Fibromyalgia Linked to Overactive Brain Networks

By Pat Anson, Editor

Many fibromyalgia sufferers have been told that the pain is “all in their head.” New research indicates there may be some truth to that, and that overactive brain networks could play a role in the hypersensitivity of fibromyalgia patients.

Fibromyalgia is a poorly understood disorder characterized by deep tissue pain, fatigue, headaches, mood swings and insomnia. There is no known cause and successful treatments have been elusive.

In a lengthy study published in the journal Scientific Reports, an international team of researchers at the University of Michigan and in South Korea report that patients with fibromyalgia have brain networks primed for rapid responses to minor changes. This abnormal hypersensitivity is known as called explosive synchronization (ES).

"For the first time, this research shows that the hypersensitivity experienced by chronic pain patients may result from hypersensitive brain networks," says co-senior author Richard Harris, PhD, an associate professor of anesthesiology at Michigan Medicine’s Chronic Pain and Fatigue Research Center.

In ES, a small stimulus can lead to a dramatic synchronized reaction throughout the network, as can happen when a power outage triggers a major grid failure or blackout. Until recently, this phenomenon was studied in physics rather than medicine. Researchers say it's a promising avenue to explore in the quest to determine how a person develops fibromyalgia.

"As opposed to the normal process of gradually linking up different centers in the brain after a stimulus, chronic pain patients have conditions that predispose them to linking up in an abrupt, explosive manner," says first author UnCheol Lee, PhD., a physicist and assistant professor of anesthesiology at Michigan Medicine.

The researchers tested their theory by conducting electroencephalogram (EEG) tests on the brains of 10 female patients with fibromyalgia. Baseline EEG results showed the patients had hypersensitive brain networks, and that there was a strong correlation between the degree of ES conditions and the self-reported intensity of their pain during EEG testing.

Lee's research team and collaborators in South Korea then used computer models of brain activity to compare the stimulus responses of the fibromyalgia patients to those of healthy ones. As expected, the fibromyalgia model was more sensitive to electrical stimulation.

"We again see the chronic pain brain is electrically unstable and sensitive," Harris says.

Harris says this type of modeling could help guide future treatments for fibromyalgia. Since ES can be modeled outside of the brain in computers, researchers can test for influential regions that transform a hypersensitive network into a more stable one. These regions could then be targeted in living humans using noninvasive brain modulation therapies such as transcranial magnetic stimulation, which is currently used to treat fibromyalgia and depression.

“We expect that our study may ultimately suggest new approaches for analgesic treatments. ES provides a theoretical framework and quantitative approach to test interventions that shift a hypersensitive brain network to a more normal brain network,” researchers reported. 

“It may be possible to convert an ES network to a non-ES network just by modulating one or two hub nodes. Indeed, transcranial magnetic stimulation and/or transcranial direct current stimulation may be improved by ‘targeting’ these sensitive hub nodes. The application of deep brain stimulation to critical nodes that could modify ES conditions is another therapeutic possibility that could be explored.”

The research was funded by the Cerephex Corporation, James S. McDonnell Foundation, and the National Institutes of Health

FDA: Opioid Cold Meds Too Risky for Kids

By Pat Anson, Editor

The Food and Drug Administration has ordered stronger warning labels for cough and cold medications containing opioids and said they should no longer be prescribed to patients younger than 18. The agency also signaled it that it could enact new limits on the dose and duration of other types of opioid prescriptions.

“Given the epidemic of opioid addiction, we’re concerned about unnecessary exposure to opioids, especially in young children. We know that any exposure to opioid drugs can lead to future addiction,” said FDA Commissioner Scott Gottlieb, MD. “It’s become clear that the use of prescription, opioid-containing medicines to treat cough and cold in children comes with serious risks that don’t justify their use in this vulnerable population.”

The FDA action involves nine different types of cough and cold medicines, four of which contain codeine and five that have hydrocodone. The brand names include Tuxarin ER, Tuzistra XR, Triacin C, FlowTuss and Zutripro. Several of the medications also come in generic form.

The FDA said it conducted an extensive review of the products and convened a panel of pediatric experts, who said the risk of misuse, abuse and addiction outweighed the benefits in patients younger than 18.

“These products will no longer be indicated for use in children, and their use in this age group is not recommended.  Health care professionals should reassure parents that cough due to a cold or upper respiratory infection is self-limited and generally does not need to be treated.  For those children in whom cough treatment is necessary, alternative medicines are available,” the FDA said in a statement.

The agency also ordered stronger “Black Box” warning labels on opioid cough and cold medicines to make them more consistent with safety warnings that come with opioid pain medications.

‘Too Many People Prescribed Opioids’

The FDA this week also released its 2018 Strategic Policy Roadmap, which outlines four priority areas in the year ahead.

The agency's first goal is to reduce the abuse of opioid medication. The FDA said opioid addiction and overdoses were claiming lives at a “staggering rate” of 91 deaths every day – although it failed to point out that most of those deaths involve illegal opioids such as heroin and illicit fentanyl, not prescription pain medication. Also unmentioned in the “roadmap” is that opioid prescriptions have been declining since 2010.

“Too many people are being inappropriately prescribed opioid drugs. When these prescriptions are written, they are often for long durations of use that create too much opportunity for addiction to develop,” the FDA said.

“We need to take steps to reduce exposure to opioid drugs by helping to make sure that patients are prescribed these drugs only when properly indicated, and that when prescriptions are written, they are for dosages and durations of use that comport closely with the purpose of the prescription.” 

Several states have already enacted limits on opioid prescriptions for acute, short term pain. Minnesota, for example, recently adopted strict new guidelines that limit the initial supply of opioids for acute pain to just three days. 

