Opioid Tapering Disrupts Healthcare and Worsens Doctor-Patient Relationships

By Pat Anson, PNN Editor

Tapering patients on long-term opioid therapy results in more emergency department visits and hospitalizations, according to a large new study that found reduced opioid use was particularly disruptive to the healthcare of pain patients with diabetes and high blood pressure.

The study by researchers at University of California Davis is the latest to document the “unintended negative consequences” of policies that limit opioid prescribing. A previous study by the same research team found that tapering raises the risk of an overdose and mental health crisis.

In their latest study, UC Davis researchers analyzed health data for over 113,000 patients who were on opioid therapy for at least 12 months, comparing those who were not tapered to those who had their dose reduced by 15% or more.

Their findings, published in JAMA Network Open, showed that tapering significantly increased hospitalizations and ED visits, while at the same time reducing the number of primary care (PC) visits. Researchers think the latter is at least partially due to “ruptures in relationships” with primary care providers (PCPs) due to patient dissatisfaction with tapering.

Opioid tapering was also associated with a significant reduction in patients taking medication for hypertension or diabetes – even though their blood pressure and blood sugar levels rose when their opioid doses were reduced.

“Tapering may be associated with reduced medication adherence due to an increased patient focus on managing pain and psychological distress due to the taper, disruption in PC due to more frequent ED visits and hospitalizations, or fracture of the PCP-patient relationship,” wrote lead author Elizabeth Magnan, MD, a family medicine physician at UC Davis Medical Center.

“Although cautious interpretation is warranted, these outcomes may represent unintended negative consequences of opioid tapering in patients who were prescribed previously stable doses.” 

Opioid prescribing has fallen dramatically in the U.S. over the past decade, particularly after the release of the CDC’s 2016 opioid guideline. Although millions of patients were affected by the guideline’s recommendations, few efforts were made at the federal level to see what happened to patients who had their opioid doses reduced or even stopped.

A recent study found the number of cancer patients seeking treatment for pain in emergency departments has doubled. Of the 35 million ED visits made by cancer patients, over half were deemed preventable – meaning the visits could have been avoided if the patient has received proper care earlier.

Constant Pain Can Lead to Diabetes, High Cholesterol and Heart Problems

By Dr. Forest Tennant, PNN Columnist

Intractable Pain Syndrome (IPS) is constant pain with cardiovascular, metabolic and hormonal complications. Constant pain is a severe stressor that causes the adrenal hormones cortisol and adrenalin to rise in the blood as the body attempts to reduce stress.

These hormonal elevations can lead to serious metabolic consequences that need to be well known to persons who have IPS, as well as their family and medical practitioners. High levels of adrenalin cause blood pressure and the pulse rate to rise. When cortisol is elevated, it causes the hormone insulin and blood sugar (glucose) to rise in the blood.

If blood sugar remains too high for too long, a person can develop diabetes or pre-diabetes, which is often called “insulin resistance.” Most persons believe that diabetes is a metabolic disease and is unrelated to hormones. The fact is that insulin, cortisol and adrenaline are hormones.

In addition to diabetes, a person with constant pain is also at high risk of developing or experiencing any or all of the following: 

• Heart Attack

• Heart Pain (Angina)

• Stroke

• Dementia

• Arteriosclerosis

Some persons with IPS have died suddenly and unexpectedly, sometimes while asleep. Often these cases are falsely labelled as a drug overdose.

There are three reasons for sudden, unexpected death in persons with IPS who are undertreated and have cardiovascular, metabolic and hormonal complications.

• Cardiac Arrythmia

• Adrenal Failure          

• Hypoglycemia (Excess Insulin)

Every person with IPS needs to be evaluated for diabetes, pre-diabetes, hypertension, tachycardia and excess cholesterol. Steps must be taken to eliminate or reduce any or all of these IPS complications. Consult your medical practitioner at your earliest opportunity for an evaluation of these complications. 

Forest Tennant, MD, DrPH, is retired from clinical practice but continues his research on intractable pain and arachnoiditis. This column is adapted from newsletters recently issued by the IPS Research and Education Project of the Tennant Foundation. Readers interested in subscribing to the newsletter can sign up by clicking here. The Tennant Foundation gives financial support to Pain News Network and sponsors PNN’s Patient Resources section.     

Gabapentinoids and Anti-Depressants Recommended for Diabetic Neuropathy

By Pat Anson, PNN Editor

People with painful diabetic neuropathy (PDN) should be treated with gabapentinoids, anti-depressants and sodium channel blockers, according to updated guidelines from the American Academy of Neurology (AAN). The guidelines also recommend some alternative treatments, such as ginkgo biloba, capsaicin patches and cognitive behavioral therapy, but strongly discourage the use of opioids.

The AAN’s new guidelines, published online in the journal Neurology, acknowledge that many of the recommended therapies for PDN don’t directly treat physical pain, but they improve mood and sleep, and that helps reduce “pain perception.”

“In treating patients with PDN, it is important to assess other factors that may also affect pain perception and quality of life. Patients with diabetes are more likely to have mood disorders (most commonly, major depression) and sleep disorders (especially obstructive sleep apnea) than the general population,” an AAN panel of experts found. “Therefore, treating concurrent mood and sleep disorders may help reduce pain and improve quality of life, apart from any direct treatment of the painful neuropathy.”

Nearly 26 million Americans have diabetes and about half have some form of neuropathy, according to the American Diabetes Association. PDN causes nerves to send out abnormal signals, causing patients to feel stinging or burning pain, as well as loss of feeling in their toes, feet, legs, hands and arms. More severe cases can result in ulcers or amputation of the affected limbs.

