking tanezumab experienced worsening of their disease and needed joint replacements. Another safety issue arose in 2012 because the drug caused “adverse changes in the sympathetic nervous system of mature animals.”

There is some concern that NGF antibodies work too well and encourage osteoarthritis patients to become more active, which accelerates joint deterioration. More than 27 million Americans live with osteoarthritis, 11 million of whom have moderate-to-severe OA.

Tanezumab is also being evaluated as a treatment for cancer pain due to bone metastases in a Phase 3 study. At one time, it was studied as a possible treatment for low back pain, but Pfizer and Eli Lilly are now mainly focused on tanezumab as a treatment for osteoarthritis.

Voltaren Arthritis Gel Approved for OTC Despite Safety Risks

By Pat Anson, PNN Editor

The U.S. Food and Drug Administration has approved three drugs for over-the-counter (OTC) sale that were previously only available by prescription. One of them is Voltaren Arthritis Pain, a topical gel made by GlaxoSmithKline.

The active ingredient in Voltaren gel is diclofenac, a non-steroidal anti-inflammatory drug (NSAID) that’s been linked to cardiovascular disease and other serious health problems. The gel contains a 1% solution of diclofenac sodium.

Voltaren Arthritis Pain was first approved by the FDA in 2007 as a prescription drug for the temporary relief of osteoarthritis joint pain in the hands, knees and feet. When taken as directed, the agency considers the gel safe to use.

“As a result of the Rx-to-OTC switch process, many products sold over-the-counter today use ingredients or dosage strengths that were available only by prescription 30 years ago,” said Karen Mahoney, MD, acting deputy director of the Office of Nonprescription Drugs in the FDA’s Center for Drug Evaluation and Research.

“Approval of a wider range of nonprescription drugs has the potential to improve public health by increasing the types of drugs consumers can access and use that would otherwise only be available by prescription. This includes providing the millions of people that suffer with joint pain from arthritis daily over-the-counter access to another non-opioid treatment option.”

The FDA said Voltaren Arthritis Pain may take up to 7 days to work. Consumers should stop using it and seek medical attention if their arthritis pain is not improved in 7 days or if they need to use the product for more than 21 days.

The warning label cautions that diclofenac may cause a severe allergic reaction, especially in people allergic to aspirin. Liver damage may also occur if the gel is used more often or longer than directed, or when used with other products containing diclofenac. The label cautions that diclofenac and other NSAIDs increase the risk of heart attack, heart failure and stroke.

Diclofenac One of Riskiest NSAIDs

Diclofenac is not well-known in the United States, but it is the most widely used NSAID in the world. Some experts consider diclofenac so risky it should be banned as an OTC drug.

A large 2018 study in Denmark found that people using diclofenac were 50 percent more likely to have cardiovascular problems, such as atrial fibrillation, heart failure and stroke.

For every 1,000 people who used diclofenac, the study estimated that four would develop a major health problem within a year.

“It is time to acknowledge the potential health risk of diclofenac and to reduce its use. Diclofenac should not be available over the counter.”

— Dr. Morten Schmidt, Aarhus University Hospital

"It is time to acknowledge the potential health risk of diclofenac and to reduce its use," wrote lead author Morten Schmidt, MD, Aarhus University Hospital. “Diclofenac should not be available over the counter, and when prescribed, should be accompanied by an appropriate front package warning about its potential risks.”

Diclofenac was rated as one of the seven riskiest NSAIDs in a 2016 study published by the British Medical Journal. Researchers estimated the risk of heart failure doubled for people taking diclofenac at very high doses.

“The selective COX 2 inhibitors and diclofenac have repeatedly been associated with higher cardiovascular risk, and therefore it seems prudent to avoid them and consider lower risk naproxen at the lowest effective dose,” researchers warned.

According to the FDA’s Adverse Events Reporting System, there have been over 19,000 serious medical cases involving diclofenac sodium since 2010, including 2,294 deaths.  