An Open Letter to My Senator: CDC Has Killed Me

(Editor’s Note: Charles Malinowski is a 59-year old Paso Robles, California man who lives with Reflex Sympathetic Dystrophy (RSD), degenerative disc disease, ankylosing spondylitis, spinal stenosis and other chronic pain conditions.  He recently wrote this open letter to U.S. Senator Kamala Harris (D-CA). We thought his letter worth sharing with PNN readers.)

Dear Senator Harris,

The CDC has killed me!

Let me repeat that: The CDC has killed me!

I have a severe neurological condition that causes me unspeakable and crippling pain. Pain medication is literally the only thing keeping me alive. But with the issuance of the CDC’s short sighted, so-called voluntary opioid prescribing guidelines -- which are being rammed down the throats of medical providers -- my pain management doctor has cut me off of opiates.

For the last 10 years, I have been subjected to nearly every type of physical therapy, medical treatment and medication applicable to my affliction. The one and only thing that has ever had any demonstrable benefit in even temporarily suppressing my pain to a tolerable level has, unfortunately, been opiates.

In early October, I was told that I would have to stop taking either the oral opiates or the intrathecal opiates, as it was now illegal for a person to receive two different types of opiates via two different delivery methods concurrently. This was a major problem, as even with both oral and intrathecal opiates, my pain was severely under-managed to the point where I was almost completely bedridden. I left the house only to go to doctor's appointments.

When I was told that my pain management regimen - specifically the opiates - was going to be cut in half, even though my pain was already grossly under-managed, I spoke out about this.

CHARLES MALINOWSKI

As a result, not only was I cut off from the oral opiates, I got kicked out of the pain management practice where I have been a patient for more than seven years. The doctor said he didn't want to risk his license - but was perfectly willing to risk my life - over the CDC opioid guidelines.  These guidelines are supposed to be voluntary and are not supposed to take desperately needed pain medication away from legitimate chronic pain sufferers such as myself.

I expect that within 60 days, I will be dead from either heart failure or a stroke due to my body's inability to cope with the stress of the unrelenting pain. My neuropsychologist, who has been treating me for nearly 10 years, has consistently rated my level of pain as moderate to extreme, even while being medicated with both oral and intrathecal opiates, which I am now denied.

I'm not dead yet, but within 60 days I expect that the CDC will have effectively killed me. I honestly don't see myself being able to tolerate the pain any longer than that.

Congress, in going along with this blindly, will be explicitly complicit in this negligent homicide - or homicide by depraved indifference, take your pick - of one Charles James Malinowski, that being myself.

I would like to thank you, Senator, and all the rest of your colleagues for murdering me.

To help ease your conscience, it is not just me that Congress is complicit in murdering, but thousands, possibly tens of thousands of people in like positions.

Sincerely,

Charles Malinowski

Pain News Network invites other readers to share their stories with us. Send them to editor@painnewsnetwork.org

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

Ibuprofen Linked to Reduced Male Fertility

By Pat Anson, Editor

If you’re a man who uses ibuprofen regularly for muscle pain or  headache, you could be compromising your ability to have children, according to a small new study.

French and Danish researchers enrolled 31 young male volunteers between the ages of 18 and 35 in the study, and gave about half of them 600 milligrams of ibuprofen twice a day -- the highest recommended dose. The other participants were given a placebo.

After just 14 days, the researchers noted signs of hormonal dysfunction in the men who took ibuprofen, who had high levels of luteinizing hormone, which the pituitary gland produces to stimulate testosterone production in the testicles. 

That condition -- known as hypogonadism -- is usually seen in older men who have low testosterone levels. Hypogonadism is associated with reduced fertility, lower sex drive, depression, fatigue and an increased risk of cardiovascular problems.

“We normally see this condition in elderly men, so it raises an alarm,” study co-author Bernard Jégou, PhD, of the French National Institute of Health and Medical Research, told The Guardian. “We are concerned about it, particularly for healthy people who don’t need to take these drugs. The risk is greater than the benefit.” 

Researchers say the disorder was mild in the ibuprofen group and went away when the men stopped taking ibuprofen. But they worry what would happen to men who take the pain reliever for longer periods. Many professional athletes regularly take high doses of ibuprofen.

“Our immediate concern is for the fertility of men who use these drugs for a long time,” said co-author David Møbjerg Kristensen, PhD, a professor of biology at the University of Copenhagen. “These compounds are good painkillers, but a certain amount of people in society use them without thinking of them as proper medicines.”

The study was published online in the Proceedings of the National Academy of Sciences .

“Ibuprofen appears to be the preferred pharmaceutical analgesic for long-term chronic pain and arthritis. Therefore it is also of concern that men with compensated hypogonadism may eventually progress to overt primary hypogonadism, which is characterized by low circulating testosterone and prevalent symptoms including reduced libido, reduced muscle mass and strength, and depressed mood and fatigue,“ the researchers warned.

The same team of researchers reported in earlier studies that aspirin, acetaminophen and ibuprofen affected the testicles of male babies born to mothers who took the drugs during pregnancy.

Ibuprofen is a widely used over-the-counter pain reliever found in brand name products such as Motrin and Advil.   

Acetaminophen May Slow Language Development

By Pat Anson, Editor

Another study has linked acetaminophen to learning difficulties in young children born to mothers who used the over-the-counter pain reliever during pregnancy.

Researchers at the Icahn School of Medicine in New York City say toddlers exposed to acetaminophen in the womb had a slower rate of language development at 30 months. The findings are consistent with other studies reporting higher rates of autism, attention deficit disorder (ADHD) and behavioral problems in children born to mothers who used acetaminophen while pregnant.  