The last update to the AAN guideline was in 2011, when opioids such as morphine and oxycodone were said to be “probably effective and should be considered.” Much has changed over the last decade, and the AAN no longer supports their use for PDN.

"Current evidence suggests that the risks of the use of opioids for painful diabetic neuropathy therapy outweigh the benefits, so they should not be prescribed," said lead author Brian Callaghan, MD, an associate professor of neurology at University of Michigan Health.

‘Probably’ Better Than Placebo

The only oral medications the AAN now recommends for PDN are gabapentinoids (pregabalin and gabapentin); serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine; tricyclic anti-depressants such as amitriptyline; and sodium channel blockers such as valproic acid, which are usually used to treat seizures. An SNRI can also be combined with a weak opioid like tramadol for PDN.

There are caveats to all of these drugs since the evidence for them is limited and they were originally developed for other conditions such as depression or epilepsy. For example, the guidelines state gabapentin is “probably more likely than placebo to improve pain” and pregabalin is “possibly more likely” to help with PDN.

Topical medications such as capsaicin and buprenorphine patches also get the lukewarm endorsement of “possibly” being better than a placebo.

When one class of medication doesn’t work for PDN, experts say patients should try another.

“Managing expectations is also important,” Callaghan said. “Our second recommendation urges the provider to be frank with patients that the goal is to reduce their pain. It may not be possible to completely resolve the symptoms.”

A 2017 study by the Agency for Healthcare Research and Quality found that duloxetine (Cymbalta) and some other anti-depressants are moderately effective at relieving PDN, but found little or no evidence that opioids and gabapentinoids are helpful in treating neuropathic pain.

Researchers say a significant limitation for all pain relievers – not just opioids – is that few studies examine their safety and efficacy longer than three months. PDN is a progressive disorder that is likely to last a lifetime.  

“Given the chronicity of pain in those with diabetic neuropathy and the potential for evolving side effects, long-term studies are needed to better inform the long-term pain management in this population. Specifically, future studies should focus on the long-term effects (positive and negative) of opioids in this population to determine whether there is any role for these medications in this population,” the AAN’s expert panel concluded.

Stem Cells Could Help Diabetics Produce Their Own Insulin

By Pat Anson, PNN Editor

With insulin prices soaring out-of-reach for many U.S. patients, there’s hope on the horizon for people with Type 1 diabetes. Researchers are making significant progress in developing stem cell therapies that could restore their ability to produce their own insulin.

Interim findings from two early stage clinical trials, published today in the journals Cell Stem Cell and Cell Reports Medicine, show that pancreatic endoderm cells derived from human pluripotent stem cells (PSCs) began producing insulin in diabetic patients within months of being implanted in a tiny device under the skin.

While the amount of insulin secreted by the cells was not enough to cure Type 1 diabetes, they were sufficient enough to reduce the insulin requirements of some patients by as much as 20% and increase the amount of time spent in their targeted blood glucose range. Both studies showed that the stem cells can survive up to 59 weeks after implantation.

"A landmark has been set. The possibility of an unlimited supply of insulin-producing cells gives hope to people living with type 1 diabetes," says Eelco de Koning, MD, of Leiden University Medical Center in the Netherlands, who co-authored a commentary published in Cell Stem Cell. "Despite the absence of relevant clinical effects, this study will remain an important milestone for the field of human PSC-derived cell replacement therapies as it is one of the first to report cell survival and functionality one year after transplantation."

There are a number of caveats here. Less than three dozen patients participated in the Phase 1/2 studies, the outcomes were highly variable, and there were no control groups to compare the results with. The implanted stem cells were also derived from donors – meaning the patients had to take immunosuppressive drugs to prevent their bodies from rejecting the implants, leaving them vulnerable to infections. At least two patients experienced serious adverse events associated with having their immune systems suppressed.

Researchers still need to determine at what stage the stem cells are optimal for transplantation and the best place to implant them. It is also not clear how long the cells remain effective and whether the need for immunosuppressive therapy can be eliminated.

But the studies demonstrate that stem cells can mimic the insulin-producing pancreas cells that diabetics lack.

“A landmark has been set. The possibility of an unlimited supply of insulin-producing cells gives hope to people living with type 1 diabetes.”

— Eelco de Koning, MD

"The clinical road to wide implementation of stem cell-derived islet replacement therapy for type 1 diabetes is likely to be long and winding,” de Koning says. "But an era of clinical application of innovative stem-cell based islet replacement therapy for the treatment of diabetes has finally begun."    

About 460 million people worldwide have diabetes mellitus, a disorder in which the body does not produce enough insulin, causing blood sugar (glucose) levels to be abnormally high.  In Type 1 diabetes, the body’s immune system attacks the insulin producing cells of the pancreas. Left untreated, diabetes damages blood vessels and significantly raises the risk of stroke, heart attack and diabetic neuropathy.

Diet, exercise and regular insulin injections can help control Type 1 diabetes. But with insulin selling for about $300 a vial in the United States – 10 times more than in other developed countries --  some diabetics have rationed or even stopped taking the life-saving injections.

Another encouraging stem cell study -- involving just one patient -- was recently reported by Vertex Pharmaceuticals. A chronically ill man with Type 1 diabetes who has been taking insulin injections for decades – up to 34 units per day – began producing his own insulin after being injected with an experimental stem cell product called VX-880.

As a test, researchers only injected him with about half the targeted amount of VX-880, but within 90 days the man had reduced his need for insulin injections by 91 percent.

