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.”

Stopping Long-Term Use of Benzodiazepines Increases Risk of Death

By Pat Anson, PNN Editor

Abruptly stopping long-term treatment with benzodiazepines nearly doubles the risk of a patient dying within a year, according to a large new study.

Benzodiazepines such as Valium and Xanax have long been used to treat anxiety, insomnia and seizures, but their coprescribing with opioids is controversial because both drugs cause respiratory depression, increasing the risk of an overdose.

In 2016, the CDC warned doctors to avoid coprescribing opioids and benzodiazepines “whenever possible.” That same year, the FDA warned that taking the drugs concurrently has serious risks, including “profound sedation, respiratory depression, coma and death.”

Those warnings led many prescribers to abruptly take their patients off benzodiazepines, which many used safely for years. Some patients took opioids and benzodiazepines with a muscle relaxant, a combination known as the “Holy Trinity.”  

Researchers at the University of Michigan analyzed the insurance claims of over 350,000 adults prescribed benzodiazepines long-term from 2013 to 2019, expecting to find the FDA and CDC warnings validated. To their surprise, the risk of death from suicide, accidents and other causes rose for patients in the 12 months after benzodiazepines were discontinued.

“These results were unexpected,” researchers reported in JAMA Network Open. “Given the increased OD (overdose) risk and mortality associated with benzodiazepine prescribing, particularly when coprescribed with opioids, we anticipated that discontinuing benzodiazepine prescriptions would be associated with a lower mortality risk.

“However, for every outcome examined in this analysis, discontinuation was associated with some degree of increased risk — at odds with the assumption underlying ongoing policy efforts that reducing benzodiazepine prescribing to long-term users will decrease harms.”

Researchers found that patients on opioids who stopped taking benzodiazepines had a 6.3% risk of dying over the next year, compared to 3.9% of those who continued taking both drugs. Patients who were discontinued also had a slightly higher risk of a nonfatal overdose, suicidal thoughts, and emergency department visits.

Risk of Death for Opioid Patients Taken Off Benzodiazepines

JAMA NETWORK OPEN

"I think it is important to revisit the assumption that tapering stable long-term users should be the default and instead, perhaps, focus on those with clearly elevated risk of harms," lead author Donovan Maust, MD, a geriatric psychiatrist at UM Health, told MedPage Today.

Maust and his colleagues say patients discontinued from benzodiazepines could be suffering the effects of withdrawal or may be turning to other substances such as cannabis or alcohol. Given the risks involved, they urge prescribers to be “judicious” when prescribing benzodiazepines for the first time and to carefully limit their long-term use.

Opioid Therapy Is Controversial, But Why?

By Barby Ingle, PNN Columnist

There are many factors that contribute to the controversy surrounding opioids, which have been used for thousands of years for pain relief.

Mainstream media often say that opioid medication is harmful and increase the risk of addiction, overdose and death. Many media outlets do not distinguish between FDA approved medications and street drugs, or show the life-giving side of opioid medication.

That is the root cause of the controversy. If people don't understand or are misinformed, they go with what they hear -- right or wrong.

Let’s explore these issues and, hopefully, set the record straight.

Rx Opioid Side Effects

All medications have side effects, including opioids. At least 50% of patients in clinical trials experience a side effect from opioid therapy, such as nausea, vomiting, constipation, dizziness, dry mouth or sedation. These side effects vary and can decrease or increase with long-term use.

Most side effects of opioids improve shortly after therapy begins or following a dose increase. However, itching and constipation can persist throughout treatment. Most of the chronic pain patients I have met on my journey are okay with these side effects and wish to continue with treatment. For others, opioid therapy is discontinued when the side effects are too severe.

A variety of respiratory issues can be caused by opioids, including inadequate breathing, erratic breathing, and impairment of the upper airways. That can lead to respiratory depression, a precursor to an overdose. Patients in acute pain management who are new to opioids are most at risk of respiratory depression because they have not developed tolerance to opioids.

To be clear, an overdose from prescription opioids is relatively rare. A recent study found the risk of a fatal overdose at 90 morphine milligram equivalents (MME) – a fairly high daily dose – is only 0.26%. The risk is even lower at 50 MME – just 0.16%.