As PNN has reported, the FDA has effectively slammed the door shut on new opioid pain medications because of the controversy over opioid addiction and overdose. The agency is promoting the use of “safer” non-opioid drugs and recently approved a cocaine-based analgesic nasal spray.

Experimental Drug Rebuilds Cartilage in Knee Osteoarthritis Patients

By Pat Anson, PNN Editor

An experimental treatment shows promise in slowing the progression of knee osteoarthritis by increasing the thickness of cartilage in the knee joint, according to results of an early clinical trial published in the Journal of the American Medical Association (JAMA).

Researchers at the University of Maryland School of Medicine gave 549 volunteers with knee osteoarthritis injections of the drug sprifermin or a placebo. Sprifermin is a disease modifying drug that stimulated the production of cartilage-producing cells in animal studies.

The researchers found that participants who received a 100 microgram dose of sprifermin either twice or once yearly experienced a statistically significant but slight gain in joint cartilage thickness after two years.  Those given smaller doses had smaller gains in cartilage that were not statistically or clinically significant.

"While the increase in cartilage thickness is a positive sign, we do not know at this point whether it has any clinical significance," said lead investigator Marc Hochberg, MD, a Professor of Medicine at UMSOM. "It is not known whether those who experience increased cartilage thickness over time will be able to avoid or delay knee replacement surgery."

Interestingly, patients treated with a high dose of sprifermin did not experience any significant improvement in their arthritis symptoms – such as pain and stiffness -- compared to those given lower doses or placebo injections.

All of the injections were stopped after 18 months. The Phase 2 study is designed to continue for a total of five years and future analyses of the findings are planned.

About 10 percent of Americans over age 60 have knee osteoarthritis, a progressive condition caused by the breakdown of joint cartilage. Knee osteoarthritis causes pain, physical disability, lower quality of life and is associated with early death and cardiovascular problems.

The pain is usually treated with over-the-counter pain relievers, anti-inflammatory drugs, steroid injections, and sometimes surgery. No disease-modifying osteoarthritis drugs have been approved in the United States or Europe.

Arthroscopic and knee replacement surgeries are increasingly being used to treat knee osteoarthritis. But a number of recent studies have found the arthroscopic surgery does not relieve knee pain any better than physical therapy or over-the-counter pain relievers. Researchers have also found that about a third of patients who had knee replacement surgery continued to have pain after the procedure.

Arthritis Foundation Releases First CBD Guideline

By Pat Anson, PNN Editor

The Arthritis Foundation has become the first major patient advocacy group to release guidelines on the use of cannabidiol (CBD) to treat arthritis pain.  

About 54 million Americans have been diagnosed with arthritis. According to a recent national survey, 79 percent of arthritis patients are currently using CBD, have tried it in the past, or are considering it.

CBD infused products – from edibles to lotions to beverages -- are rapidly going mainstream, even though there is little scientific evidence to support their use. There has also been little guidance for consumers on what products to use or in what doses — until now.

“We are intrigued by the potential of CBD to help people find pain relief and are on record urging the FDA to expedite the study and regulation of these products,” the Arthritis Ffoundation said in a statement.

“While currently there is limited scientific evidence about CBD’s ability to help ease arthritis symptoms, and no universal quality standards or regulations exist, we have listened to our constituents and consulted with leading experts to develop these general recommendations for adults who are interested in trying CBD.”  

CBD is largely extracted from a hemp, a marijuana strain that has only trace amounts of THC, the active ingredient that makes people high.

"Millions of people in the U.S. are likely trying to use cannabinoids to treat pain, and many are doing this in ways that might cause more harm than good, especially when they use high doses of THC," said Daniel Clauw, MD, a professor of anesthesiology at the University of Michigan who was one of the experts the foundation consulted.

"It's important that the Arthritis Foundation has taken a stand on CBD,” Clauw said in a statement. “Right now, it appears to be fairly safe and might help certain types of pain. It's far better to give this guidance, even if preliminary, because otherwise people will have no guidance whatsoever." 