“These results from the first patient treated with VX-880 are unprecedented. What makes these results truly remarkable is that they were achieved with treatment at half the target dose,” Bastiano Sanna, PhD, Executive Vice President of Vertex, said in a statement. “While still early, these results support the continued progression of our VX-880 clinical studies, as well as future studies using our encapsulated islet cells, which hold the potential to be used without the need for immunosuppression.”

Vertex plans to expand the study to eventually include up to 17 patients, at multiple sites in the U.S. and Canada.

Topical Gel Shows Promise as Treatment for Neuropathic Pain

By Pat Anson, PNN Editor

An experimental gel developed to prevent skin damage caused by aging and ultraviolet light is showing promise as a treatment for chronic neuropathic pain, according to research underway in Australia.

The topical gel – known as RM191A – contains a copper-based compound that is absorbed by the skin and prevents the buildup of free radicals that cause skin damage associated with aging and skin cancer.

In a study recently published in the journal Redox Biology, RM191A was found to have potent antioxidant, anti-inflammatory and wound-healing properties in laboratory mice.

The gel is currently being evaluated in 24 patients at a Sydney hospital as a treatment for chronic nerve pain caused by surgery, chemotherapy, trauma and diabetes.  Results are expected later this month.

“Early sample uses of this topical formulation indicated it could be a significant in the management of certain types of chronic nerve pain,” says Llewellyn Casbolt, chief scientist and co-founder of Sydney-based RR MedSciences, which is developing the gel.

“In many ways, scientists see our discovery as a new class of anti-inflammatory that acts by the modulation of free radicals as well as reducing several inflammatory cytokines, providing a drug that can be therapeutically useful where the reduction of inflammation, as well as cellular and tissue healing - indeed pain relief - is also advantageous for a patient.”

The company plans to release an over-the-counter version of its gel in the next 12-18 months as a treatment for skin damage. It will take longer to get regulatory approval for the gel as a treatment for nerve pain and may require a prescription.

RR MedSciences (RRMS) plans to conduct further trials and is seeking additional partners and funding to accelerate the gel’s development.

“The management of pain, often related to conditions of inflammation or trauma that results in nerve or chronic pain is an area of great need.  Advancing the ability for people to modulate their pain, in a safe and effective manner that improves quality of life, is a core objective,” said Helena Libershal Casbolt, CEO and co-founder of RRMS.

A subsidiary of RRMS is currently selling a copper-based body cream called Blue Healer Care as a treatment for damaged skin and for relief from skin irritation and muscle soreness.

Living With Chronic Pain and Finding Happiness During a Pandemic

By Victoria Reed, Guest Columnist

These are trying times. For those of us struggling with chronic pain, we know what it means to be tough. We battle our own bodies, doctors and even unsympathetic family members every day. We know what it’s like to struggle and make sacrifices -- because that’s what we have to do to survive.

With the arrival of Covid-19, it has added another layer to our already complex lives. But how do we learn to live with this virus and find happiness in the face of overwhelming adversity? I don’t have all the answers, but I do know what’s working for me and what brings me joy. 

I have lived with chronic pain for all of my adult life. My first problem began during my teens, when I developed persistent, unexplained pelvic pain. After many doctor visits and three exploratory surgeries, a sympathetic and kind OB/GYN reproductive endocrinologist finally gave me the answer: endometriosis.

Receiving treatment for endometriosis, which included hormone therapy and surgery to remove adhesions, didn’t take all of the pain away, but it did restore my fertility and allow me to eventually have babies.

Then, during my mid 20’s, my back suddenly went out. I had had no falls, accidents or injuries that I could recall. That would set the stage for another type of pain to take over my life, which there really was no cure for. I got a diagnosis of degenerative disc disease at age 27.

I managed the pain with physical therapy to tighten my core muscles, regular use of ice and heat, rest and pain medication. I also had a caudal nerve block. But by age 32, I began having new symptoms of joint swelling in random joints. Back to the doctor I went!

During that visit with a rheumatologist, I had requested to be tested for rheumatoid arthritis (RA) because my twin sister had recently received that diagnosis. Sure enough, blood tests confirmed that I did indeed have antibodies specific to RA. For those of you who have RA, you know that it is.a.beast.

VICTORIA REED

Over time, beating back RA became like a full-time job; take this medication, take that medication, inject this, apply that. Eventually, after trials of several expensive biologic medications and DMARD’s (disease-modifying antirheumatic drugs), we found one that worked. I get it by IV infusion about once a month at the Cleveland Clinic.

Biologics suppress the immune system to help bring down the inflammation that damages the joints, heart and lungs. RA also causes chronic, debilitating fatigue. It’s like you haven’t slept in a month and got run over by a truck, not like the tiredness you feel when you only had a few hours of sleep the night before.

Then a year or two later, during a routine visit with my rheumatologist, she listened to me as I described being sore all over. After a thorough exam, I received the diagnosis of fibromyalgia, another chronic and painful condition.

Here we go again! When will it stop? Some people might just want to give up, but I had three kids to raise, and it was important for me to fight for my health for them. My 18-year marriage had become a casualty and giving up was not an option!

With the diagnosis of fibromyalgia, I had to adapt to the reality that I was never going to be free of pain and fatigue. They had become my constant companions. I managed, and my kids grew up watching my struggle. They are now 16, 19 and 21 and are happy, well-adjusted individuals, but they’ve had to watch me deal with pain their entire lives. 