Acetaminophen (paracetamol) is one of the most widely used pain relievers in the world. It is the active ingredient in Tylenol, Excedrin, and hundreds of other pain medications. Researchers say over half the pregnant women in the United States and European Union use the drug.

“Given the prevalence of prenatal acetaminophen use and the importance of language development, our findings, if replicated, suggest that pregnant women should limit their use of this analgesic during pregnancy,” said senior author Shanna Swan, PhD, Professor of Environmental and Public Health at the Icahn School of Medicine at Mount Sinai.

“It’s important for us to look at language development because it has shown to be predictive of other neurodevelopmental problems in children.”

The study involved 754 women who enrolled in the Swedish Environmental Longitudinal, Mother and Child, Asthma and Allergy study (SELMA) during weeks 8-13 of their pregnancy. Researchers asked the women to report the number of acetaminophen tablets they took between conception and enrollment, and tested the acetaminophen concentration in their urine.

A delay in a child's language development, defined as the use of fewer than 50 words at 30 months of age, was measured by a nurse and a follow-up questionnaire filled out by the mothers.

Girls born to mothers with high exposure -- those who took acetaminophen more than six times in early pregnancy -- were nearly six times more likely to have language delay than girls born to mothers who did not take acetaminophen.

While the number of acetaminophen tablets and concentration in urine were associated with a significant increase in language delay in girls, there was only a slight increase in boys.  The findings suggest that acetaminophen use in pregnancy results in the loss of the well-recognized female advantage in language development in early childhood.

The study is published online in the journal European Psychiatry. Researchers will follow-up with the children and re-examine their language development at age seven.

A 2016 study of over 2,600 Spanish women linked acetaminophen to autism and attention deficit problems in their children. Studies in Denmark and New Zealand have also linked acetaminophen to a higher risk of ADHD.

Over 50 million people in the U.S. use acetaminophen each week to treat pain and fever. The pain reliever has long been associated with liver injury and allergic reactions such as skin rash. In the U.S. over 50,000 emergency room visits each year are caused by acetaminophen, including 25,000 hospitalizations and 450 deaths.

Stem Cells: Signs of Progress in a Rigged Game

By A. Rahman Ford, Columnist

The Wall Street Journal recently published an article on the use of stem cell therapies for knee problems, including arthritis.  Overall, the perspective of the piece was positive and it has several laudable aspects.  Physicians from large academic institutions, such as Harvard University and Stanford University, were interviewed to provide their opinions on the use of autologous stem cells derived from a patient’s own fat or bone marrow for certain painful orthopedic indications. 

The article rightly acknowledges the high patient demand for these autologous therapies. It also mentions how the U.S. lags behind other countries in offering them and the disturbing fact that this therapy is not covered by medical insurance.  The doctors who were interviewed also discussed how conventional approaches to osteoarthritis in knees – meniscus surgery, microfracture surgery, etc. – often fail to demonstrate long-term benefit.  These doctors, along with many others around the world, recognize that we need new therapies for orthopedic conditions.

Any positive portrayal of the clinical uses of stem cells should be welcomed. The unfortunate truth is that many potential patients are scared off by publications that focus their reporting on the alleged malfeasance of a few bad-actor stem cell clinics.  These same publications often neglect to cover the countless stem cell success stories from clinics in the U.S. and abroad. 

A focus on these promising results may help allay those fears and convince some of those fearful patients that stem cells are, in fact, a viable medical option for their chronic orthopedic pain. 

Less fear can lead to self-education and increased awareness of the safety and potential of stem cells.  Patients may even try stem cell therapy and become advocates.  In this sense, the WSJ piece is good public relations for stem cell therapies overall.

However, there is an unsettling undertone in the WSJ piece and media coverage in general of stem cells, which places too much emphasis on the opinions of clinicians from certain large institutions.  That diminishes the value of work being done in smaller stem cell clinics, which have been safely and effectively treating patients with orthopedic conditions for years. 

The unintended implication is that Harvard and Stanford physicians’ assessments are more legitimate because of the perceived prestige of their employers, and because they follow the guidelines that the FDA set forth for pursuing such treatments.  Of course, these institutions have millions of dollars in capital that it takes to conduct clinical studies and comply with these guidelines, while smaller clinics often do not.  We must take care to avoid creating or reinforcing illegitimate hierarchies that give some physicians more scientific authority than others, based solely on money, perceived prestige, or the ability to adhere to an unfair set of rules.

The sad truth is that the stem cell game is rigged.  The FDA’s rules regarding the use of autologous stem cell therapies favor those with more financial resources because they can afford expensive clinical trials.  Medical innovation cannot be strictly the domain of wealthy institutions with the finances to play on a tilted field.  The FDA’s “minimal manipulation” and “homologous use” regulatory standards for using stem cells are unduly burdensome and need to be relaxed for autologous stem cell uses. 

Recently, the FDA issued a warning letter to American Cryostem, a company involved in the manufacture of adipose stem cell products derived from a patient’s body fat.  In addition to manufacturing violations, the company was accused of violating the FDA’s “minimal manipulation” and “homologous use” standards. 

Setting the merits of the case aside, it is emblematic of the FDA’s crackdown on clinics that are much smaller than Harvard and Stanford, but which have been relieving patients’ pain with autologous therapies for years.  Their scientific contributions must not be subordinated or dismissed as illegitimate or inconsequential.

Stories of how stem cells are entering mainstream medicine can help us realize the goal of available, affordable stem cell therapy for all Americans.  However, valorization of those institutions with the means to “play within the rules” must not come at the expense of sounding the alarm that the rules themselves are patently unfair.

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. He earned his PhD at the University of Pennsylvania.

Rahman lives with chronic inflammation in his digestive tract and is unable to eat solid food. He has received stem cell treatment in China.  