Opioids have more respiratory effects during sleep. Several fatalities have been reported in patients with obstructive sleep apnea, who may be contraindicated to opioid therapy. Patients with sleep apnea who take other central respiratory depressants, such as benzodiazepines, should be cautious about this. If opioids are prescribed to patients with sleep apnea, a nocturnal respiratory assessment will be needed.

Patients may absorb more opioids from transdermal opioid formulations if they have a fever or other illnesses. This is also true if they are exposed to heat, such as a sauna.

Is Pain Inevitable?

The Japanese author Haruki Murakami once wrote, "Pain is inevitable. Suffering is optional." Murakami was writing about running a marathon, but it’s an apt description for someone with chronic pain. Does their suffering have to be inevitable?

I didn't understand that concept as a collegiate coach or as an athlete until I developed chronic intractable pain and needed treatment. It is difficult to understand chronic pain or intractable pain if you haven't lived with them.

So that we are all on the same page, chronic pain is defined as pain lasting over three months. Intractable pain is complex and can last a lifetime, causing immense suffering. Acute pain is pain that lasts for less than three months.

Acute pain is usually caused by an injury, trauma or medical condition. Left untreated, acute pain can progress to the chronic stage, causing long-term disability, depression, and impaired quality of life. Therefore, it is essential to identify and treat pain as soon as possible, preferably in the acute stage.

Different approaches, including medication, physical therapy, and lifestyle changes, can be used to manage pain. Finding the right approach for each patient is crucial, as something that worked for one patient may not work for another. It is essential to consider all options before selecting the most appropriate treatment.  

Barby Ingle is a reality TV personality living with multiple rare and chronic diseases. She is a chronic pain educator, patient advocate, motivational speaker, and the founder and former President of the International Pain Foundation. You can follow Barby at www.barbyingle.com. 

Study Finds Low Risk of Overdose From Prescription Opioids

By Pat Anson, PNN Editor

A large new study that identifies the top risk factors for an overdose involving prescription opioids has inadvertently shown just how low the risk is in the first place.

In a systematic review published in the Canadian Medical Association Journal, researchers at McMaster University looked at 28 studies involving nearly 24 million patients in the United States, Canada and the United Kingdom who were prescribed opioids for chronic pain.

They found 10 “predictors” associated with a higher risk of a fatal or nonfatal overdose, such as a patient taking high doses, having a substance abuse problem, and having multiple prescribers or pharmacies.

Many of these risk predictors are already well-known. What’s different about this study is that the researchers calculated the odds of an overdose happening in different situations and doses. That’s where things get interesting:

“High-certainty evidence from 14 studies involving 1,315,173 patients showed a linear dose–response relationship with opioid overdose. The association was small at a 50-mg morphine equivalent dose/day (OR 1.69, 95% CI 1.50–1.90) and large at 90 mg (OR 2.57, 95% CI 2.08–3.18), with an absolute risk 2.6 per 1000 for fatal overdose and 5.1 per 1000 for nonfatal overdose at a 90-mg morphine equivalent dose/day.”

In plain English, the risk of a fatal overdose at 90 morphine milligram equivalents (MME) is not “large.” It’s only 0.26% at 90 MME, which is considered a fairly high dose. The risk of a fatal overdose is even lower at 50 MME – just 0.16% -- a level that researchers say is “small-to-trivial.”

I’m not a statistician, but 0.26% and 0.16% seem like pretty small odds – similar to the lifetime risk of dying in a car accident, fire or drowning. Unlike opioids, there is no talk of a ban on swimming pools, motor vehicles or matches.

“I think that most people living with chronic pain would agree with your interpretation,” says co-author Jason Busse, DC, a clinical epidemiologist and professor of anesthesia at McMaster University. “I do think, however, that a minority of patients will place greater value on the possibility of overdose and death even though the absolute risk is small.”

Busse’s involvement in the study is notable, because he was the lead investigator in Canada’s 2017 opioid guideline, which suggest that initial doses of opioids be kept under 50 MME and strongly recommend that they never exceed 90 MME. The CDC opioid guideline in the United States makes similar recommendations.

Given the small risk of an overdose actually happening at 50 or 90 MME, the new study would seem to debunk both guidelines. Busse sees it a bit differently, telling me by email that the overdose calculations will help patients understand the risks associated with prescription opioids.