Since it was obvious that my body hated me, why would it stop assaulting and insulting me? Guess what? It did not. I have since been diagnosed with FOUR more autoimmune and related disorders: Hashimoto’s thyroiditis (thyroid attack), Sjogren’s syndrome (mucous membrane attack), Raynaud’s phenomenon (small artery abnormality) and the loveliest of all: LADA (Latent Autoimmune Diabetes of Adulthood), a form of Type 1 diabetes that is primarily treated with insulin.

Fast forward to 2020. Covid-19 arrives? No problem! I’m used to challenges. I’m used to pills, needles, pain and fatigue. Wearing a mask is the least of my worries, as I’ve been fighting to stay alive and healthy for all of my adult life and a few of my teenage years.

These days, I make time to do the things that please me, such as riding my 2-wheel Italian scooter, gardening, camping and traveling. I even learned how to ride a motorcycle at age 50! I do not dwell on my pain.

Living in northeast Ohio limits year-round sunshine, but when it is warm and sunny outside, that’s where you’ll always find me! Peace comes when I am at one with nature. Happiness is a state of mind. We can choose to be miserable or we can choose to be happy, and despite my health challenges, I am grateful and thankful for the blessings that I do have.

So, to all of you pain warriors, hang in there! Look for and hold onto the positive. Surround yourself with positive people. Cut out those friends and family that are negative energy (I did). Make time to do things you enjoy. It’s not easy, but it is possible to find peace and happiness in the face of overwhelming adversity.

Let’s hope that Covid-19 will someday be a thing of the past. But if not, we’ll be alright. 

Victoria Reed lives in Cleveland, Ohio.

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

‘Radical Shift’ Predicted in Fibromyalgia Diagnosis and Treatment

By Pat Anson, PNN Editor

New research has uncovered a previously unknown connection between fibromyalgia and the early stages of diabetes, which could dramatically change the way the chronic pain condition is diagnosed and treated.

In a small study of 23 fibromyalgia patients and two control groups, researchers at The University of Texas Medical Branch at Galveston (UTMB) were able to separate patients with fibromyalgia (FM) from healthy individuals using a common blood test for insulin resistance, or pre-diabetes. They then treated the fibromyalgia patients with a medication targeting insulin resistance (IR), which dramatically reduced their pain levels.

“Although preliminary, these findings suggest a pathogenetic relationship between FM and IR,  which may lead to a radical paradigm shift in the management of this disorder,” researchers reported in the online journal PlosOne.

Fibromyalgia is a poorly understood disorder that causes widespread body pain, fatigue, insomnia, headaches and mood swings. The cause is unknown, the symptoms are difficult to treat and there is no universally accepted way to diagnose it.

"Earlier studies discovered that insulin resistance causes dysfunction within the brain's small blood vessels. Since this issue is also present in fibromyalgia, we investigated whether insulin resistance is the missing link in this disorder," said Miguel Pappolla, MD, a professor of neurology at UTMB.

Pappolla and his colleagues found that patients with fibromyalgia can be identified by their hemoglobin A1c levels, a protein in red blood cells that reflects blood sugar levels. A1c tests are widely used to diagnose type 2 diabetes and pre-diabetes, and are routinely used in diabetes management.

Researchers say pre-diabetics with slightly elevated A1c levels carry a higher risk of developing widespread body pain, a hallmark of fibromyalgia and other chronic pain conditions.

"Considering the extensive research on fibromyalgia, we were puzzled that prior studies had overlooked this simple connection," said Pappolla. "The main reason for this oversight is that about half of fibromyalgia patients have A1c values currently considered within the normal range.

“However, this is the first study to analyze these levels normalized for the person's age, as optimal A1c levels do vary throughout life. Adjustment for the patients' age was critical in highlighting the differences between patients and control subjects."

After identifying the fibromyalgia patients with elevated A1c levels, researchers treated them with metformin, an oral medication that manages insulin resistance by restoring normal blood sugar levels. The patients showed dramatic reductions in their pain levels, with half (8 of 16 patients) having a complete resolution of pain.

“Our data provides preliminary evidence suggesting that IR may be a pathological substratum in FM and sets the stage for future studies to confirm these initial observations. If confirmed, our findings may translate not only into a radical paradigm shift for the management of FM but may also save billions of dollars to healthcare systems around the world,” researchers reported.

Growing Abuse of Gabapentin

By Christine Vestal, Stateline

Doctors who are cutting back on prescribing opioids increasingly are opting for gabapentin, a safer, non-narcotic drug recommended by the Centers for Disease Control and Prevention.

By doing so, they may be putting their opioid-using patients at even greater risk.

Recently, gabapentin has started showing up in a substantial number of overdose deaths in hard-hit Appalachian states. The neuropathic (nerve-related) pain reliever was involved in more than a third of Kentucky overdose deaths last year.

Drug users say gabapentin pills, known as “johnnies” or “gabbies,” which often sell for less than a dollar each, enhance the euphoric effects of heroin and when taken alone in high doses can produce a marijuana-like high.

Medical researchers stress that more study is needed to determine the role gabapentin may have played in recent overdose deaths. However, a study of heroin users in England and Wales published last fall concluded that combining opioids and gabapentin “potentially increases the risk of acute overdose death” by hampering breathing and reversing users’ tolerance to heroin and other powerful opioids.

Kentucky last year classified gabapentin as a controlled substance, making it harder for doctors to prescribe it in copious quantities and for long durations. The new classification also allows police to arrest anyone who illicitly sells the drug, although the state’s drug control chief, Van Ingram, said that was not the intent of the new law.