DRUG POLICY ALLIANCE

The new guideline is largely cautionary and does not explicitly recommend CBD as a treatment, stating only that it “may help” with arthritis-related symptoms such as pain, insomnia and anxiety.

When taken in moderate doses, experts say CBD has no major safety issues, although it may interact with some drugs commonly taken for arthritis, such as naproxen (Aleve), celecoxib (Celebrex), tramadol (Ultram), gabapentin (Neurontin), pregabalin (Lyrica) and some antidepressants.

The Arthritis Foundation recommends taking CBD in oral sprays or tinctures so the liquid can be taken under the tongue and be absorbed directly into the bloodstream.

Experts say a “go slow” approach is best, starting with a few drops twice a day and increasing the dose gradually over a period of weeks until an effective dose is reached.

The guideline strongly discourages inhaling or vaping CBD because of the risk of respiratory problems. It also discourages taking CBD in edibles, such as gummies and cookies, because the dosing is unreliable. Experts say the effectiveness of topical lotions and creams with CBD is unclear because they often contain other ingredients.

Other key takeaways from the guideline:

• CBD should never be used to replace disease-modifying drugs that help prevent permanent joint damage in inflammatory types of arthritis.

• CBD use should be discussed with your doctor in advance, with follow-up evaluations every three months or so.

• Buy from a reputable CBD company that has each batch tested for purity, potency and safety by an independent laboratory and provides a certificate of analysis.  

Unlike prescription drugs approved by the Food and Drug Administration, the manufacturing process for CBD products is not subject to FDA review, and there has been no FDA evaluation of their effectiveness, proper dosage, how they could interact with drugs, or whether they have side effects. 

The Federal Trade Commission recently warned companies that make CBD products to stop making unsubstantiated claims that cannabidiol can be used to treat arthritis and other chronic pain conditions.

Use of NSAIDs Risky for Osteoarthritis Patients

By Pat Anson, PNN Editor

It’s long been known that nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen can raise the risk of cardiovascular problems. A large new study in Canada has documented how NSAIDs can significantly raise the risk of heart disease, congestive heart failure and stroke in people with osteoarthritis.

Osteoarthritis (OA) is a joint disorder that leads to thinning of cartilage and progressive joint damage. NSAIDs are frequently used to treat the pain and inflammation caused by OA.

The Canadian study, published in the journal Arthritis & Rheumatology, looked at nearly 7,750 osteoarthritis patients in British Columbia and compared them with a control group of over 23,000 patients without OA. The average age of the participants was 65 and a little over half were women.

The risk of developing cardiovascular disease was found to be about 23% higher among people with OA than the control group. Researchers attributed about 41% of that increased risk to the use of NSAIDs.

NSAIDs appeared to play a significant role in several cardiovascular problems. The risk of congestive heart failure was 42% higher among people with OA, followed by a 17% greater risk of heart disease and a 14% greater risk of stroke.

"To the best of our knowledge, this is the first longitudinal study to evaluate the mediating role of NSAID use in the relationship between osteoarthritis and cardiovascular disease in a large population-based sample," said senior author Aslam Anis, PhD, of the School of Population and Public Health at the University of British Columbia.

"Our results indicate that osteoarthritis is an independent risk factor for cardiovascular disease and suggest a substantial proportion of the increased risk is due to the use of NSAIDs. This is highly relevant because NSAIDs are some of the most commonly used drugs to manage pain in patients with osteoarthritis."

The association of cardiovascular disease with NSAIDs is consistent with previous research.  A large international study in 2017, for example, found that prescription strength NSAIDs raises the risk of a heart attack as soon as the first week of use.

NSAIDs are used to alleviate pain and reduce inflammation, and are found in a wide variety of over-the-counter products, including cold and flu remedies. They are found in so many products -- such as Advil and Motrin -- that many consumers may not be aware how often they use NSAIDs. 