“Our work in this area has suggested that most people living with chronic pain, who have not found sufficient relief with non-opioid therapy, would be interested in a trial of opioids. Specifically, when provided with the evidence for benefits and harms, including the risk of overdose, that most patients in whom non-opioid therapy has proven insufficient would elect to pursue a trial of opioid therapy,” Busse said.

“By presenting the evidence to patients, and helping them to understand the anticipated benefits and harms, we can help ensure that the decisions they make are the right ones for themselves.”

Unfortunately, pain patients in the U.S. and Canada don’t get to make decisions for themselves. Decisions are made for them by doctors, pharmacists, regulators, and law enforcement. Patients increasingly have trouble finding a provider willing to treat them or getting a prescription filled at a pharmacy.

And because the “voluntary” opioid guidelines are usually treated as mandatory,  patients who are prescribed opioids are often kept at ineffective low doses that are well below 90 or even 50 MME.

‘Opiods Kill and Opioids Are Bad’

Experts say the low risk of overdose from prescription opioids was established in previous studies, but people got caught up in opioid hysteria and ignored the evidence. The new study, they say, is no different.

“This paper examines well plowed ground and provides no new insight. Quite the contrary, it obfuscates through oversimplification of the problem,” says Stephen Nadeau, MD, a Professor of Neurology at the University of Florida College of Medicine. “The essential message is that opioids kill and opioids are bad.”

Nadeau says Busse and his co-authors ignored factors like genetic differences in opioid metabolism and put too much emphasis on the risk of a patient having multiple prescribers or pharmacies. The latter could simply be a sign that they were abandoned by a doctor or turned away by a pharmacy, not doctor shopping. Statistics mined from databases don’t tell you that.

“This paper takes a rigorous statistical approach to explain what is happening in a highly heterogeneous population in which there is a high probability of misconstruing the sources of variance. I think it would have been OK if published in 2015, but we have learned a thing or two since then and now the paper serves only to obfuscate and mislead,” said Nadeau.

Two findings in the study worth highlighting are that researchers found little risk of an overdose when a patient is co-prescribed opioids with benzodiazepines, sedatives or muscle relaxants – the so-called “Holy Trinity.” The overdose risk is also “small-to-trivial” when a patient is given long-acting opioids instead of short-acting ones. Those findings contradict the recommendations made in the U.S. and Canadian guidelines.

“The opioid crisis has generated interest in identifying patients at higher risk of addiction or overdose and has led to the development of several screening tools; however, these instruments have either not been validated or shown poor psychometric properties,” wrote lead author Li Wang, PhD, a researcher at McMaster University. “Our findings suggest that awareness of, and attention to, several patient and prescription characteristics, may help reduce the risk of opioid overdose among people living with chronic pain.”

One of the co-authors of the study is David Juurlink, MD, a member of Physicians for Responsible Opioid Prescribing (PROP), an anti-opioid activist group. Like several other PROP members, Juurlink disclosed that he has been a paid expert witness in legal cases involving opioids.

Previous studies have also found that the risk of overdose is small — 0.3% — in Medicaid and Medicare patients prescribed opioids for the first time. Another study of Medicare patients found that over 90% had little to no risk of overdosing. Low risk patients had only 0.006% chance of an overdose.

Army Veteran Is Latest Casualty of DEA’s War on Drugs

By Pat Anson, PNN Editor

Becky Snyder and her husband Vance were soldiers when they first met in 1979 at Fort Lewis, Washington. Becky was a legal clerk for the Army, while Vance was a combat medic who later became an Army-trained physician assistant and chief warrant officer. They soon married and had a son.

After years spent defending their country, Vance and Becky could not have imagined they’d windup becoming unintended casualties of the DEA’s failed War on Drugs. Vance lost the love of his life when Becky died last month at the age of 70, after a lifetime of suffering from chronic pain.

“She had scoliosis her whole life, probably congenital. And that made it hard for her to do sit ups in the in the military and probably injured her spine trying to do that,” said Vance. “She could walk with difficulty. Usually when we went out, we used a wheelchair.”

Becky’s back pain progressively worsened and she became bedridden after developing intractable pain from two very serious complications: Complex Regional Pain Syndrome (CRPS) and arachnoiditis, a chronic inflammation of spinal nerves.

Both conditions are incurable and cause severe pain, but Becky found relief under the care of two Los Angeles-area doctors, Forest Tennant and David Bockoff. 