In the last two years, Illinois, Ohio, Massachusetts, Minnesota, Tennessee, Virginia and Wyoming also have moved to control the flow of gabapentin by requiring doctors and pharmacists to check a prescription drug database before prescribing it to patients to make sure they aren’t already receiving gabapentin, or some other medication that interacts with it, from another physician.

In a statement to Stateline, Pfizer communications director Steven Danehy said, “Reports of misuse and abuse with this class of medicines are limited and typically involve patients with a prior history of substance abuse, including opioids.”

The drugmaker also pledged to “continue working with regulatory authorities and health officials to evaluate and monitor the safety of these medicines.”

Prescribed for Many Conditions

Approved by the FDA in 1993 for the treatment of epilepsy and the nerve pain associated with shingles, gabapentin is sold by Pfizer under the brand name Neurontin. A generic form of the drug has been available since 2004 and is now sold by several other companies as well.

Gabapentin is now one of the most popular prescription drugs in the United States, according to the New England Journal of Medicine. It was the 10th-most-prescribed medication in 2016. Its more expensive cousin, pregabalin, sold as Lyrica and also made by Pfizer, was the eighth best-selling.

Many doctors recommend gabapentin to patients for a long list of disorders, including hot flashes, migraines, restless leg syndrome, fibromyalgia, and neuropathic pain associated with diabetes and spinal injuries. Some doctors also prescribe it for anxiety and insomnia.

Now, research is underway to determine whether gabapentin may be effective as a treatment for alcoholism.

Already, it is widely used to ease the symptoms of drug and alcohol detoxification. And addiction specialists routinely use gabapentin to manage pain in people who are either addicted or at risk of addiction to opioids and other substances.

Alone, high doses of gabapentin have not been found to affect breathing. The vast majority of gabapentin deaths, about 4 in 5, also involved opioids, according to the journal Addiction.

People who stop taking the medication abruptly, however, can suffer withdrawal symptoms such as trembling, sweats and agitation.

In February, Food and Drug Administration director Scott Gottlieb said the agency was reviewing the misuse of gabapentin and, for now, had determined no action was necessary. Similarly, the CDC has not issued a warning about gabapentin, nor has the Drug Enforcement Administration.

(Editor's note: the CDC opioid guidelines recommend gabapentin without any mention of the risk of abuse or overdose associated with the drug, or of possible side effects such as weight gain, anxiety and mood disorders.)

Early Signs of Abuse

In Kentucky, Ingram said it has been clear to police and pharmacists for the last three or four years that gabapentin was becoming an increasingly popular street drug. “People were seeking early refills, claiming they lost their prescriptions and openly conducting transactions in parking lots outside of drug stores,” he said.

But since it wasn’t a controlled substance, nothing was done about it. That’s likely to start changing with the new law, he said.

“Misuse of gabapentin is just one more collateral effect of the opioid epidemic,” said Caleb Alexander, an epidemiologist at Johns Hopkins University who has been studying the heroin and prescription drug epidemic. When one drug becomes less available, drug users historically seek out alternatives, he said. “What is most surprising is the sheer magnitude of its use.”

The share of Appalachian drug users who reported using gabapentin to get high increased nearly 30-fold from 2008 to 2014, according to a 2015 study in the American Journal of Psychiatry.

Paul Earley, an addiction doctor practicing in Georgia and a board member of the American Society of Addiction Medicine, said, “We knew that a small subset of our addiction patients would abuse gabapentin.” But he said it wasn’t until 2016, when Ohio sounded an alarm about the drug’s association with overdose deaths, that addiction doctors started taking the problem more seriously.

“For years, we considered gabapentin to be ‘good for what ails you,’” Earley said. “But I’m much more cautious than I used to be. If there’s anything we’ve learned from the opioid epidemic, it’s that we need to rethink how we prescribe drugs we once assumed were safe.”

This is story is republished with permission by Stateline, an initiative of The Pew Charitable Trusts.

Light Therapy Used to Treat Neuropathic Pain

By Pat Anson, Editor

For someone with peripheral neuropathy, even the slightest touch can cause burning, stinging or shooting pain, usually in the hands or feet.

The pain is caused when the peripheral nervous system is damaged by diabetes, shingles, chemotherapy or some other medical condition. About 8% of adults worldwide suffer from some form of neuropathy. Medications prescribed to dull the pain – such as opioids, anti-depressants or gabapentin (Neurontin) -- often prove to be ineffective, don’t last long or have unwanted side effects.

Scientists in Italy have now discovered an experimental way to treat neuropathy that provides pain relief for weeks at a time without the use of medication. In experiments on laboratory mice, researchers at the European Molecular Biology Laboratory (EMBL) in Rome identified a specific set of nerve cells in mouse skin that play a significant role in neuropathic pain.

NATURE COMMUNICATIONs

When injected with a light-sensitive chemical and then exposed to infrared light, the nerve cells pull away from the skin’s surface and stop sending pain signals. The pain-relieving effects of the light therapy appear to last for weeks.

The accompanying image shows the skin of a mouse, with the nerve cells that are responsible for sensitivity to touch highlighted in green. The neurons are primarily located around hair follicles.

The EMBL's research, first reported in the journal Nature Communications, is still in its early stages. But scientists say human skin tissue is similar to that of mice, indicating that light therapy might be effective in managing neuropathic pain in humans.

"In the end, our aim is to solve the problem of pain in both humans and animals," says Paul Heppenstall, PhD, EMBL group leader. "Of course, a lot of work needs to be done before we can do a similar study in people with neuropathic pain. That's why we're now actively looking for partners and are open for new collaborations to develop this method further, with the hope of one day using it in the clinic."

