Can Naproxen Help You Live Longer?

By Pat Anson, PNN Editor

There may be a hidden benefit to the pain reliever naproxen. The non-steroidal anti-inflammatory drug (NSAID) is primarily used to treat arthritis, muscle aches and joint pain, but might also give a boost to your life expectancy, according to the results of a preliminary study.

An international research team analyzed 12-years of health records for over 500,000 people enrolled in the UK Biobank study to see if prescription drugs taken for at least 3 months were associated with higher or lower death rates. Over 400 medications were studied, with patients who were prescribed the drugs compared to control groups that didn’t take them.

“As expected, most drugs harbor a negative effect on lifespan, probably due to the underlying negative effect of the disease the drug is intended for. Importantly, a few drugs seem to have a beneficial effect on lifespan,” wrote lead author Alejandro Ocampo, PhD, a professor at the University of Lausanne and CEO of Epiterna, a Swiss company studying ways to slow the ageing process.        

Ocampo and his colleagues identified four medications associated with lower death rates:

• Naproxen   

• Atorvastatin (a statin)

• Estradiol (female hormone replacement)

• Sildenafil (Viagra)

Statins have long been known to reduce the risk of heart attack and stroke, while estradiol lowers the risk of osteoporosis and bone fractures in post-menopausal women. Sildenafil is well known for treating erectile dysfunction, but also improves cardiovascular health and may even protect against Alzheimer's disease. It’s easy to see how those drugs might increase life expectancy.

The inclusion of naproxen is a bit of a surprise. The active ingredient in Aleve and other over-the-counter pain relievers, naproxen raises the risk of a heart attack, stroke or internal bleeding when taken in high doses or used long-term. High doses of naproxen in 250mg and 500mg tablets are available by prescription, which is what people in the study were taking.

Even at those high doses, researchers found that naproxen was associated with a 10% lower death rate when compared to people who didn’t take the drug. The protective effect was strongest for men on naproxen, who had mortality rates that were 13% lower.

The findings are preliminary, have not been peer-reviewed, and don’t establish a cause-and-effect relationship. We don’t know why or how naproxen helps people live longer, only that it’s associated with a longer lifespan.  

Interestingly, the research team found that two other pain relievers – morphine and paracetamol (acetaminophen) – are associated with shorter lifespans. Again, this may have more to do with the underlying conditions the drugs were prescribed for, rather than the medications themselves.

Ocampo says more research and clinical studies are needed to get a better understanding of the long-term harms and benefits of medication.

“The benefit on lifespan observed for several drugs in this retrospective study could only be truly determined by performing randomized controlled trials. Such studies would aim at treating a healthy aging population with a drug during a sufficiently long follow-up to be able to observe the effect on all-cause mortality,” Ocampo wrote.

If the life expectancy benefits are proven, researchers say it could result in some drugs being “repurposed” as anti-aging treatments for otherwise healthy older adults.

Naltrexone Shortage Disrupts Addiction Treatment

By Pat Anson, PNN Editor

An inexpensive drug used to manage chronic pain and treat substance use disorders has joined the growing list of medications that are in short supply in the United States.

The Food and Drug Administration and the American Society of Health-System Pharmacists (ASHP) both recently added naltrexone tablets to their drug shortage lists. It’s not clear what caused the shortage, but the ASHP says “there is insufficient supply for usual ordering.”  

Naltrexone is FDA-approved to treat both alcohol and opioid use disorder, and is also used off-label in low doses to treat some chronic pain conditions.

In 50mg doses, naltrexone blocks opioid receptors in the brain and reduces cravings for opiates or alcohol. But in smaller doses of 5mg or less, patients have found low-dose naltrexone (LDN) to be an effective pain reliever for interstitial cystitis, Ehlers-Danlos syndrome, fibromyalgia, and other painful conditions.

LDN advocates believe the drug modulates the immune system, reduces inflammation and stimulates the production of endorphins, the body's natural painkiller. Because it is an opioid antagonist, naltrexone should not be taken with opioid medication.

So far, the shortage only affects 50mg naltrexone tablets. Pain patients usually obtain LDN by prescription from compounding pharmacies, which make the low dose versions in-house.

Several drug makers are reporting short supplies of 50mg tablets, including Accord Healthcare, Major, Elite Laboratories, SpecGx, Sun Pharma, Tagi Pharma, and Avet Pharmaceuticals. The companies didn’t provide the ASHP with a reason for the shortage, but said the tablets are on back order and would be released when they become available.    

The naltrexone shortage comes at an inopportune time, as more people abused alcohol and other substances during the pandemic and sought treatment. The drug that helps them stay sober is now hard to get.

"People are coming in with more cravings," Dr. Aviva Zohar, an addiction medicine provider, told Philly Voice. "Even the feeling of, 'I don't know when my medicine is coming in,' is a huge struggle. It's horrific (and) causing a lot of stress.”

To make up for the shortage, some providers are giving patients Vivitrol, an injectable, extended-release formulation of naltrexone taken once a month. A single Vivitrol injection costs about $1,700, while a month’s supply of 50mg naltrexone tablets costs about $48.

The cheap price of naltrexone may be responsible for the shortage. Most drugs in short supply are low-cost generics with slim profit margins. Some manufacturers have reduced or stopped making generics because they’re not worth the cost of production or the risk of litigation.   

Three generic opioids commonly taken for pain — immediate-release oxycodone, oxycodone-acetaminophen, and hydrocodone-acetaminophen tablets — have been on the ASHP shortage list for nearly a year, with no end in sight.

Can Two Questions Identify ‘High Risk’ Pain Patients?

By Pat Anson, PNN Editor

“Have you ever felt your pain is terrible and it's never going to get any better?”

“Have you ever used an illegal drug or prescription medication for non-medical reasons?”

If you answered yes to both questions, you’d be considered at high risk of a “poor pain outcome” at Duke University’s Health System. You’d also be invited into a specialized pain management program that takes a more holistic approach to pain treatment.

Duke’s Integrated Pain and Wellness (IPW) Program was launched in 2019 to identify and treat pain patients at high risk of long-term opioid use, which can result in more frequent and costly visits to hospitals and emergency rooms. It’s one of several efforts in recent years aimed at identifying high risk patients, such as the controversial analytical software used by NarxCare or the far simpler Opioid Risk Tool survey.