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represent the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

Little Evidence Cannabis Can Treat Chronic Pain

By Roger Chriss, Columnist

There is an abundance of research on medical cannabis. Everything from basic science to clinical trials and even major reviews have been conducted on the effectiveness of cannabis in treating chronic pain and other conditions. But the results don’t necessarily say what people want to hear.

As Leafly shows in a comprehensive list, most states in the U.S. that have legalized medical cannabis include chronic pain or painful conditions among the accepted indications for use. But these same states also note that research supporting medical cannabis for chronic pain is thin.

Minnesota, for example, accepts “intractable pain” but then says that “the literature assessing the effects of medical cannabis treatments for non-cancer chronic pain is sparse and patchy.”

Similarly, the California Medical Association’s “Physician Recommendation of Medical Cannabis” states that the approved list of 12 serious medical conditions that cannabis can be used for “is broad, and in most cases not supported by solid clinical research.”

In other words, medical cannabis has been approved for use, despite having not been rigorously demonstrated to be useful.

The existing research supports this view. A recent systematic review of two dozen clinical trials published in the journal Pain Physician found that “the majority of studies did not show an effect.” The review concludes that cannabis-based medications “might be effective for chronic pain treatment, based on limited evidence, primarily for neuropathic pain (NP) patients.”

Another recent review of randomized placebo-controlled studies of smoked cannabis published in the journal Pharmacotherapy found that “cannabis did not outperform placebo on experimentally evoked pain.”

And a systematic review of the efficacy of cannabis in patients with neuropathic pain, multiple sclerosis or receiving  chemotherapy concluded that “there is incomplete evidence of the efficacy and safety of medical use of cannabis” and that “confidence in the estimate of the effect was again low or very low.”

Even reviews of medical cannabis for disorders that involve a chronic pain component are lackluster. A 2017 systematic review looked at randomized controlled trials of cannabis and its derivatives in treating psychiatric, movement, and neuro-degenerative disorders. The review found that "definitive conclusion on its efficacy could not be drawn” because the trials were low quality and had methodological limitations.

These results run contrary to the public perception of cannabis efficacy and the exuberance of media coverage about marijuana in any form. This has not escaped the notice of researchers. A 2017 study from Europe found that “public perception of the efficacy, tolerability, and safety of cannabis-based medicines in pain management and palliative medicine conflicts with the findings of systematic reviews and prospective observational studies conducted according to the standards of evidence-based medicine.”

Moreover, the Pain Physician study notes another significant trend: More recent studies tend to report more favorable results. It is not clear why this is happening, though a shift in cultural attitudes, ongoing advocacy in favor or cannabis legalization, and changes in the available strains of cannabis have been suggested. In particular, an increasingly positive attitude toward cannabis among study participants may be augmenting the placebo effect.

There are other limitations to the existing research -- from problems with blinding, lack of a good placebo and small study size – that make it open to criticism. Much of the commentary on cannabis research seems to have less to do with a close reading of the literature than with a desire for cannabis to gain widespread acceptance.

There is, of course, growing evidence for the use of cannabis in the treatment of some disorders, such as epilepsy and chronic neuropathic pain.  Medical cannabis may also have some value for people who are not benefiting from or cannot tolerate pharmaceutical drugs and other established therapies. So cannabis should remain an option -- intractable pain is sufficiently horrible that we need as many options as possible.

Medical research is about accumulating evidence through clinical trials and laboratory study. One trial is rarely ever enough to demonstrate efficacy. Even one major review is not sufficient. But an abundance of reviews all pointing in one direction should not go ignored.

Medical cannabis certainly merits further study. But the above reviews clearly show that efficacy is limited in many cases. Cannabis may well prove useful in treating certain disorders, but it is not a panacea and not likely to outperform existing treatments.

Roger Chriss lives with Ehlers Danlos syndrome and is a proud member of the Ehlers-Danlos Society. Roger is a technical consultant in Washington state, where he specializes in mathematics and research.

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

5 Steps to Successful Advocacy for Pain Community

By Barby Ingle, Columnist

When it comes to advocating for the pain community, there are many roles to fill and many ways to go about doing it. There are patient advocates, legislative activists, social media activists and self-advocates.

I do a little of each and see that the most common mistake in activism is when patients join an organization without fully understanding the legislative process, how long it takes, and that there’s no guarantee that the desired outcome will be reached.

This is a topic I have seen on many of the upcoming pain conference agendas for 2018. I have been asked to speak at a conference about it, and while preparing my talk I realized that patients need more information on what it takes to build a pain organization into a successful change maker in public policy and legislation.

There is a 5-step process that I use to insure that a message is heard, supported, and goes from being an idea to actual legislation at the federal or state level. It takes a never-give-up attitude, with a big influx of time, effort, follow-up and social media support.

First, when crafting legislation to improve patient care or some other goal, you need to start by creating an implementation plan. This plan should outline a budget, strategies, leadership responsibility and timelines for goals to be met.

Second, the team leader must clarify the roles of the advocacy team and communicate that role to the rest of the leadership team, staff and volunteers. There are many personalities and challenges that will come up, so having the right people in place working together is very important.

Third, confirm that all team leaders express support for the initiative in meetings with legislators and their staffs. Allow additional time for the implementation of each step. Things tend to take longer than they should when working with teams and with government officials. The leadership should organize volunteers, create training resources, reach out to the media (and have patient stories ready for them), and provide effective speakers for hearings and press conferences. Be sure to include healthcare professionals and patients on your team.

Fourth, monitor the progress of the legislation closely. There are usually a lot of “hurry up and wait” situations and it could take years before a bill gets out of committee or comes up for a vote.  Sometimes mid-course corrections and negotiations are needed with legislators to gain their support and to keep a bill from dying, especially if a mandate or money is involved. 