Canada adopted guidelines in 2017 that recommend NSAIDs as an alternative to opioid pain medication. The guideline makes no mention of the health risks associated with NSAIDs, but focuses on their cost effectiveness.

“NSAID-based treatment may have lower mean costs and higher effectiveness relative to opioids,” the guideline states. “Naproxen-based regimens in particular may be more cost effective compared to opioids and other NSAIDs, such as ibuprofen and celecoxib.”

Opioid guidelines released in 2016 by the U.S. Centers for Disease Control and Prevention also recommend NSAIDs as an alternative to opioids, but acknowledge the medications “do have risks, including gastrointestinal bleeding or perforation as well as renal and cardiovascular risks.”

In 2015, the Food and Drug Administration ordered warning labels for all NSAIDs to indicate they increase the risk of a fatal heart attack or stroke. The FDA warning does not apply to aspirin.

The European Society of Cardiology recommends limited use of NSAIDs by patients who are at risk of heart failure. People already diagnosed with heart failure should refrain from using NSAIDs altogether.

The Hidden Benefits of Glucosamine

By Pat Anson, PNN Editor

Do you take glucosamine supplements to reduce joint pain and stiffness? You’re not alone if you do. According to a 2007 survey, nearly 20 percent of U.S. adults take glucosamine to prevent or treat pain from osteoarthritis, back pain and other conditions.

The evidence to support the use of glucosamine for joint pain is thin, but a large new study in The BMJ suggests regular use of the supplement can reduce the risk of cardiovascular disease.

Researchers at Tulane University analyzed 7 years of extensive health data for almost half a million adults aged 40 to 69 enrolled in the UK Biobank study. Those who regularly took glucosamine were about 15% less likely to develop heart disease or have a stroke.

Glucosamine occurs naturally in the fluid around joints and plays an importantly role in building cartilage. Glucosamine is extracted from shellfish and is often combined in supplements with chondroitin, a similar substance that is also found in joints.

People who took glucosamine in the BMJ study were more likely to be women, older, more physically active, have healthier diets and take other supplements.

Over the course of seven years, 2.2% of those who did not use glucosamine had a heart attack or stroke, compared to 2.0% of people who did use glucosamine. People who used glucosamine were also less likely to die from a heart attack or stroke, 0.5% vs. 0.7% of those who didn’t use the supplement.

The difference doesn’t appear to be significant, but when adjusted for risk and other factors, it means that glucosamine users had a 22% lower risk of dying from a heart attack or stroke.

For smokers, the benefits of regular glucosamine use were even greater. They had 37% less risk of having coronary heart disease compared to smokers who didn’t use the supplements.

Researchers didn’t establish the reason why glucosamine lowers the risk of cardiovascular disease (CVD), but they believe the supplements help reduce inflammation – one of the main factors involved in the development of heart disease, as well as chronic pain.

“Several potential mechanisms could explain the observed protective relation between glucosamine use and CVD diseases. In the National Health and Nutrition Examination Survey (NHANES) study, regular use of glucosamine was associated with a statistically significant reduction in C reactive protein concentrations, which is a marker for systemic inflammation,” researchers reported. “Other mechanisms might also be involved, and future investigations are needed to explore the functional roles of glucosamine in cardiovascular health.”

The UK’s National Health Service (NHS) downplayed the study findings, pointing out the cardiovascular benefits of glucosamine are “quite small.”

“If you want to reduce your risk of having a heart attack or stroke, it would be much better to concentrate on living a healthy lifestyle, rather than paying for glucosamine supplements,” the NHS said.

CreakyJoints Under Scrutiny for Ties to Drug Makers

By Pat Anson, PNN Editor

Patient advocacy groups are coming under scrutiny again for their financial ties to drug companies. The latest is the Global Healthy Living Foundation (GHLF), a non-profit charity that created CreakyJoints, a website and social media platform that raises awareness about arthritis and other chronic illnesses. 