Many pain patients feel stigmatized by these risk assessments, and feel they’ve been weaponized solely to deny them treatment with opioids.   

The IPW program is a little different. Patients are encouraged – but not required – to reduce their use of opioids, try non-opioid treatments, and undergo behavioral health therapies to help them learn how to accept their pain without being obsessed by it.     

“Our goal was to establish a comprehensive, integrated approach to pain management that prioritizes early intervention, reduces the dependency on opioids by providing alternative pain management strategies, and decreases the utilization of acute care resources,” wrote Padma Gulur, MD, a Professor in Anesthesiology and Population Health Sciences at Duke University School of Medicine. 

Gulur and her colleagues assessed how 432 patients at the highest risk of poor pain outcomes did after being enrolled in the IPW program.  

Their findings, published in NEJM Catalyst, show that about half the patients (224) reduced their opioid use within 30 days, while a small number (50) increased their opioid use. 

The average improvement in self-reported pain scores was modest (from 6.56 down to 6.11), as were minor improvements in physical function, anxiety, depression and fatigue.  

There were more robust signs of the IPW program’s success in reducing healthcare utilization, with emergency room visits falling by 26% and hospital admissions declining by 43% among the high-risk patients. 

“This approach led to marked patient improvements in both physical and psychological health outcomes,” Gulur said. "By demonstrating the effectiveness of early identification and intervention for patients at risk of poor pain outcomes, this research can inform the development of new therapies and treatment approaches focused on prevention.” 

One hurdle that remains is getting more patients to participate. Of the 13,561 patients who answered “yes” to both questions in the high-risk assessment, less than 11% accepted a referral into the IPW program. Researchers say many were already being treated at pain clinics outside Duke Health and declined to participate.

A Case Study in the Undertreatment of Surgical Pain

By Dr. Stefan Franzen

“Patient Z” is a close family member who has an incurable form of arthritis known as ankylosing spondylitis. His back is partially fused and his large joints are so damaged that they all need replacement. Each step he takes, even with a walker using his arms as the main support, is exceedingly painful. Just getting into a car to go to a doctor’s office is excruciating.

Several years ago, Patient Z went through an opioid rotation from morphine/oxycodone to buprenorphine. This was a forced choice. His pain clinic told him that they would make a final push to taper him to a daily dose of 120 MME (morphine milligram equivalents). That was the statewide cap on prescribing. Patient Z had reduced gradually for years to accommodate them, but when the dose fell below 180 MME, he felt miserable much of the time.

Patient Z transferred to a pain institute where he was prescribed pure buprenorphine for pain. The doctors at the institute had conducted clinical studies and found buprenorphine to be as effective as morphine. When Patient Z reached the maximum daily dose of buprenorphine in sublingual form, he felt relief.

Patient Z might never have chosen buprenorphine, but he found that it managed his pain on most days. In his experience, the dose was as effective as 200 MME of morphine and oxycodone. But pain flares can overwhelm even that dose.

A surgeon urged surgery because stenosis and deformation of the neck caused by ankylosing spondylitis could lead to paralysis. Realizing that he was losing sensation in his arms and hands, Patient Z scheduled the surgery.

At the pre-op, he was told that the surgery required an incision in the front and back of his neck. The surgeon would implant a metal brace that was about 5 cm long. Patient Z asked the surgeon’s nurse about pain management and she assured him that he would be comfortable in the hospital.

He also asked his pain clinic what they would do to help with post-operative pain. They told him to rely on hospital care. Patient Z knew the constraints on the pain clinic and did not push the point. When he arrived for surgery, he still did not know what was planned for post-surgical pain control.

‘My Pain Level is 10’

The surgery was successful. Patient Z woke up in a hospital bed with a neck brace. But he could not move. After a few hours the pain set in. He could not believe that pain could be so all-consuming. Even lying motionless in bed, his body throbbed with pain radiating out from the back of his neck. He felt like he was nailed to the bed.

The nurses were told not to give him buprenorphine on the first night. One nurse said he was afraid that Patient Z would suffer respiratory depression. At first, they only gave him acetaminophen and pregabalin.

In the middle of the night, Patient Z called the nurse and said something he never thought he would say: “My pain level is 10.”

The nurse left to contact the doctor in charge. An hour passed. It seemed like an eternity to Patient Z, who was in agony. Finally, the nurse returned with a muscle relaxant and a two-milligram hydromorphone pill. That is the equivalent of 8-10 milligrams of oral morphine.

Patient Z knew how low this dose was, but he swallowed the pill and hoped the pain would stop. It did not. Patient Z is stoic and had suffered from extreme pain in the past, but he had to speak up. The pain was truly unbearable. His collapsed hips were throbbing. Pain was shooting down his arms and legs. Any movement brought on involuntary spasms.

Finally, at 5 am, a nurse gave Patient Z a two-milligram injection of hydromorphone. The pain abated and he could finally rest. This dynamic of denial and waiting until Patient Z was nauseous from pain before providing relief continued for three more days. Nurses rotated in and out, and the doctors made decisions that left him miserable most of the time.

On the fourth day after surgery, Patient Z was released from the hospital. Patient Z asked what he should do to control the pain. The surgeon looked unhappy. He said that the pain of surgery should pass within a week and Patient Z had already received ample pain medication. Other pain was not the surgeon’s concern, and he was told to consult with his pain physician.

By this time, one of the nurses who had seen Patient Z several times came to understand how debilitating his pain was. The nurse told Patient Z that she had observed many recovering surgery patients. She said that neck operations with an incision from the back is one of the most painful.

Patient Z was lucky that people could see his struggle with pain. Many patients have pain that is not recognized. Even so, the nurse told him that they could not write a prescription for opioid pain medication. Someone must have decided that Patient Z really did have unmet pain needs.

Maybe the nurse advocated for him because, as Patient Z was being released the nurse unexpectedly gave him a vial of pain medication. She said that it would be enough to keep him comfortable until the neck pain subsided. When Patient Z arrived home and looked at the vial, he saw that the oral hydromorphone dose was 12 milligrams daily, the equivalent of approximately 50 MME. And he only had a six-day supply.