Fifth and finally, carry out your strategies to achieve your goals. Your leadership team and volunteers should understand the bill and the legislative process, and be using marketing and social media tools to gain public support and awareness about why the legislation is needed. Staying motivated is critical to success. Keep your staff and volunteers involved and committed to making a difference in their own lives and the lives of others.

If you are a chronic pain patient and want to get involved, understand that this type of work takes physical action, but it doesn’t have to be all encompassing. Volunteer with advocacy groups or non-profits that are already working on legislative issues that interest you. See what fits you and volunteer to be a team leader or social media supporter. Share your story and why the bill is important to you, or even testify in person at a legislative hearing.

Be the change agent that we all need in getting proper and timely healthcare for the chronically ill.

Barby Ingle suffers from Reflex Sympathetic Dystrophy (RSD) and endometriosis. Barby is a chronic pain educator, patient advocate, and president of the International Pain Foundation. She is also a motivational speaker and best-selling author on pain topics.

More information about Barby can be found at her website.

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

FDA Warns New Jersey Stem Cell Company

By Pat Anson, Editor

The U.S. Food and Drug Administration has warned a New Jersey biotechnology company to stop producing and marketing a stem cell product, the latest in a series of steps the agency has taken to rein in the fast growing stem cell industry.

The FDA sent a warning letter to American CryoStem Corporation for marketing adipose derived stem cells without FDA approval and for “significant deviations” from manufacturing guidelines.

American CryoStem is using adipose tissue – a patient’s own body fat – to create a product called Atcell, which is promoted as a treatment for stroke, brain injuries, Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis.

The FDA said there was “more than minimal manipulation” of adipose tissue in the manufacturing of Atcell, which introduced the potential for contamination. The agency said Atcell should undergo clinical trials and an FDA review to prove its safety and effectiveness before being marketed.

“The use of Atcell raises potential significant safety concerns, due in part to the fact that there is little basis on which to predict how the product will perform in a patient,” said Peter Marks, MD, director of the FDA’s Center for Biologics Evaluation and Research. “In addition, this product may also cause harm to patients who may put their trust in an unproven therapy and make the decision to delay or discontinue medical treatments proven to be safe and effective.”

The FDA issued new guidelines for stem cell therapy last November, a “risk-based approach” that critics say could slow the development of novel treatments for autoimmune diseases, cancer, diabetes, neuropathy, back pain and other illnesses.  

As PNN has reported, hundreds of stem cell clinics have opened around the country, often mixing hope with hype by making claims such as, “You don’t have to accept chronic pain as a fact of life.”  The treatments are expensive and usually not covered by insurance. 

Some patients receiving stem cell therapy have reported remarkable recoveries from chronic conditions once deemed untreatable.  Sara Bomar, for example, was confined to a wheelchair after being diagnosed with arachnoiditis, a painful inflammation of nerves in her spinal column. She started walking again after a high dose infusion of stem cells made from her adipose tissue.

The warning letter to American CryoStem was sent nearly six months after FDA investigators inspected the company’s laboratory in Monmouth Junction, New Jersey, finding “significant safety concerns” and “objectionable conditions.”  The firm has implemented changes at its lab to respond to the FDA’s concerns, however the agency said the response “inadequately addresses" the problems and failed to recognize that Atcell is an unlicensed product.  The FDA gave the company 15 working days to respond to its warning letter.

American CryoStem did not respond to PNN’s request for comment.  The company bills itself as a “biotechnology pioneer” in the use of adipose stem cells, and has laboratories in Hong Kong, mainland China and Japan. It recently licensed the patent rights to its stem cell technology in China and plans to expand its operations there.

Sessions Resumes Enforcement of Marijuana Laws

By Pat Anson, Editor

Attorney General Jeff Sessions has followed through on his threat to resume enforcing federal laws that outlaw the cultivation, distribution and possession of marijuana.

Session has rescinded the Cole memo, a lenient policy adopted by the Justice Department in 2013 that instructed U.S. Attorneys not to investigate or prosecute marijuana cases in states that have legalized cannabis. Although 29 states and the District of Columbia have legalized marijuana in some form, federal law still prohibits its sale or possession under the Controlled Substances Act.

ATTORNEY GENERAL JEFF SESSIONS

In a one-page memorandum sent to U.S. Attorneys around the country, Sessions called the Cole memo “unnecessary” and authorized prosecutors to use their own discretion in investigating and prosecuting marijuana cases.

"It is the mission of the Department of Justice to enforce the laws of the United States, and the previous issuance of guidance undermines the rule of law and the ability of our local, state, tribal, and federal law enforcement partners to carry out this mission," Sessions said in a statement.

"Therefore, today's memo on federal marijuana enforcement simply directs all U.S. Attorneys to use previously established prosecutorial principles that provide them all the necessary tools to disrupt criminal organizations, tackle the growing drug crisis, and thwart violent crime across our country."

“This change will allow any US Attorney who is looking to make a name for themselves to take unilateral action, thus depriving any semblance of certainty for state-lawful consumers or businesses moving forward," said Justin Strekal, NORML Political Director.

Sessions released his memo just three days after California legalized the recreational use of marijuana by adults – the eighth and largest state to do so. California was the first state to legalize medical marijuana in 1996.

It is not yet clear how rigidly Sessions plans to enforce federal marijuana laws. Since 2013, Congress has attached a rider to the Justice Department budget that prevents it from using federal funds to enforce federal law in states where medical marijuana is legal. The Rohrabacher-Blumenauer amendment is still in force, but is set to expire on January 19 unless it is extended by Congress.

Sessions’ memo drew a swift and angry response from some members of Congress.