Heppenstall says light therapy works on the treated nerve cells the same way spicy food or capsaicin patches can cause nerve fibers to retract.  

"It's like eating a strong curry, which burns the nerve endings in your mouth and desensitizes them for some time," says Heppenstall. "The nice thing about our technique is that we can specifically target the small subgroup of neurons causing neuropathic pain."

There are many different types of nerve cells in skin, which respond to different sensations like vibration, cold, heat or normal pain. Researchers say those cells are not affected by the light treatment. The skin is only desensitized to a gentle touch, breeze, or tickling.

Previous attempts to develop drugs to treat neuropathic pain have mostly focused on targeting single molecules.

"We think however, that there's not one single molecule responsible, there are many," Heppenstall explains. "You might be able to succeed in blocking one or a couple, but others would take over the same function eventually. With our new illumination method, we avoid this problem altogether."

The neuropathic pain in mice was assessed with a simple touch. The mice would normally quickly withdraw their paw when it was gently touched, but after light therapy they exhibited normal reflexive response to touch. The effect of the therapy lasted for a few weeks, until the nerve endings grew back and the gentle touch caused pain again.

When Chronic Wounds Don’t Heal

By Marisa Taylor, Kaiser Health News

Carol Emanuele beat cancer. But for the past two years, she has been fighting her toughest battle yet. She has an open wound on the bottom of her foot that leaves her unable to walk and prone to deadly infection.

In an effort to treat her diabetic wound, doctors at a Philadelphia clinic have prescribed a dizzying array of treatments. Freeze-dried placenta. Penis foreskin cells. High doses of pressurized oxygen. And those are just a few of the treatment options patients face.

“I do everything, but nothing seems to work,” said Emanuele, 59, who survived stage 4 melanoma in her 30s. “I beat cancer, but this is worse.”

The doctors who care for the 6.5 million patients with chronic wounds know the depths of their struggles. Their open, festering wounds don’t heal for months and sometimes years, leaving bare bones and tendons that evoke disgust even among their closest relatives.

Many patients end up immobilized, unable to work and dependent on Medicare and Medicaid. In their quest to heal, they turn to expensive and sometimes painful procedures, and products that often don’t work.

CAROL EMANUELE (KAISER HEALTH NEWS)

According to some estimates, Medicare alone spends at least $25 billion a year treating these wounds. But many widely used treatments aren’t supported by credible research. The $5 billion-a-year wound care business booms while some products might prove little more effective than the proverbial snake oil. The vast majority of the studies are funded or conducted by companies who manufacture these products. At the same time, independent academic research is scant for a growing problem.

“It’s an amazingly crappy area in terms of the quality of research,” said Sean Tunis, who as chief medical officer for Medicare from 2002 to 2005 grappled with coverage decisions on wound care. “I don’t think they have anything that involves singing to wounds, but it wouldn’t shock me.”

A 2016 review of treatment for diabetic foot ulcers found “few published studies were of high quality, and the majority were susceptible to bias.” The review team included William Jeffcoate, a professor with the Department of Diabetes and Endocrinology at Nottingham University Hospitals Trust. Jeffcoate has overseen several reviews of the same treatment since 2006 and concluded that “the evidence to support many of the therapies that are in routine use is poor.”

A separate Health and Human Services review of 10,000 studies examining treatment of leg wounds known as venous ulcers found that only 60 of them met basic scientific standards. Of the 60, most were so shoddy that their results were unreliable.

Paying for Treatments That Don't Work

While scientists struggle to come up with treatments that are more effective, patients with chronic wounds are dying.

The five-year mortality rate for patients with some types of diabetic wounds is more than 50 percent higher than breast and colon cancers, according to an analysis led by Dr. David Armstrong, a professor of surgery and director of the Southern Arizona Limb Salvage Alliance.

Open wounds are a particular problem for people with diabetes because a small cut may turn into an open crater that grows despite conservative treatment, such as removal of dead tissue to stimulate new cell growth.

More than half of diabetic ulcers become infected, 20 percent lead to amputation, and, according to Armstrong, about 40 percent of patients with diabetic foot ulcers have a recurrence within one year after healing.

“It’s true that we may be paying for treatments that don’t work,” said Tunis, now CEO of the nonprofit Center for Medical Technology Policy, which has worked with the federal government to improve research. “But it’s just as tragic that we could be missing out on treatments that do work by failing to conduct adequate clinical studies.”

Although doctors and researchers have been calling on the federal government to step in for at least a decade, the National Institutes of Health and the Veterans Affairs and Defense departments haven’t responded with any significant research initiative.

“The bottom line is that there is no pink ribbon to raise awareness for festering, foul-smelling wounds that don’t heal,” said Caroline Fife, a wound care doctor in Texas. “No movie star wants to be the poster child for this, and the patients … are old, sick, paralyzed and, in many cases, malnourished.”

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The NIH estimates that it invests more than $32 billion a year in medical research. But an independent review estimated it spends 0.1 percent studying wound treatment. That’s about the same amount of money NIH spends on Lyme disease, even though the tick-borne infection costs the medical system one-tenth of what wound care does, according to an analysis led by Dr. Robert Kirsner, chair and Harvey Blank professor at the University of Miami Department of Dermatology and Cutaneous Surgery.

Emma Wojtowicz, an NIH spokeswoman, said the agency supports chronic wound care, but she said she couldn’t specify how much money is spent on research because it’s not a separate funding category.