This was not nearly enough to give Patient Z relief from the neck pain, back pain, hip pain and systemic inflammatory pain. To make matters worse, the instructions stated that he should not take buprenorphine for the six days he was on hydromorphone.

After one day, Patient Z’s misery escalated because he was going through withdrawal while also recovering from neck surgery. After two days, Patient Z resumed taking buprenorphine and stopped taking hydromorphone. At least the buprenorphine gave him partial relief.

Few patients take buprenorphine for pain in the U.S. It has been reported that hydromorphone is compatible with buprenorphine in post-surgical pain management.  Yet doctors and nurses appeared unfamiliar with buprenorphine, which is also used to treat opioid addiction when combined with naloxone. Their comments in the hospital showed that they did not understand that buprenorphine is safer than other opioids and can also be used to treat pain.

The combination of misunderstanding buprenorphine and the current practice of giving as little pain medication as possible put a severely ill patient through an unnecessary ordeal. Today, most medical education and pain research is solely aimed at reducing or eliminating opioids, rather than using buprenorphine and other alternative opioids to provide at least some relief.

Buprenorphine is slow-acting and therefore not the ideal medication for acute pain. But studies have shown that it can be combined with other opioids to provide relief. For some types of pain, there is no substitute for opioid pain medication.

Stefan Franzen, PhD, is a Professor of Chemistry at North Carolina State University.

He is the author of “Patient Z” – a book that looks at pain, addiction and the opioid crisis through the eyes of a loved one who can’t find good pain care.

Franzen recently published a sequel to Z’s story and his use of buprenorphine for pain, called “Z’s Odyssey.”

Oregon Medical Board Has ‘No Limits’ on Prescription Opioids

By Pat Anson, PNN Editor

The Oregon Medical Board has come full circle in its regulation and enforcement of pain management guidelines. After years of taking disciplinary action against doctors for prescribing high dose opioids without a “legitimate medical purpose,” the board has acknowledged that its policies had a chilling effect on doctors who no longer felt safe treating chronic pain with opioids.

“The Board is well aware some number of clinicians have shied away from long-term pain management in part or in whole for fear of Board sanctions. We wish it weren’t so, and the Board is hopeful the realignment in prescribing guidance will provide reassurance to those licensees caring for patients with long-term pain,” David Farris, MD, Medical Director of the Oregon Medical Board (OMB), recently wrote in the board’s newsletter.

The board’s “realignment” came a year after the Centers for Disease Control and Prevention revised its own opioid guideline to give doctors more flexibility in treating pain patients.

In 2016, the CDC initially recommended that daily opioid dosages not exceed 90 MME (morphine milligram equivalents), which was widely seen as a mandatory dose limit.

But after numerous reports of patients being rapidly tapered, going into withdrawal and dying by suicide, the CDC guidance was revised in 2022 to eliminate any dose thresholds. Physicians were instead urged to prescribe opioids cautiously at the “lowest possible effective dose.”   

“There are no set regulatory limits on the daily dosage of opioids that can be prescribed in Oregon. There is also not a requirement to rapidly taper or discontinue opioids for patients.”

— Oregon Medical Board

In a “Statement of Philosophy” adopted in January, the OMB urged doctors to read the CDC guideline and heed its advice about treating patients individually and to allow “shared decision making” about their treatment.

“In alignment with this statement and CDC guidelines, there are no set regulatory limits on the daily dosage of opioids that can be prescribed in Oregon. There is also not a requirement to rapidly taper or discontinue opioids for patients on existing opioid doses. The Board wants to ensure licensees accepting new patients on existing chronic opioid therapy do not feel pressured to rapidly change a patient’s current opioid dose,” the OMB said.

‘More Harm Than Good’

Opioids have been a contentious issue in Oregon for several years. In 2018, the state considered rule changes to its Medicaid program that would have limited coverage of opioids to just 90 days for patients with neck or back pain. The proposal, which would have forcibly tapered thousands of patients on long-term opioid therapy, was supported by Physicians for Responsible Opioid Prescribing (PROP), an anti-opioid activist group.     

The plan was scrapped after pain management experts signed a joint letter warning that Oregon’s tapering plan was unsupported by treatment guidelines and would do “substantially more harm than good.”

The Medical Board’s decision to give more leeway to doctors reflects a growing awareness that the crackdown on opioids is harming pain patients and may be worsening the drug crisis.    

“The Board wishes to reassure and encourage licensees to assume the prescribing responsibilities for such patients, regardless of MME level, at least temporarily, in order to avoid patients going into withdrawal or turning to illicit sources,” Farris wrote.

“It is gratifying to see the OMB finally recognize that their arbitrary opioid dosing policies harmed people with chronic pain and the providers caring for them. It seems as though the Board may have been adversely affected by advice received from home state clinicians aligned with PROP, and, inevitably, the chickens have come home to roost in that regard,” said Bob Twillman, PhD, former Executive Director of the Association of Integrative Pain Management, who signed the 2018 joint letter.

“I hope this change in stated policy will be reflected in changes to Board investigations and to the state-developed CME (Continuing Medical Education) program on pain management that is mandated for all prescribers in the state. It's going to take years to repair the damage done so far, but I'm hoping the pendulum can finally come to rest somewhere near the midpoint of the extremes we've seen over the last 30 years.”

Opioid prescribing in Oregon has been falling for nearly a decade – as it has nationwide – but overdose deaths in the state keep rising. According to CDC data, Oregon has one of the lowest rates of fatal overdoses involving prescription opioids in the country. Deaths linked to illicit fentanyl, stimulants, methamphetamine and heroin are far more common in Oregon.  

Where is CDC’s Guidance About Its Opioid Guideline?

By Carol Levy, PNN Columnist

By happenstance, I recently came across the CDC's 2022 revised opioid prescribing guideline. Too many doctors and states saw the agency’s original 2016 guideline as being written in stone -- not the voluntary set of recommendations they were intended to be.

To their credit, the CDC tried to address that misconception in its updated guideline:

“Recommendations are voluntary and are intended to support, not supplant, individualized, person-centered care. Flexibility to meet the care needs and the clinical circumstances of a specific patient is paramount.”

The CDC also acknowledged the damage done by its 2016 guideline, when many pain patients were forcibly tapered or cutoff from opioids, regardless of their diagnosis or condition. 