BECKY SNYDER AND SON

The careers of both physicians effectively ended after their offices were raided by DEA agents, Dr. Tennant in 2017 and Dr. Bockoff in 2022. They were targeted by the DEA for giving patients like Becky with complex medical conditions high doses of opioid pain medication — which, in the eyes of the DEA, has no legitimate medical use.

There is no evidence that any of Tennant’s patients were harmed or overdosed while under his care, but he retired in 2018 rather than face a costly legal battle with the DEA and Department of Justice.

Becky and other Tennant patients became “opioid refugees,” scouring the country for doctors because no one was willing to treat them locally. Several eventually found their way to Bockoff, with some traveling thousands of miles from out-of-state to see him and get their prescriptions filled in California. That made Bockoff a target for the DEA.

Last November, the DEA suspended Bockoff’s license to prescribe opioids and other controlled substances, even though he practiced medicine for over 50 years in California with no record of any disciplinary action or complaints filed with the state medical board. The DEA claimed five of Bockoff’s patients were in “imminent danger,” but then waited a year to suspend him.  

Patient Deaths

While Bockoff appeals his suspension, at least three of his former patients have died, including one who committed suicide with his wife and another who died after buying opioid medication in Mexico. Becky Snyder is the most recent death.        

“The last six years have been very difficult, because we couldn’t get the amount of medicine that Dr. Tennant gave. Dr. Bockoff, I mean to his credit he did the best he could, but he couldn’t give the amount that Forest Tennant was willing to give,” said Vance.

“But if there hadn’t been Dr. Bockoff, I think she would have died even sooner.”

Becky didn’t die from withdrawal, but from pancreatic cancer. She was diagnosed earlier this summer after complaining of stomach pain, and the cancer quickly metastasized. Becky didn’t drink, and Vance is convinced that poorly treated pain contributed to her death.

BECKY SNYDER

“I was in Army medicine. Clinically and diagnostically, pain can be an important indicator of what’s wrong with a patient. You have to take the suffering seriously,” Vance told PNN. “I believe pain kills people all the time because it just wears the person out. It leads to all kinds of conditions, whether it’s endocrine, whether it’s cancer, whether it’s depression and suicide. There’s all kind of things that pain causes.”

“Cancer follows intractable pain like night follows day,” says Tennant, who believe Becky’s death was preventable. “Because if you can’t get the pain relieved, you disturb your hormonal systems and your immune system. I can’t tell you how common cancer is in these people who can’t get care. It’s just one of the complications.

“I’m sure if I was still in practice or Dr. Bockoff was, she’d still be alive.“

Vance Snyder says intractable pain took a toll on Becky’s physical and mental health, and she aged considerably in her final years. He believes high dose opioids is what kept her alive.

“For the worst, worst cases of intractable pain, opioids have to be part of the package. The idea that nerve blocks, epidurals, aromatherapy, cognitive behavioral therapy and all those things are going to make a big difference with the worst kind of pain is ridiculous,” he said.

Snyder has joined with several other Bockoff patients in a lawsuit asking the U.S. Court of Appeals to give them legal standing as interested parties in the Bockoff case. 

In an open letter, Snyder urged the court to find a “proper balance” between appropriate pain care and the needs of law enforcement.

“Severe intractable pain does not exist in isolation, but is connected to every other aspect of the patient’s overall health,” he wrote. “Becky is gone now, but there are many thousands of agonized patients who are desperate and on the verge of suicide. Please think about them when you make your decisions.”     

New VA Guideline: Opioids Should Not Be Used for Chronic Pain

By Pat Anson, PNN Editor

The U.S. Department of Defense (DoD) and Department of Veterans Affairs (VA) have doubled down on a guideline first released in 2017 that strongly recommends against the use of opioids for chronic pain.

In an updated clinical practice guideline, the agencies continue to recommend that opioids not be used to manage chronic non-cancer pain, especially in younger patients, and that long-acting opioids not be used to treat patients with short-term, acute pain.

The VA/DoD guideline will potentially affect millions of service members, veterans and their families. Nearly 1.5 million Americans serve in the armed forces and over 800,000 in the National Guard and Reserves. The Veterans Administration provides health services to another 6 million veterans and their families.

The updated guideline was quietly released in May 2022, but is only drawing attention now in a mostly favorable review published in the Annals of Internal Medicine.