According to Bloomberg News reporter Ben Elgin, the foundation and CreakyJoints have long had a cozy relationship with Pfizer, Amgen, Johnson & Johnson and other corporate donors. Pfizer has donated nearly $1 million to the foundation over the past decade and one of its vice-presidents even serves on GHLF’s board of directors.

In a speech to drug makers in 2010, GHLF president Seth Ginsberg reportedly sought their donations -- while at the same time promising the companies “higher profits” and “sales rep participation in our programs.”

Ginsberg, who was diagnosed with spondyloarthritis as a teenager, co-founded GHLF in 1999 with marketing executive Louis Tharp.

In addition to CreakyJoints, GHLF has two other “grassroots” programs, Fail First Hurts and the 50-State Network, which advocate for healthcare policies that often align with the interests of its donors.  

According to GHLF’s 2017 tax return, the foundation had over $5 million in annual revenue. Ginsberg was paid a salary of $384,000, while Tharp received $220,000 as Executive Director.  Nearly $300,000 was also paid to a for-profit marketing company established by the two men, although it’s unclear what the payment was for.

Bloomberg reported that GHLF’s tax returns “reflect errors and unexplained entries that have obscured the amounts of money flowing to its cofounders.”

“Are they operating in a way that is extremely transparent? It’s safe to say they’re not,” Brian Mittendorf, a professor of accounting at Ohio State University told Bloomberg. “From looking at their disclosures, you have no idea how closely they’re related to some of the entities it pays.”

At least one GHLF board member and several patient volunteers reportedly left the organization because they were troubled by its relationships with donors.

GHLF did not grant an interview to Bloomberg, but replied to questions in writing.

“The only time we engage in advocacy is when it helps patients. If it doesn’t help patients, we don’t do it,” the foundation said in a statement. “Our mission is to engage in patient-centered research, provide advocacy for access-to-care, and to support people living with chronic disease by providing a supportive environment and accessible education.”

In a related story, Bloomberg reported that several other recently formed non-profits – such as the U.S. Rural Health Network --  appear to be little more than front organizations for the pharmaceutical industry.

“There are a number of groups created by pharma companies that look and act like patient organizations, but they’re 100 percent funded by industry,” said Marc Boutin, chief executive officer of the National Health Council. “They sound and look like patient organizations, but they take positions that industry wants.”

Drug Companies Fined for Co-Pay Programs

Last week two drug companies agreed to pay $125 million in fines to settle allegations that they used charitable foundations as front organizations to bilk Medicare.

Amgen and Japanese drug maker Astellas Pharma paid the foundations to establish co-pay prescription drug programs for Medicare patients. Federal prosecutors say the programs were primarily designed not to help patients, but to illegally pay their co-pays for Astellas and Amgen products.

Federal anti-kickback laws prohibit pharmaceutical companies from making any kind of payment to induce Medicare patients to purchase their drugs. The prohibition includes co-pays.

“The companies’ payments to the foundations were not ‘donations,’ but rather were kickbacks that undermined the structure of the Medicare program and illegally subsidized the high costs of the companies’ drugs at the expense of American taxpayers,” U.S. Attorney Andrew Lelling said in a statement.

“When pharmaceutical companies use foundations to create funds that are used improperly to subsidize the co-pays of only their own drugs, it violates the law and undercuts a key safeguard against rising drug costs,” said U.S. Assistant Attorney General Jody Hunt.

Last year, Pfizer paid nearly $24 million to settle allegations that it also used a co-pay program to pay Medicare for the company’s prescription drugs.

U.S. Pain Foundation Co-Pay

The U.S. Pain Foundation is under investigation by the U.S. Senate Finance Committee for a similar co-pay program established with Insys Therapeutics, a controversial Arizona drug company. Insys makes Subsys, an expensive and potent fentanyl spray blamed for hundreds of overdose deaths.