Some patients were abandoned by doctors who no longer wanted to risk going to prison for prescribing opioids. Other physicians retired or closed their offices, sometimes without warning. And several states passed legislation limiting how many days initial opioid prescriptions could be written for.

It is always hard to put the genie back in the bottle. Two years after the revised guideline was released, about 90% of patients still have trouble getting their opioid prescriptions filled at pharmacies. Others have to fight with their insurance company to get opioid medication covered.

Patients are still being forced into withdrawal and disability, despite a history of taking opioids safely and responsibly. Some will have to leave jobs they could only perform with the help of opioids. Others can’t play with their kids, walk the dog or even get out of bed, because they are no longer able to get the medication that helped them lead relatively normal lives.

It should not have taken CDC six years to revise the opioid guideline, to make clear that they were only recommendations and never a mandate.

Is there a way to undo the damage? For the doctors who closed their practices or stopped treating pain, it is probably too late. For the patients who chose suicide because they could no longer get opioids, it is definitely too late

But maybe, just maybe, we can persuade doctors, pharmacists, lawmakers and insurers to take another look at the revised opioid guideline and convince them they are out of line.

It would be helpful if the CDC joined in an effort to fix the mess that it helped create.

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. 

‘Smart Opioid’ Relieves Pain with Lower Risk of Overdose

By Pat Anson, PNN Editor

An experimental form of hydrocodone relieves moderate-to-severe acute pain without the risks of traditional opioids, according to the results of an early-stage Phase 1 clinical trial.

Elysium Therapeutics say its proprietary “SMART” formulation of hydrocodone – called Oral Overdose Protected (O2P) hydrocodone – releases therapeutic levels of the pain medication when exposed to trypsin, a digestive enzyme in the small intestine. Conversely, the drug can also inhibit production of trypsin – and slow the release of hydrocodone -- if a "supratherapeutic" (more than recommended) dose is ingested.

In theory, that will reduce the risk of abuse, diversion and overdose.

"Because non-opioid options are ineffective and existing opioids have no protection against their inherent risks, moderate-to-severe acute pain is not adequately managed in greater than 80% of patients in the US,” Greg Sturmer, CEO of Elysium Therapeutics said in a press release.

“As shown in our human study, our SMART opioids, led by O2P hydrocodone, mitigate the major risks associated with existing prescription opioids without sacrificing their superior analgesic efficacy, especially when compared to currently marketed non-opioid alternatives and those in development."

The proof-of-concept study included 93 healthy participants who were not in pain, but had previously used and tolerated prescription opioids. Their blood plasma levels were measured after taking O2P hydrocodone and compared to plasma levels after taking traditional hydrocodone. Participants were also given naltrexone as a safety measure to block the sedative effect of the drugs.

Investigators say the plasma concentrations of hydrocodone were significantly lower after taking the O2P formulation, but were high enough to be “potentially lethal” from traditional hydrocodone. No adverse events were reported from O2P hydrocodone, even when taken at supratherapeutic doses.

"The results from the O2P-001 study indicate that Elysium's O2P technology could yield safer opioids that address the key issues inherent in current opioids that have fueled the opioid crisis, while providing patients with highly effective pain relief," said Leela Vrishabhendra, MD, principal investigator of the study.

Many U.S. hospitals have started using non-opioid pain medications such as ibuprofen, acetaminophen and gabapentinoids to treat post-operative acute pain. Studies have found that some patients are not happy with the results and want more pain control. O2P hydrocodone would give them an alternative.

Phase I clinical studies are preliminary in nature and usually just measure the safety and tolerability of a drug, not its effectiveness. Elysium hopes its findings will lead to a “breakthrough therapy” designation from the FDA, which will speed up the development of its O2P technology and lead to larger clinical trials that would better assess pain relief.   

"Given the robust Phase 1 human proof-of-concept data, we plan to meet with the FDA to discuss next steps, finalize our dose form for remaining clinical studies, and seek partners and investors who share our passion to disrupt the pain and opioid use disorder markets with safer medicines that reduce trauma and save lives," said CEO Greg Sturmer.

UK Crisis Grows Over Pregabalin Misuse

By Pat Anson, PNN Editor

Nearly 3,400 people in the UK have died from overdoses involving pregabalin in the last five years, according to an investigation by The Sunday Times.

One of them was a young man named Alex Cottam, who spiraled into drug abuse, addiction and a fatal overdose after he started taking pregabalin for anxiety and depression.   

“It’s hard to imagine somebody’s whole life revolved around a pill, but it did,” said Cottam’s mother, Michelle. “It completely changed him, like it was an obsession.”

The Sunday Times’ story about Cottam and other pregabalin users sparked a frenzy in British tabloids about the growing misuse of the drug.

“Our Pregabalin nightmare” was the headline in the Daily Mail, which shared the story of a woman with arthritis who said she “felt like I was losing my mind” after taking the drug for six months. Another woman told the tabloid she began seeing “dead people” within 30 minutes of her first dose.  

In a first-person account published in The Telegraph, Miranda Levy wrote about the severe withdrawal she experienced when she stopped taking pregabalin for depression.

“First came the pins and needles, closely followed by the sweating,” said Levy. “Add to this the progression of unremitting nausea, retching, diarrhea, jitteriness, dizziness so bad you can’t stand up and the feeling you’re about to die.”

Pregabalin – commonly known as the brand name Lyrica -- was never intended to treat anxiety, depression or arthritis. It was originally developed as an anticonvulsant that was first approved by the FDA in 2004 as a treatment for epilepsy. Since then it has been prescribed for dozens of painful conditions such as fibromyalgia and diabetic neuropathy, and is sometimes hailed as a “wonder drug” that is safer than opioids.

Pregabalin has helped some pain patients, but for many it’s also had severe side effects such as fatigue, insomnia and cognitive decline. Margaret Heath started taking pregabalin two years ago for Complex Regional Pain Syndrome (CRPS) and says it ruined her life.

"I've been on every type of morphine you can be put on... this is by far and away the worse drug to be on. It's worse than fentanyl. There is absolutely no comparison with the viciousness of the withdrawal of pregabalin," Heath told LBC News. "There would be days where I would not be able to do anything except lie there... it was debilitating."