“Compared with the 2017 recommendation against initiation of long-term opioid therapy, the updated recommendation against opioid therapy in general for chronic pain is broader and reflects the evidence that opioid therapy for any duration may be harmful,” wrote lead author James Sall, PhD, Director of VA’s Office of Evidence-Based Practice.

“Ultimately, despite finding some evidence for a small improvement in musculoskeletal and noncancer neuropathic pain, the guideline development group maintained that the potential for catastrophic harms of opioids and serious adverse events, especially with long-term use, outweighed any potential benefits of temporarily improved pain severity and functional status in patients with chronic pain.”

‘Potentially Transformative’ for U.S. Healthcare

The updated opioid guideline has 20 recommendations, nine of which are based on weak or inconclusive evidence. Unlike the recently revised CDC opioid guideline, there were no public hearings or opportunities for the public to comment or provide input. There is also no discussion of dose thresholds or morphine milligram equivalents (MME), suggesting the authors believe that any dose of opioids is potentially risky.

Three new recommendations in the new VA/DoD guideline involve opioid tapering, mental health evaluations, and the use of buprenorphine to treat pain.

The guideline urges doctors to consider using buprenorphine instead of full agonist opioids for patients needing opioids daily for chronic pain. Although the quality of the evidence for this recommendation was deemed “insufficient,” the VA/DoD believe buprenorphine as a partial agonist has less risk for overdose and misuse, and is less likely to cause euphoria.

Buprenorphine is a Schedule III opioid that is FDA approved for pain when used alone. Buprenorphine is also used to treat opioid use disorder when combined with naloxone in drugs like Suboxone. The DEA recently eliminated the “X-Waiver” program for buprenorphine, which is likely to significantly increase the number of doctors that prescribe it and the number of patients that receive it.

An editorial published in the Annals of Internal Medicine called the recommendation that buprenorphine be used for pain “potentially transformative” and "likely to expand into the greater U.S. healthcare system."

"The updated VA/DoD guideline is both conservative and radical," wrote co-authors Chinazo Cunningham, MD, and Joanna Starrels, MD, both from Albert Einstein College of Medicine. "Although the VA/DoD guideline recommends that buprenorphine be prescribed for chronic pain if daily opioids are prescribed, the recommendation itself is likely to change decision-making about whether opioids should be prescribed."

Although several recent studies have found that opioid tapering significantly raises the risk of an overdose, withdrawal or mental health crisis, the VA/DoD guideline found there is “insufficient evidence to recommend for or against any specific tapering strategies.” It only recommends that doctors and patients “collaborate” on reducing opioid doses and that tapering not be forced.

“The potential benefits of opioid tapering outweighed the potential harms of opioid withdrawal,” the guideline claims.

Before opioids are prescribed for either acute or chronic pain, the guideline recommends that the mental health of patients be evaluated for depression, anxiety, psychotic disorders and suicide. Although some patients may resent being screened for mental health problems, the guideline says “it is better for providers to know about underlying behavioral health comorbidities than to initiate long-term opioids without this clinical knowledge.”

The revised guideline reaffirms previous recommendations that benzodiazepines not be co-prescribed with opioids and that patients on long-term opioid therapy be regularly screened with urine drug tests “to decrease the risk of self-directed violence.”

Opioid prescribing to veterans, family members and those on active duty has declined significantly in recent years, as it has for the rest of the population. The revised VA/DoD guideline notes – without a hint of irony – that reduced prescribing has led to an increased use of illicit opioids by veterans and higher overdose rates.

Judge Won’t Stop DEA Despite Patient Deaths

By Pat Anson, PNN Editor

A federal judge in California has refused to grant a temporary restraining order that would have allowed Dr. David Bockoff to resume prescribing opioid medication to hundreds of pain patients at his practice in Beverly Hills. 

The Drug Enforcement Administration suspended Bockoff’s license to prescribe controlled substances on November 1, claiming five of his patients were in “imminent danger” because he prescribed high doses of opioids and kept inadequate medical records. Since the DEA’s suspension, however, at least two of Bockoff’s patients have died -- not because of his medical care, but from the lack of it.

Danny Elliott and his wife were so distraught over his inability to find another doctor and get opioid treatment that they both committed suicide on November 7.  Four weeks later, Jessica Fujimaki died at her home, apparently from complications caused by pain and opioid withdrawal. Both Elliott and Fujimaki had incurable conditions that cause severe pain and needed high dose opioids to have any quality of life.