“This reported action directly contradicts what Attorney General Sessions told me prior to his confirmation. With no prior notice to Congress, the Justice Department has trampled on the will of the voters in CO and other states,” Sen. Cory Gardner (R-CO) said in a tweet. “I am prepared to take all steps necessary, including holding DOJ nominees, until the Attorney General lives up to the commitment he made to me prior to his confirmation.”

“This is outrageous. Going against the majority of Americans -- including a majority of Republican voters -- who want the federal government to stay out of the way is perhaps one of the stupidest decisions the Attorney General has made,” said Rep. Earl Blumenauer (D-OR), one of the co-authors of the Rohrabacher-Blumenauer amendment.

“One wonders if Trump was consulted -- it is Jeff Sessions after all -- because this would violate his campaign promise not to interfere with state marijuana laws.”

In an interview during the 2016 campaign, President Trump said he would not change the federal enforcement policy on marijuana. “I wouldn’t do that, no,” Trump said. “I think it’s up to the states. I’m a states’ person. I think it’s up to the states, absolutely.”

According to a recent Gallup Poll, 64% of Americans say marijuana should be legalized. The issue has broad bipartisan support, with 51% of Republicans and 72% of Democrats supporting legalization.

“The rollback of this policy towards state legalized marijuana will only create chaos and confusion for an industry that is currently responsible for creating over 150,000 American jobs and generating countless millions in state tax revenue. This instability will only push consumer dollars away from these state sanctioned businesses and back into the hands of criminal elements," said Erik Altieri, NORML Executive Director.

"This is not just bad policy, but awful politics and the Trump Administration should brace itself for the public backlash it will no doubt generate."

Scientists Building a Safer Opioid

By Pat Anson, Editor

Researchers at the University of North Carolina believe they’ve found a way to create a new type of opioid medication that relieves pain without risky side effects.

Currently, opioid painkillers bind to several opioid receptors on the surface of brain cells, triggering a wide range of side effects -- from nausea, numbness and constipation to anxiety, addiction and potentially fatal respiratory depression.

The UNC researchers report in the journal Cell that they have created a new drug compound that only activates the kappa opioid receptor – the brain receptor that is the key to pain relief.

"To create better opioids, we need to know the structure of their receptors," said senior author Bryan Roth, MD, a professor in the Department of Pharmacology at UNC School of Medicine.

"Until recently, this was impossible. But now we know the structure of the activated kappa opioid receptor. And we showed we can actually use the structure to make a drug-like compound with better properties than current opioids."

The compound was created in cell cultures in Roth's lab, and still needs to be tested in animal models. But knowing the detailed structure of the kappa opioid receptor (KOR) has opened the door to developing other drug-like compounds that are highly selective for specific opioid receptors.

KAPPA OPIOID RECEPTOR (unc IMAGE)

"Tens of thousands people who take opioids die every year, and so we need safer and more effective drugs for treating pain and related conditions," Roth said in a news release. "One of the big ideas is to target KORs because the few drugs that bind to it don't lead to addiction or cause death due to overdose. Those side effects are mainly related to actions at the mu opioid receptor."

Drugs that bind to KORs can still have side effects, such as hallucinations and dysphoria - a state of unease or dissatisfaction with life related to anxiety and depression. That is why scientists say it’s important to know how this receptor is activated – so they can figure out a way to bind a compound to KORs so that it only relieves pain.

"Now we have a much better understanding of the direction we have to explore in order to create a selective drug to activate only kappa opioid receptors," said corresponding author Daniel Wacker, PhD, UNC School of Medicine.

The UNC research was funded by the National Institutes of Health, the Mayday Fund, and the Peter F. McManus Trust.

A Pained Life: An Unexpected Gift

By Carol Levy, Columnist

This past Christmas I started thinking about a Christmas long past.

I lived in New York City at the time, but was spending the holidays at my mother's house outside Philadelphia. My family had been estranged for many years (especially from me), and for some reason one of my two sisters came to the house to spend Christmas with my mother and I.

The presents were opened, gifts from my mother to us and from us to our mother. I had nothing for my sister and expected nothing from her.

There were a few more boxes under the tree, but I assumed they were gifts for other people for later that day. To my amazement and consternation, my sister picked up one of them and handed it to me. “This is for you,” she said.

I took it with trepidation. “Why is she giving me a gift?” I asked myself while slowly removing the wrapping. I worked hard to keep my expression neutral as I pulled off the tissue paper and looked at the gift.

It was a blouse, bilious green decorated with farm animals, silos, barns and ribbons. It was probably the ugliest thing I had ever seen.

I smiled nicely, thinking what is her point? Why waste money to tell me via a blouse how much she dislikes me?

“Oh, thank you. This is.... really... nice,” I said.

My sister’s only reply was, “You're welcome.” There was nothing to indicate she meant it as the insult it sure as heck seemed to be.

Later on I walked into the kitchen. My mother was crying, “I can't believe she would give you something like that!”

It was awful. How mean, childish, and cruel. Such a waste of money merely to hurt someone, and for reasons never explained.

I returned home to New York. I hate the idea of wasting anything, so instead of throwing out the blouse, I decided I would use it as junk clothing, for painting or using solvents, etc. Nothing I could do to it would make it worse than it already was.

I had not taken it out of the box. I did so now and put it on. I looked in the mirror. To my amazement, it was adorable. In the box it was a horror, but somehow once I put it on, the ugly worked its way into cute.

I wore it until it wore out. I can't count the number of compliments I got, like “Boy, is that adorable.”

So what is the take away?

I didn't give the shirt a chance. I jumped on the meaning of it – horrid, mean and nasty. I didn't say anything to my sister or ask why she would give me something so ugly. I knew what it meant. I didn't need any help with the translation.