Nearly nine million prescriptions for pregabalin were written in the US in 2021, the last year for which data is available. A similar number were written in England and Wales the following year, despite growing concerns in the UK that pregabalin is being misused to boost the euphoric effects of other drugs.

Pregabalin has become so popular with illicit drug users that it frequently appears in overdose toxicology reports. The number of fatal overdoses in the UK involving pregabalin has risen by nearly 11,000% since 2011, followed by a 3,275% increase in gabapentin-related drug deaths.    

UK Drugs With Biggest % Increase in Deaths (2011-2022)

DAILY MAIL GRAPHIC

Pregabalin and gabapentin (Neurontin) belong in a class of nerve medication known as gabapentinoids. Their mechanism of action – how they affect the brain and central nervous system – is still unclear two decades after their medical use was approved.

The UK drug statistics are mirrored in a recent analysis of drug tests in the US, which found gabapentin in over 13% of urine samples that tested positive for fentanyl. That’s about twice the number of drug tests in which prescription opioids were found.

Just because a drug is “involved” in an overdose or appears in a drug test doesn’t necessarily mean that drug caused the overdose or is a red flag for addiction. But experts say its long past time for doctors to be more careful about prescribing pregabalin, and to warn patients about potential side effects and the risk of withdrawal.

“How can there be rising deaths from pregabalin and a huge explosion of prescriptions, with all these troubles, and yet doctors are using this drug to treat anxiety?” asks Dr. Mark Horowitz, a clinical research fellow at the UK’s National Health Service.

“Doctors are selling cars without brakes,” Horowitz told The Sunday Times. “It boggles the mind when a drug is showing all these dangers to then use it on a wider variety of people.”

Prescription Opioids Play Only Minor Role in Overdose Crisis

By Pat Anson, PNN Editor

The role of prescription opioids in the nation’s overdose crisis continues to shrink.

In a new study from the drug testing firm Millennium Health, researchers say multiple substances were found last year in nearly 93% of urine samples in which fentanyl was detected. That is not altogether surprising, as “polysubstance” use increased as fentanyl came to dominate the illicit drug supply, appearing in more and more street drugs such as heroin, cocaine and methamphetamine.

What is surprising is the minimal role that prescription opioids now play. In 2013, opioid pain medication was the most common substance found in fentanyl-positive drug tests in the United States, appearing in over 70% of urine samples.  A decade later, prescription opioids were detected in less than one in ten samples — ranking far behind methamphetamine, cannabis, cocaine and heroin.

In fact, you are about twice as likely to find two other medications -- benzodiazepines (15.8%) and gabapentin (13.3%) -- than you are prescription opioids (7.6%) in urine samples testing positive for fentanyl.

Substances Detected in Fentanyl-Positive Drug Tests (2023)

MILLEnNIUM HEALTH

Millennium based its findings on over 4.1 million urine drug tests (UDTs) collected from 2013 to 2023 and analyzed through mass spectrometry. Because many of those samples came from people being treated for a substance use disorder, they offer a clear insight into drug trends that are driving the overdose crisis.

Now in its “fourth wave,” Millennium says a tidal shift has occurred in the so-called opioid epidemic, with illicit drug users far more likely to use non-opioid substances like stimulants than prescription opioids.

“National, regional, and state-level UDT data all suggest that people who use fentanyl are now, intentionally or unintentionally, much more likely to also use methamphetamine and cocaine,” the report found. “The results of our analyses also reveal shifting patterns of opioid use among those who use fentanyl. More specifically, they showed progressive declines in prescription opioid use from 2015 to 2023.”

The declining role of prescription opioids can be traced back to the 2016 CDC opioid guideline and a multiyear campaign by the DEA to slash opioid production quotas, which has reduced the supply of oxycodone and hydrocodone by about two-thirds. There is little evidence either of those federal efforts reduced the number of overdoses. The CDC estimates there were over 111,000 drug deaths in the 12-month period ending in September 2023 — nearly double the number of fatal overdoses in 2016.

The growing use of stimulants such as methamphetamine makes it difficult for public health campaigns to address the problem. Unlike opioids, there are no FDA-approved medications for stimulant use disorder, leaving behavioral therapies and abstinence as the only “evidence-based” treatments for people with a stimulant problem.

“Stimulants are a serious national challenge emphasizing the need for continued progress on the national plan to address methamphetamine supply, use, and consequences,” Millennium said.

Rx Opioid Misuse Rare in Children with Sickle Cell Disease

By Pat Anson, PNN Editor

Children with sickle cell disease show no signs of misusing or becoming addicted to opioids after being treated for an acute pain crisis, according to a new study.

Sickle cell disease is a genetic disorder that causes red blood cells to form in a crescent or sickle shape, which creates painful blockages in blood vessels – known as a vaso-occlusive crisis (VOC) -- that can lead to seizures, strokes and organ failure. About 100,000 Americans live with sickle cell disease, primarily people of African or Hispanic descent.

In a retrospective cohort study involving 725 children with sickle cell disease (SCD), researchers at Georgia State University found “no concerning patterns of long-term or increasing use of opioids” within 3 years of their first opioid prescription.

A VOC is a life-threatening condition that is the most common reason for an SCD patient to visit a hospital or emergency room. Guidelines for emergency VOC treatment call for opioids and other analgesics to be administered with one hour. However, due to the stigma associated with opioids and fears of addiction, many SCD patients face long delays before receiving treatment, as well as discrimination and suspicion that they are seeking opioids to get high.

The study findings, published in JAMA Pediatrics, found little evidence to justify those fears. In the 725 children who were studied – all under the age of nine – only one pattern of low opioid use was found.  Most of the children used opioids sparingly, with only one in four (25.4%) having an opioid prescription for codeine or hydrocodone filled for them within five days of being discharged from a hospital after a VOC.

Researchers say more studies are needed to determine whether the limited use of opioids shows the effectiveness of nonopioid pain management or highlights “an unintended and potentially harmful treatment access problem” caused by opioid phobia.

"Because of the opioid epidemic, it's important to make sure that people understand that when giving prescriptions for children with sickle cell disease, you aren't creating folks who are going to misuse opioids," lead author Angela Snyder, PhD, of the Georgia Health Policy Center at Georgia State University, told MedPage Today.