“Chronic wounds don’t fit neatly into any funding categories,” said Jonathan Zenilman, chief of the division for infectious diseases at Johns Hopkins Bayview Medical Center and a member of the team that analyzed the 10,000 studies. “The other problem is it’s completely unsexy. It’s not appreciated as a major and growing health care problem that needs immediate attention, even though it is.”

Commercial manufacturers have stepped in with products that the FDA permits to come to market without the same rigorous clinical evidence as pharmaceuticals. The companies have little incentive to perform useful comparative studies.

“There are hundreds and hundreds of these products, but no one knows which is best,” said Robert Califf, who stepped down as Food and Drug Administration commissioner for the Obama administration in January. “You can freeze it, you can warm it, you can ultrasound it, and [Medicare] pays for all of this.”

When Medicare resisted coverage for a treatment known as electrical stimulation, Medicare beneficiaries sued, and the agency changed course.

“The ruling forced Medicare to reverse its decision based on the fact that the evidence was no crappier than other stuff we were paying for,” said Tunis, the former Medicare official.

In another case, Medicare decided to cover a method called “noncontact normothermic wound therapy,” despite concerns that it wasn’t any more effective than traditional treatment, Tunis said.

“It’s basically like a Dixie cup you put over a wound so people won’t mess with it,” he said. “It was one of those ‘magically effective’ treatments in whatever studies were done at the time, but it never ended up being part of a good-quality, well-designed study.”

Questionable Research

The companies that sell the products and academic researchers themselves disagree over the methodology and the merits of existing scientific research.

Thomas Serena, one of the most prolific researchers of wound-healing products, said he tries to pick the healthiest patients for inclusion in studies, limiting him to a pool of about 10 percent of his patient population.

“We design it so everyone in the trial has a good chance of healing,” he said.

“If it works, like, 80 or 90 percent of the time, that’s because I pick those patients,” said Serena, who has received funding from manufacturers.

But critics say the approach makes it more difficult to know what works on the sickest patients in need of the most help.

Gerald Lazarus, a dermatologist who led the HHS review as then-director of Johns Hopkins Bayview Medical Center wound care clinic, said Serena’s assertion is “misleading. That’s not a legitimate way to conduct research.” He added that singling out only healthy patients skews the results.

The emphasis on healthier patients in clinical trials also creates unrealistic expectations for insurers, said Fife.

“The expensive products … brought to market are then not covered by payers for use in sick patients, based on the irrefutable but Kafka-esque logic that we don’t know if they work in sick people,” she said.

“Among very sick patients in the real world, it may be hard to find a product that’s clearly superior to the others in terms of its effectiveness, but we will probably never find that out since we will never get the funding to analyze the data,” added Fife, who has struggled to get government funding for a nonprofit wound registry she heads. Not surprisingly, she said, the registry data demonstrate that most treatments don’t work as well on patients as shown in clinical trials.

Patients say they often feel overwhelmed when confronted with countless treatments.

“Even though I’m a doctor and my wife is a nurse, we found this to be complicated,” said Navy Cmdr. Peter Snyder, a radiologist who is recovering from necrotizing fasciitis, also known as flesh-eating bacteria. “I can’t imagine how regular patients handle this. I think it would be devastating.”

To heal wounds on his arms and foot, Snyder relied on various treatments, including skin-graft surgery, special collagen bandages and a honey-based product. His doctor who treats him at Walter Reed National Military Medical Center predicted he would fully recover.

peter snyder examined at walter reed medical center (khnphoto)

Such treatments aren’t always successful. Although Emanuele’s wound left by an amputation (of her big toe) healed, another wound on the bottom of her foot has not.

Recently, she looked back at her calendar and marveled at the dozens of treatments she has received, many covered by Medicare and Medicaid.

Some seem promising, like wound coverings made of freeze-dried placenta obtained during births by cesarean section. Others, not — including one plastic bandage that her nurse agreed made her wound worse.

Emanuele was told she needed to undergo high doses of oxygen in a hyperbaric chamber, a high-cost treatment hospitals are increasingly relying on for diabetic wounds. The total cost: about $30,000, according to a Medicare invoice.

Some research has indicated that hyperbaric therapy works, but last year a major study concluded it wasn’t any more effective than traditional treatment.

“Don’t get me wrong, I am grateful for the care I get,” Emanuele said. “It’s just that sometimes I’m not sure they know what they’re using on me works. I feel like a guinea pig.”

Confined to a wheelchair because of her wounds, she fell moving from the bathroom to her wheelchair and banged her leg, interrupting the healing process. Days later, she was hospitalized again. This time, she got a blood infection from bacteria entering through an ulcer.

She has since recovered and is now back on the wound care routine at her house.

“I don’t want to live like this forever,” she said. “Sometimes I feel like I have I no identity. I have become my wound.”

Kaiser Health News, a nonprofit health newsroom whose stories appear in news outlets nationwide, is an editorially independent part of the Kaiser Family Foundation.

Lyrica and Cymbalta Advised for Diabetic Neuropathy

By Pat Anson, Editor

New guidelines by the American Diabetes Association for the treatment of diabetic neuropathy strongly discourage the use of opioids to treat nerve pain, while recommending pregabalin (Lyrica) and duloxetine (Cymbalta).

Nearly 26 million people in the United States have diabetes and over half have some form of neuropathy, which often causes a painful stinging or burning sensation in the hands or feet.  Nerve pain is often the first symptom that prompts people to seek medical care before getting a diabetes diagnosis.

Researchers at the University of Michigan led a group of internationally recognized endocrinologists and neurologists, and teamed up with the American Diabetes Association (ADA) to craft a new position statement on the prevention, treatment and management of neuropathy. The ADA last released a statement on diabetic neuropathy in 2005.