I think of this story sometimes, when someone I thought I had a good relationship with says to me, “Your pain can't be that bad” or “I've seen you climb the stairs, so I know you can.”

That’s like waving a red flag before a bull. Or a ringing bell to a boxer. How dare they! What does it take to get them to accept my pain and disability? My anger rises with my blood pressure. I am ready for a fight. 

But maybe I am jumping to a conclusion that never was.  Could they have meant something else? Maybe even an awkward kindness like, “I don't want you to have pain that bad. I don't want you to be so disabled.”

Maybe Ogden Nash said it best in his poem, “I Never Even Suggested It.” It was written about men and women quarreling, but I think the last line is what counts: 

In real life it takes only one to make a quarrel.

Carol Jay Levy has lived with trigeminal neuralgia, a chronic facial pain disorder, for over 30 years. She is the author of “A Pained Life, A Chronic Pain Journey.” 

Carol is the moderator of the Facebook support group “Women in Pain Awareness.” Her blog “The Pained Life” can be found here.

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represent the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

Lyrica and Neurontin Use Triples

By Pat Anson, Editor

The use of gabapentin (Neurontin) and pregabalin (Lyrica) has soared in the United States, with little attention paid to their safety and effectiveness, according to a research letter published in JAMA Internal Medicine.

Gabapentin and pregabalin belong to a class of nerve medication known as gabapentinoids, which are increasingly prescribed as alternatives to opioids in treating neuropathy, fibromyalgia and other types of chronic pain.

In an analysis of health data for nearly 350,000 patients, researchers found that the use of gabapentinoids more than tripled in the past decade, from 1.2% of patients in 2002 to 3.9% in 2015.

Use of the drugs was concentrated in older patients with numerous other health problems, who were often co-prescribed opioids or benzodiazepines, a class of anti-anxiety medication.

“The combination of a dearth of long-term safety data, small effect sizes, concern for increased risk of overdose in combination with opioid use, and high rates of off-label prescribing, which are associated with high rates of adverse effects, raises concern about the levels of gabapentinoid use,” wrote lead researcher Michael Johansen, MD, of OhioHealth, a large non-profit health system based in Ohio.

“While individual clinical scenarios can be challenging, caution should be advised in the use of gabapentinoids, particularly for those individuals who are long-term opioid users, given the lack of proven long-term efficacy and the known and unknown risks of gabapentinoid use.”

JAMA INTERNAL MEDICINE

Johansen’s research adds to a growing body of evidence that pregabalin and gabapentin are overprescribed and being abused. A recent study by Canadian researchers found that there was “no clear rationale” for the off-label use of the drugs and warned that they have a “significant risk of adverse effects” such as dizziness, fatigue and diminished mental activity.

Lyrica (pregabalin) and Neurontin (gabapentin) are both made by Pfizer and are two of the company’s top selling drugs, generating billions of dollars in annual sales. Lyrica is approved by the FDA to treat diabetic nerve pain, fibromyalgia, post-herpetic neuralgia caused by shingles and spinal cord injuries; while Neurontin is approved to treat epilepsy and post-herpetic neuralgia. Both drugs are also widely prescribed off label to treat back pain, depression, migraine and other conditions.

Sales of pregabalin and gabapentin have risen steadily in recent years, in part because of CDC prescribing guidelines that recommend the two drugs as alternatives to opioid pain medication. About 64 million prescriptions were written for gabapentin in the U.S. in 20l6, a 49% increase in just five years.

“We believe… that gabapentinoids are being prescribed excessively — partly in response to the opioid epidemic,” Christopher Goodman, MD, and Allan Brett, MD, recently wrote in a commentary published in The New England Journal of Medicine. “We suspect that clinicians who are desperate for alternatives to opioids have lowered their threshold for prescribing gabapentinoids to patients with various types of acute, subacute, and chronic noncancer pain.

Gabapentinoids are increasingly being used recreationally by addicts who have found the medications enhance the effects of heroin and other opioids. Lyrica and Neurontin have been linked to heroin overdoses in the United Kingdom, where prescriptions for both drugs have soared in recent years. 

Lawmakers Ask FDA to Lift Kratom Warning

By Pat Anson, Editor

A bipartisan group of 17 congressmen is asking the Food and Drug Administration to lift a public health warning about kratom, an herbal supplement used by millions of Americans to treat chronic pain, addiction, depression and anxiety.

In a joint letter to FDA commissioner Scott Gottlieb, MD, the lawmakers said kratom was “a natural alternative to opioids” and was “found to be as safe as coffee.”  The letter was drafted by Rep. Jared Polis (D-CO) and Rep. Dave Brat (R-VA).

“We have heard from many constituents who have used kratom to successfully end their dependence on dangerous opioids, and maintaining legal access to kratom is important to many Americans to maintain sobriety,” the letter states. “We believe that if legal access to professionally-manufactured kratom were made difficult or illegal, instances of kratom laced with opioids or other dangerous compounds would likely become more common.”

The FDA issued a public health advisory in November, warning that there were “increasing harms associated with kratom” and that the herb was involved in 36 deaths. The agency did not say when or where the deaths occurred.

“There is no reliable evidence to support the use of kratom as a treatment for opioid use disorder. Patients addicted to opioids are using kratom without dependable instructions for use and more importantly, without consultation with a licensed health care provider about the product’s dangers, potential side effects or interactions with other drugs,” Gottlieb said in a statement.

Kratom comes from the leaves of a tree that grows in southeast Asia, where it has been used for centuries for its medicinal properties. The leaves are usually ground up to make tea or turned into powder and used in capsules. Most kratom users say the herb has a mild analgesic and stimulative effect.