In 2020, a report by the National Academies of Sciences, Engineering, and Medicine called for major changes in the way sickle cell disease is treated in the United States, including an end to the discrimination and stigma that many sickle cell patients face.

DEA Urged to End ‘Red Flag’ Policy for Pharmacies

By Pat Anson, PNN Editor

A coalition of telehealth companies is urging the U.S. Drug Enforcement Administration to stop telling pharmacies to be careful about filling prescriptions for opioids and other controlled substances that originate from out-of-state.

The DEA’s “red flag” policy has had a chilling effect on doctors and patients nationwide, including those that use telehealth services. Many pain patients have found that pharmacies won’t fill opioid prescriptions written by doctors that are not near them geographically.  

In an open letter to the DEA, the American Telemedicine Association and a handful of telehealth providers said “clearer green lights” were needed from the DEA on how to safely dispense controlled substances, not more red flags.

“The DEA should provide explicit guidance to the pharmacy community that geography of a prescriber in relation to the patient or the pharmacy should not be a ‘red flag’ when a prescription is a result of a telehealth visit,” the letter states. “The distance of a telehealth prescriber from the patient alone should not give a pharmacist a signal that the prescription may be illegitimate.”

The DEA relaxed telehealth rules three years ago at the start of the Covid-19 pandemic, to allow for opioids, stimulants, sedatives and other controlled substances to be prescribed remotely via telehealth. Those temporary rules have been extended until the end of 2024, to give the DEA more time to develop permanent ones to govern telehealth.

Many pharmacies haven’t gotten the message. In a recent PNN survey, over 90% of pain patients with an opioid prescription said they had trouble getting a pharmacy to dispense their medication. Drug shortages are the primary cause, but so is the fear of some pharmacists that they could get in trouble or even lose their jobs if they filled a prescription deemed suspicious because it comes from out-of-state.

“In conversations with the pharmacy community and in our experience as prescribers, we have determined many pharmacies and pharmacists are currently considering geography as a ‘red flag.’ While red flags are not defined in statute or regulations or other official guidance, in the wake of the overprescribing and overdispensing contributing to the opioid epidemic, pharmacists have been directed to do so as a part of their corresponding responsibility, or due diligence to ensure that prescriptions are legitimate,” the letter from the telehealth coalition states.

‘An Unusual Distance’

Federal laws and regulations may not clearly define what a red flag is, but the onus is clearly put on pharmacies to catch them:

“[A] pharmacist or pharmacy may not dispense a prescription in the face of a red flag (i.e., a circumstance that does or should raise a reasonable suspicion as to the validity of a prescription) unless he or it takes steps to resolve the red flag and ensure that the prescription is valid.”

Under a 2022 opioid litigation settlement, drug distributors and big chain pharmacies agreed to tightly limit the supply of opioids and be on the lookout for suspicious orders. That includes patients with prescriptions for “highly diverted controlled substances” written by doctors from a zip code 50 miles or more from a pharmacy. Pharmacies with a high volume of those prescriptions risk having their drug supplies further restricted or cutoff.

DEA investigators and federal prosecutors have long targeted doctors and pharmacies that have out of state patients. In 2021, for example, DEA suspended the license of a Florida pharmacy that “repeatedly ignored obvious red flags of abuse or diversion,” including a high number of patients who traveled “an unusual distance” to obtain their prescriptions.

Contrary to popular belief, opioid diversion is rare. The DEA estimates that less than one percent of oxycodone (0.3%) and hydrocodone (0.42%) medications are lost, stolen or diverted.

Another example of a provider being red-flagged came in 2022, when DEA suspended the controlled substance license of Dr. David Bockoff, a California physician who treated many chronically ill patients from out of state who couldn’t find local providers.

Within days of Bockoff’s suspension, one of his patients and his wife died by suicide at their home in Georgia. A few weeks later, another patient died at her home in Arizona, apparently from complications caused by opioid withdrawal. Neither of those patients were using telehealth to see Dr. Bockoff, but their deaths highlight how red flags and heavy-handed oversight of medical providers can have serious consequences.    

“DEA must use this opportunity to make clear what their expectations are for pharmacists in filling telehealth prescriptions of controlled substances,” the letter from the telehealth coalition warns. “If DEA simply adds recordkeeping, reporting, or data requirements to the overwhelming workload pharmacies and pharmacists already face, access issues will only be exacerbated.”

Medical Marijuana Saved Me After Forced Opioid Tapering

By Christine Kucera

I can tell you outright that medical marijuana saved my life!  

I am an intractable pain patient who was harmed in 2019 when the chief medical officer at my well-known health institution decided to implement mandatory system-wide opioid policies for all doctors and patients, based on the CDC’s opioid guideline.

I am not opioid naive, don't have adverse reactions to opioids (other than some don't work on me), and I wasn't misusing or even at risk of overdose. But that didn't matter to the CMO. He forced my pain management provider to taper all his patients on opioids or risking losing his position.

I was subsequently tapered to 90 MME (morphine milligram equivalent), which was a third of the well-managed opioid regimen I was on for over 30 years.  Messed up, right?  

Medical marijuana/cannabis was the alternative of last resort for me. Unlike opioids, I'm extremely sensitive to marijuana, and need to be able to think and talk. As the taper continued, my ability to cope with unmanageable, agonizing pain went bye-bye. I couldn't sit, stand, lay down or sleep without the pain being unbearable. I was literally being tortured to death.  

I became severely ill, my health destabilized, and I was hospitalized numerous times. I became depressed and suicidal, reaching out to everyone for help as hopelessness set in. Thoughts about transitioning to death were my constant companion. 

I had a choice: fight with what's available or give in to despair. I refused to give up hope and decided to try medical marijuana. After discussing it with my provider, I applied for a Massachusetts medical marijuana license. Once approved, I immediately went to a dispensary and the experimentation began. 

Everyone will have different experiences with cannabis. Just like opioids, it depends how your body metabolizes it. I had more than a few negative experiences, but refused to give up. It took me 2 years of experimentation to figure out the right dose, strain (sativa, indica, hybrid) and preparation (flower, edibles, tinctures, topical).  

After a lot of trial-and-error, I found my goldilocks zone. It was micro dosing a 1:1 tincture (equal parts THC and CBD) and applying a 1:1 cream. That regime saved my life!  