U.S. Pain received $2.5 million from Insys to launch the “Gain Against Pain” program, which ostensibly helped Medicare patients pay for drugs prescribed for breakthrough cancer pain. Critics say the program was primarily used to increase prescriptions for Subsys, which can cost $24,000 for just a four-day supply.

Former U.S. Pain CEO Paul Gileno initially defended the co-pay program, saying the money from Insys “does not influence our values,” but later resigned over allegations that he misappropriated $2 million from his own charity.

The Gain Against Pain program was subsequently shutdown in August 2018 and U.S. Pain said it would no longer accept funding from Insys.

Sen. Ron Wyden (D-OR), the ranking member of the Senate Finance Committee, sent a lengthy letter last December to U.S. Pain interim CEO Nicole Hemmenway asking a series of questions about the Insys co-pay program. According to the senator’s office, Wyden has still not gotten a full response.  

“The U.S. Pain Foundation has yet to provide a substantial amount of the information that Senator Wyden requested in his letter. Staff is in communication with the organization in order to get to the bottom of the organization’s financial relationship with pharmaceutical manufacturers, including Insys, and its compliance with applicable federal laws,” a Wyden spokesperson said in a statement to PNN.

A federal jury in Boston is currently in its third week of deliberations in a criminal case against Insys founder John Kapoor and four former executives of the company, who are accused of bribing doctors to boost sales of Subsys. 

U.S. Pain also remains under investigation by the Connecticut Attorney General’s office for financial irregularities that led to Gileno’s resignation.

New Safety Concerns for Osteoarthritis Drug

By Pat Anson, PNN Editor

Disappointing results from a Phase 3 clinical study are raising new safety concerns about an experimental class of pain-relieving drugs once considered a promising alternative to opioids.

Pfizer and Eli Lilly say 6.3% of osteoarthritis patients taking a 5 mg dose of tanezumab experienced rapidly progressive osteoarthritis in their joints. There was significant improvement in their pain and physical function, but the patients’ overall assessment of their condition was no better than those treated with non-steroidal anti-inflammatory drugs (NSAIDs).

Patients taking a lower 2.5 mg dose of tanezumab did not have any significant improvement in their pain, quality of life or overall condition. And 3.2% experienced rapidly progressive osteoarthritis.

“We are analyzing these findings in the context of the recent Phase 3 results as we assess potential next steps for tanezumab,” Ken Verburg, Pfizer Global Product Development, said in a statement. “We plan to review the totality of data from our clinical development program for tanezumab with regulatory authorities.”

Tanezumab is a humanized monoclonal antibody that targets nerve growth factor (NGF), a protein that increases as a result of injury, inflammation or chronic pain. Tanezumab binds to NGF and inhibits pain signals from reaching the brain.

Tanezumab was considered so promising a therapy that it was given fast track designation from the FDA in 2017, a process that speeds up the development of new therapies to treat serious conditions.

Ironically, it was the FDA that slowed the development of NGF inhibitors in 2010 because of concerns that tanezumab made osteoarthritis worse in some patients. Most clinical studies of tanezumab did not resume until 2015.

The reappearance of the same safety issue and the marginal pain relief provided by tanezumab could be the last straw for the drug, according to one analyst.

“It is hard for us to imagine how these results could have been much worse. Pfizer indicated that they ‘plan to review the totality of data’ with regulatory authorities, which suggests to us that the co-sponsors will try to find a way to resurrect the program for some subset or sub-population of patients, but recognizes that this result puts the drug’s entire future in doubt,” SVB Leerink research analyst Geoffrey Porges said in a note to clients.

A clinical study of fasinumab, another NGF inhibitor being developed by Teva and  Regeneron Pharmaceuticals, was stopped by the FDA in 2016 after a patient showed signs of severe joint disease. Regeneron and Teva are continuing to study fasinumab in patients with chronic low back pain.

Pfizer and Eli Lilly are also studying tanezumab as a treatment for low back pain, and reported promising results from a Phase 3 trial in February. Rapidly progressive osteoarthritis was also reported in a small number of patients involved in that study.