Last year, the Drug Enforcement Administration attempted to list kratom as a Schedule I controlled substance, which would have made it a felony to possess or sell. The DEA suspended its plan after an outcry by kratom supporters and a lobbying campaign that enlisted the help of dozens of senators and congressmen.

“We need to improve access to alternative pain relief options beyond addictive opioids.  For some, kratom, a cousin of the coffee plant, can be that alternative.  Like cannabis, it should be legal and available,” Rep. Polis said in a statement. “The FDA must end its bogus ‘public health warning’ that has already led to several cities banning kratom.  Patients need and deserve options.”

Kratom Pioneer Calls for Government Regulation

One of the dilemmas faced by the FDA is that kratom products are considered dietary supplements, and there are few regulatory standards applied to their importation or ingredients. The only requirement for kratom vendors is that they don't make unsubstantiated health claims.

“I know that regulation is needed and I think that is something we conscientiously have to work towards,” says Duncan Macrae, the founder of Kratom.com and one of the first commercial suppliers to bring kratom products into the United States, Canada and Europe.

“I think that direct government regulation will eventually come about. But while everybody’s waiting for that to happen, I think that vendors in the industry that are making money from this should get together and start their own internal regulation to try to be more transparent,” Macrae told PNN.

“I can tell you for sure that there are a lot of adulterated products on the market, and vendors going in and out of business the whole time, changing names and companies. There’s no central body checking or controlling anything.”

Macrae says kratom vendors should certify their products and list their ingredients – or risk the government stepping in and banning kratom altogether.

“Right now the problem is that every vendor is labeling their product ‘not for consumption.’ And there’s no information about the product or what’s inside it,” he said. “This is the regulation we need to do from inside and hopefully the government won’t (ban kratom) because it is an extremely valuable medicinal herb and they will embrace some kind of regulation that makes sense, so that kratom can be administered safely and distributed safely and people will know exactly what they’re getting.”

Macrae is working to ensure the quality of his own products by growing kratom on farms in Indonesia, as opposed to just harvesting the leaves from trees growing wild in remote jungles. He’s planted hundreds of thousands of kratom trees, with hopes of somebody mass producing kratom tea, pills and extracts.

“I think this is the future for the industry and that is the product that we need to develop, and that’s what I’ve been working on,” he said.

Legal Battles Brew Over High Cost of Arthritis Drugs

By Julie Appleby, Kaiser Health News

Early last winter, Pfizer launched its new rheumatoid arthritis treatment, Inflectra, pricing it 15 percent below the $4,000-a-dose wholesale price of Remicade, the drug for which it is a close copy.

Pfizer figured its lower price would attract cost-conscious insurers.

A year later, though, its drug has barely scratched the market and Pfizer has filed an antitrust suit against its rivals, alleging they are thwarting lower-priced competition through “exclusionary contracts” and rebates.

The outcome of the case — filed in September in U.S. District Court against Johnson & Johnson, the maker of Remicade, and Janssen Biotech — could affect the future of biosimilars, a new class of drugs. Some policy experts say these near-copies of biologics are key to slowing spending on complex and expensive specialty medications like those used to treat rheumatoid arthritis.

At the heart of the case are rebates, which are discounts off the wholesale price of drugs.

Manufacturers offer them to help keep their products on insurers’ lists of covered drugs. The money mainly goes back to insurers and pharmacy benefit managers, who say the rebates help reduce health care spending.

But Pfizer alleges that those rebates are being used to thwart biosimilars’ entry into the marketplace.

“This is the first antitrust case we’ve seen like this around biosimilars,” said Michael Carrier, a Rutgers Law School professor “Pfizer is claiming that one form of anti-competitive behavior involves withholding rebates from insurers.”

Biosimilars are costly to produce, so they are not likely to trigger the same sharp pricing drop triggered by generics. Still, their manufacturers say they could bring consumers some relief to rival biologics’ high price tags.

Pfizer’s Inflectra is one of the first biosimilars to hit the market since Congress passed legislation in 2010 to pave the way.

According to Pfizer, weeks after Inflectra gained Food and Drug Admininstration approval, J&J moved to stake out its biologic turf.

J&J began requiring insurers and PBMs to sign “exclusionary contracts … designed to block both insurers from reimbursing and hospitals and clinics from purchasing Inflectra or other biosimilars of Remicade despite their lower pricing,” alleges the case filed in federal district court in Philadelphia.

If insurers don’t agree to the J&J contracts, the loss of rebates could “for some insurers, run into the tens of millions of dollars annually,” the Pfizer case alleges.

Even with its lower price, Pfizer faced an uphill battle to win market share.

Remicade is the fifth-biggest-selling drug by revenue in the U.S., reaping more than $4.8 billion in 2016 for makers J&J and Janssen, the suit said. Often, patients are reluctant to switch once they are established on an RA drug that is working for them.

Still, Pfizer thought it would pick up newly diagnosed patients and gain ground that way. But its lawsuit says the drug accounted for only about 4 percent of total sales, with Remicade getting the rest, by early September.

“We stand by our contracts,” said J&J and Janssen Biotech in a written statement. The firms also defend rebates as “competition that is doing what competition is meant to do: driving deeper discounts that will lead to overall lower costs.”

Yet the price of Remicade has not fallen, the Pfizer case says.

Since approval of Inflectra, J&J has raised the list price of Remicade by close to 9 percent, the lawsuit alleges. As of September, Remicade’s average sales price –after discounts and rebates — is more than 10 percent higher than Inflectra.

“This case is a big deal, because it has the potential to bring to light some of the anti-competitive contracting practices at work to keep … prices extremely high,” said Jaime King, a professor at University of California-Hastings College of the Law.

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.