Key to Success: Start Slowly 

Some important things I learned along the way:  

For naive patients using cannabis for the first time, I recommend starting with a couple drops of tincture (0.25ml to 0.5 ml under the tongue) every 6-8 hours. It can take upwards of 2 hours to feel the full effects. Do not consume additional tincture too soon or you will potentially experience a compounding effect, producing unwanted side effects.

Increasing the dose, amount and frequency should only be attempted once your body adjusts. Everyone has different titration periods, which can take days or weeks. Experimenting is the only way to figure out what will work for you personally.

I suggest going slowly, incrementally increasing the dose by 0.25ml (0.5ml, 0.75ml, 1ml and so forth) over days to weeks until you reach optimal effect. I personally use <0.25ml during the day and <0.5ml at night. During my experimentation period with the 1:1 tincture, I would try increasing every 3 days.

There are many types of tinctures. I do not recommend jumping straight to a full strain tincture, using indica or sativa, without building a tolerance first

The same goes for edibles. Cut them in half or even a third to start with. Remember it can take up to 2 hours for edibles to work, so don't take more or you may experience unwanted side effects. I could successfully microdose edibles 2-4 times daily, depending on need.  

Topicals are amazing and work! I prefer the ointment over creams and gels, but the costs can add up. You can make your own inexpensive topical by mixing a tincture with a favorite ointment or cream.  

For first time users, I don’t recommend smoking marijuana flower or buds until you've first built-up tolerance with a 1:1 tincture or edibles. Smoking has a much faster mode of action and it can be difficult to manage the unwanted side effects.  

If you're willing to experiment, I recommend smoking at night at home when you have no responsibilities. I found that was best. Start slowly with one very small hit, it doesn't take much. Wait approximately 15-20 minutes before deciding to inhale a second or third hit. The side effects can be bad if you smoke too much, especially if you haven't built up tolerance.  

Always research the side effects and talk with staff at the dispensary. They can help with selecting flower or edibles that have pain, sleep, and mood helping properties. 

If you live in a state where medical marijuana is legal, get a license or card to protect yourself from discrimination, pain management contracts, and urine drug tests. I informed my providers and gave them a copy of my license to put in my medical health records.  

Before you use marijuana, be sure to talk with your prescribing provider, as you don't want to unintentionally breach your pain contract. If you smoke at home, landlords may also be an obstacle. 

The war on drugs propaganda is only meant to illicit fear. Educate yourself about the benefits of marijuana. It's not a gateway drug. Utilized responsibly, with the right strain, dose and preparation, marijuana can help reduce pain, inflammation and anxiety. It is absolutely worth trying.   

Lastly, don't give up! 

Christine Kucera lives with psoriatic arthritis, spondyloarthropy, spondylitis, polyarthritis, sacroiliitis, degenerative joint disease, dermatomyositis, mixed connective tissue disease, spinal radiculopathy, hypoparathyroidism, rare endocrine tumors, psoriasis, endometriosis stage IV, pelvic adhesive disease, and other painful conditions.

Prior to becoming disabled, Christine was a healthcare research systems developer and analyst for federally funded CMS, AHRQ, and NIH grants and programs.

Drug Distributor Surrenders DEA License Over Opioid Sales

By Pat Anson, PNN Editor

The nation’s largest independent pharmaceutical distributor has agreed to pay a $19 million fine and surrender one of its DEA licenses to settle long-standing charges that it ignored suspicious orders of opioid pain medication.

Louisiana-based Morris & Dickson delivers drugs to health systems, hospitals and independent pharmacies in 27 states. In 2018, the DEA suspended the company’s licenses to distribute opioids and other controlled substances, but delayed making a final decision on revoking them until last year. Morris & Dickson vowed to fight the revocation, saying it was “unwarranted and unjustified” and would essentially put the company out of business.   

After nearly a year of talks with the DEA, the two sides reached a settlement. In addition to the $19 million fine, Morris & Dickson “admitted to all wrongdoing” and agreed to surrender one of its two DEA Certificates of Registration. The company also promised to continue a heightened compliance system to flag suspicious orders of controlled substances.

“Drug distributors like Morris & Dickson have a responsibility to protect the safety and health of customers and maintain effective controls against diversion of highly addictive controlled substances,” DEA spokesperson Katherine Pfaff said in a press release. “At the height of the opioid crisis, Morris & Dickson failed to uphold that responsibility, and turned a blind eye as thousands of unusually large orders for hydrocodone and oxycodone went out the door. Today, Morris & Dickson takes an important first step by admitting wrongdoing and paying for its misconduct.”

In a brief statement on its website, Morris & Dickson acknowledged no wrongdoing and gave no indication of how its business operations would be impacted by the loss of one of its DEA licenses.

“Today’s announcement recognizes our extensive and voluntary efforts to improve and enhance our compliance system over the past five years. In fact, following our efforts, our state-of-the-art compliance program has been repeatedly acknowledged as impressive and above reproach by outside parties,” the company said. “We are very proud that throughout discussions with the DEA, we have continued to provide the highest levels of service.”

The DEA delayed revoking Morris & Dickson’s registration until the Associated Press reported last year that the company was still shipping opioids, despite a judge’s recommendation that its licenses be revoked for “cavalier disregard” of suspicious orders.

Complicating the case is that a top DEA official who retired from the agency in 2017 went to work as a consultant for Morris & Dickson and led efforts to improve its compliance system. Louis Milione “unretired” in 2021 and went back to work at the federal agency as the top deputy to DEA Administrator Anne Milgram. Milione resigned soon after the AP story was published, citing “person reasons.” He is now consulting again for the pharmaceutical industry.   

In fiscal year 2023, DEA said it took 143 administrative actions against doctors, pharmacies, drug makers and drug distributors for violations of the Controlled Substances Act, which regulates the prescribing, dispensing and distribution of opioids and other potentially addictive drugs.

In 2022, the nation’s three largest drug distributors – McKesson, AmerisourceBergen and Cardinal Health — agreed to strict limits on the amount of opioids and other controlled substances they sell as part of a $21 billion opioid litigation settlement.