"Our goal was to update the document so that it not only had the most up-to-date evidence, but also was easy to understand and relevant for primary care physicians," said lead author Rodica Pop-Busui, MD, a professor of internal medicine at Michigan Medicine Division of Metabolism, Endocrinology and Diabetes.

"Treatment of neuropathy pain is specifically relevant because, unfortunately, there has been much overprescribing of narcotics for neuropathic pain."

Although opioids like oxycodone and tramadol are effective in relieving nerve pain, they are not recommended by the ADA as a first, second or even a third-line treatment.

“Despite the demonstrated effectiveness of opioids in the treatment of neuropathic pain, there is a high risk of addiction, abuse, sedation, and other complications and psychosocial issues even with short-term opioid use. For these reasons, opioids are not recommended in the treatment of painful DSPN (distal symmetric polyneuropathy) before failure of other agents that do not have these associated concerns,” the guideline states.

Instead of opioids, the ADA recommends either pregabalin (Lyrica) or duloxetine (Cymbalta) as an initial treatment for neuropathic pain. Gabapentin (Neurontin) can also be considered.

PNN readers often complain of side effects from all three drugs – such as depression, fatigue, nausea, headache and weight gain -- yet the ADA statement only vaguely warns that their “adverse effects may be more severe in older patients.”

"Lyrica did help with my nerve pain but the side effects were intolerable and the withdrawal was absolute hell," said Laura.  "I gained 20 pounds in a month and was even more of a zombie than when I was on gabapentin. I had no personality, no interest in anything, and had completely lost motivation to do anything."

"I have been on Cymbalta a couple of years. It has helped overall with depression, anxiety and pain. I also can't miss a dose or try to quit cold turkey," wrote Rebecca Williams. "I become very dizzy, nauseated, night sweats, crazy dreams, electrical zaps in my head. I don't know how I would ever get off of it because the withdrawal symptoms are unbearable."

The ADA guidelines recommend that physicians try different therapies to prevent or slow the progression of diabetic neuropathy, most of which focus on controlling high blood sugar (glucose), which can cause irreversible damage to small nerve fibers. Insulin, regular exercise and a low-calorie, low-fat diet can help regulate glucose levels.

To see the ADA’s recommendations, click here.

Neuropathy More Damaging Than Previously Thought

By Pat Anson, Editor

A tingling, sometimes painful sensation in the hands and feet – the early stages of small fiber neuropathy -- may be more damaging to the peripheral nervous system than previously thought, according to new research published in JAMA Neurology.

A 3-year study by Johns Hopkins neurologists found that patients with small fiber neuropathy showed unexpected deterioration over the entire length of sensory nerve fibers, not just nerve fibers at the surface of the skin.

“I liken small fiber neuropathy to the canary in the coal mine,” says senior author Michael Polydefkis, MD, professor of neurology at the Johns Hopkins University School of Medicine and director of the Cutaneous Nerve Lab. “It signals the beginning of nerve deterioration that with time involves other types of nerve fibers and becomes more apparent and dramatically affects people’s quality of life. The results of this new study add urgency to the need for more screening of those with the condition and faster intervention.”

Nearly 26 million people in the United States have diabetes and about half have some form of neuropathy, according to the American Diabetes Association.  Small fiber neuropathy can also be caused by lupus, HIV, Lyme disease, celiac disease or alcoholism.

Diabetic peripheral neuropathy causes nerves to send out abnormal signals. Patients feel pain or loss of feeling in their toes, feet, legs, hands and arms. It may also include a persistent burning, tingling or prickling sensation. The condition can eventually lead to injuries, chronic foot ulcers and even amputations.

Polydefkis and his colleagues found that small fiber nerve damage occurs even in patients with prediabetes, and the early symptoms of burning pain may be less benign than most clinicians think. Routine nerve tests, like nerve conduction, often fail to identify nerve damage because they mostly assess injury to large diameter nerve fibers.

In an effort to measure nerve damage more accurately, Johns Hopkins researchers took small samples of skin — the size of a large freckle — from 52 patients diagnosed with small fiber neuropathy and from 10 healthy controls. Skin samples were taken from the ankle, the lower thigh near the knee and the upper thigh. Three years later, samples from the same area in the same patients were taken for comparison.

Microscopic analysis of the skin samples showed that patients with small fiber neuropathy initially had fewer nerve fibers on the ankle compared to the upper thigh, demonstrating the most nerve damage was further down the leg. But after three years, researchers found that longer nerve fibers were also lost from the lower and upper thighs, something that was not expected.

“We are all taught in medical school that the longest nerves degrade first, and we show that this isn’t always the case,” says lead author Mohammad Khoshnoodi, MD, assistant professor of neurology at Johns Hopkins,

Patients with prediabetes or diabetes had at least 50 percent fewer small nerve fibers in their ankles initially than those participants with an unknown cause for their small fiber neuropathy, indicating these patients started the study with more damage to their small nerve fibers.

The patients with prediabetes continued to have worsening damage to their small nerve fibers over the course of the study, losing about 10 percent of their nerve fiber density each year at all sites tested along the leg. Patients with diabetes also lost similar rates of nerve fibers along the three sites of the leg.

“I expected that people with diabetes would do worse, but I didn’t really expect people with prediabetes to experience a similar rate of degradation of their small nerve fibers,” says Polydefkis.

Researchers caution that their study was small, and that other factors such as high blood sugar, smoking, high blood pressure and high cholesterol, may also have contributed to the decline in nerve fibers.