Collectively, these various actions have led to tight supplies of opioid pain medication. In a recent survey of nearly 3,000 pain patients by PNN, over 90% of those with an opioid prescription said they experienced delays or problems at a pharmacy getting their medication. Nearly 20% of patients were unable get their prescriptions filled.

NSAIDs Preferred for Acute Dental Pain

By Pat Anson, PNN Editor

Nonsteroidal anti-inflammatory drugs (NSAIDs) taken alone or in combination with acetaminophen are recommended as first-line treatments for managing short-term acute dental pain in adults and adolescents aged 12 and older, according to a new guideline developed by the American Dental Association (ADA).

Opioid analgesics should only be used when NSAIDs and acetaminophen are insufficient to reduce pain or when NSAIDs are contradicted, according to the ADA guideline, which also warns dentists to avoid “just-in-case” opioid prescribing.    

“Providing prescribing guidelines for acute dental pain management is an important step towards improving patient treatment and outcomes,” Marta Sokolowska, PhD, deputy center director for substance use and behavioral health at the FDA's Center for Drug Evaluation and Research, said in a press release. “We hope this clinical practice guideline will reduce the risk of opioid addiction, overdose and diversion.”

Opioids were once routinely prescribed to dental patients after a surgical tooth extraction or even a simple toothache. In 1998, dentists wrote 15.5% of all prescriptions for immediate release opioids in the United States. Many of those prescriptions are now considered high risk because the daily dose was over 50 MME (morphine milligram equivalents) or the amount prescribed exceeded a 3-day supply.

After reviewing 82 clinical trials involving tooth extractions, the ADA’s guideline panel found that NSAIDs were more effective than opioids in reducing post-operative pain.

“When managing acute dental pain, there are several reasons to consider alternatives to opioids. First, evidence suggests that opioids may not be the best approach to managing what is often inflammation-related acute dental pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) would target the source of the pain, whereas opioids would not,” the guideline cautions.

Only in “rare instances” when pain control is inadequate with NSAIDs does the guideline recommend low doses of oxycodone or hydrocodone, in combination with acetaminophen. Opioids can also be used when NSAIDs are contradicted due to health issues, such as a patient having cardiovascular problems or a bleeding ulcer.

“When opioids are prescribed, clinicians should obtain informed consent from the patient (or the parent or guardian in the case of minors) with detailed information about potential opioid undesirable effects. This is particularly critical in adolescents and young adults who are at increased risk of subsequent misuse and substance use disorder even after a single prescription,” the guideline says.

This is the second of two ADA guidelines on acute dental pain management. A previous set of recommendations for pediatric patients under the age of 12 was published in 2023. It also recommends NSAIDs and acetaminophen as preferred analgesics. Opioids such as codeine and tramadol are not recommended for children under any circumstances.

The risk of long-term opioid use after a tooth extraction is relatively rare. A 2018 study of over 70,000 teens and young adults who had their wisdom teeth removed found that only 1.3% were still being prescribed opioids months after their initial prescription by a dentist.

Canada Seeks Feedback on Proposed Opioid and Cannabis Guidelines

By Pat Anson, PNN ditor

Health officials and pain management experts in Canada are seeking public feedback on proposed changes to Canada’s 2017 opioid prescribing guideline. They’re doing it through an online survey, with responses accepted not only from Canadians, but from providers, patients, caregivers and policymakers in the United States and other countries.

“We are very happy to receive feedback from both Canadians and Americans,” says Jason Busse, DC, a clinical epidemiologist and professor of anesthesia at McMaster University. “We are still in the process of drafting the guidelines, as the feedback we receive will affect these documents.”

Busse is leading a panel at McMaster’s Michael G. DeGroote National Pain Centre that has developed 11 draft recommendations for a revised opioid guideline. Survey respondents are being asked whether they agree or disagree with the recommendations, which focus on whether opioids should be a first line treatment for people with chronic non-cancer pain.

Consistent with the current guideline, the panel believes there are several non-opioid treatments that are just as effective as opioids and have less risk of adverse events. It also strongly recommends that opioids not be given to people with a history of opioid overdose, substance abuse, or mental health problems. For pain sufferers without such a history, the panel recommends “discussing a trial” of opioids if nonopioid treatments haven’t lessened their pain.

If opioids are prescribed, the panel suggests avoiding daily doses higher than 80 morphine milligram equivalents (MME), and strongly recommends against doses higher than 150 MME.  The estimated risk of a fatal overdose at 80 MME is relatively low at 0.23% (2.3 overdoses for every 1,000 people) and at 150mg MME is 0.5% (5 in 1,000).

The 80/150 MME recommendations are a substantial change from Canada’s current guideline, which suggest that initial doses of opioids be less than 50 MME and that they not exceed 90 MME.

For people in pain who are stable on long-term opioid therapy, the panel recommends that clinicians “initiate a discussion” of tapering to a lower dose, potentially including discontinuation. If the patient refuses, the panel recommends that another “discussion” be repeated every 6 to 12 months. Forced or involuntary tapering is not recommended.

“The Guideline Panel has formulated their recommendations based on current evidence and the values and preferences of people living with chronic pain. We are seeking public feedback on the current wording of the recommendations and associated remarks. We will review all feedback received in order to further optimize the wording and clarity of the recommendations and remarks,” Busse said in an email to PNN.

To take the opioid survey, click here.

Medical Cannabis Survey

A second survey is also being conducted by the National Pain Centre to help formulate a Canadian guideline for treating chronic pain with medical cannabis. As with the first survey, this one is open to everyone, regardless of where they live.

There are currently four draft recommendations for cannabis. The panel recommends a “trial of cannabis” for chronic pain only if a patient has tried other therapies that haven’t worked. The panel says there is evidence of small improvements in pain, physical function and sleep when cannabis was used.

Smoking cannabis is not recommended. The panel suggests that patients start with low doses of cannabis taken orally in oils and soft gels or inhaled through a vaporizer. Doses can be increased, depending how a patient responds.

Another recommendation is that cannabis be used by patients as a substitute for opioids or to help taper them to lower doses. The panel says “there is little to no difference” in effectiveness between cannabis and opioids, but that cannabis has far less risk of adverse events.

To take the cannabis survey, click here.  

Both surveys will take about 20 minutes to complete and will remain open until 12pm ET, February 29, 2024.