Despite those deaths and the threat posed to other sick patients who can’t find new providers, Judge Stanley Blumenfeld, Jr. sided with the DEA, saying the “potential impact” on Bockoff’s patients was outweighed by the DEA’s concerns about his record keeping.

“The need for careful evaluation, monitoring, and control in these circumstances is obvious; and the combination of high dosages and the lack of documentation justifying those dosages and demonstrating proper evaluation and oversight is troubling,” Blumenfeld wrote in his 7-page ruling.

“As for the public interest, the Court is certainly concerned about the potential impact on vulnerable patients who need treatment to manage their pain. This concern, however, must be evaluated in the context of a case in which the DEA is asserting abusive prescription practices and its decision is entitled to deferential review.”

Bockoff has practiced medicine for over 50 years in California without any prior record of disciplinary action or complaints. The DEA provided no evidence that any of Bockoff’s patients – including the five said to be in “imminent danger” – were harmed while under his care.

One of the five – who is only identified in court records as “EC” – has lived with severe pancreatic pain for over 15 years. Bockoff gave her prescriptions for methadone and fentanyl, a potent synthetic opioid. In its emergency suspension order, the DEA said that use of fentanyl was “not consistent with FDA approved use,” and put EC at higher risk for addiction, overdose and death.

However, in an email provided to the judge, EC said she needed high doses of fentanyl to be able to work and eat food.

“I have exacerbated pain anytime I smell food, eat food, digest food, or sometimes just randomly,” EC wrote. “This pain medication allows me to practice law and serve as a prominent traumatic brain injury litigator and managing attorney for the largest personal injury law firm in California.

“I am able to rise to this level of practice because Dr. Bockoff counsels me on how to manage my pain and prescribes medication for me that allows me to manage my pain so I can be a contributing member of society.”

Judge Blumenfeld dismissed the email, essentially saying that EC’s medical records were more important than her ability to eat and work.

“While proper pain management can have significant benefits, E.C’s email does not fully address the allegations that she was prescribed controlled substances without proper medical evaluation, monitoring, and documentation,” the judge wrote.

‘More Deaths Could Be Imminent’

Several other patients – whose full names were redacted -- also provided testimonials about their care under Bockoff.

“I want to say I appreciate Dr. David Bockoff as the rarest of physicians that actually cares about my health and well-being,” MC wrote in a letter. “If I no longer could receive my pain medication from Dr. Bockoff I would not be able to walk, do house chores, continue part time consulting work, go to school, drive, not be able to get out of bed or walk even in the house.”

“I suffer from a great deal of pain and without medication my life would be awful. I would not be able to move, stand or do any of the activities that I do perform,” said SH. “Dr. Bockoff has helped me tremendously and I need his service in order to have some quality of life.”

“Dr. Bockoff’s practice is already filled with patients who are in a dangerous medical predicament, with no medicine. As more patients run out of their last month’s medication, more deaths could be imminent,” warned DL.

Judge Blumenfeld rejected those claims as well, saying Bockoff’s attorney, Ashli Summer McKeivier, provided no evidence that Bockoff’s medical practice faced “irreparable harm” from to his suspension or that the DEA erred in suspending his license.  

“Plaintiff has not responded by producing substantial evidence to refute claims that he has been improperly dispensing high dosages of the controlled substances at issue,” Blumenfeld wrote. “Nor has Plaintiff shown that there are no other available providers able to properly treat patients who can no longer receive a prescription from him.”

“I’m very disappointed in the judge’s ruling,” McKeivier told PNN.

Munzing Testimony

Much of the government’s case against Bockoff is dependent on the opinions of Dr. Timothy Munzing, a family practice physician who has created a lucrative second career for himself by working as a consultant for the DEA and DOJ. According to GovTribe, a website that tracks federal contracts, Munzing has made over $3.4 million in the last 8 years working for the government and testifying in dozens of cases against doctors.

“Dr. Munzing will testify that Dr. Bockoff’s patient care fell below the standard of care in California and the prescriptions resulting from several examinations were not for a legitimate medical purpose,” the DEA said in court documents. Munzing was not called to testify before Judge Blumenfeld.

McKeivier says the DEA failed to prove there was any “imminent danger” or harm done to Bockoff’s patients, even though Munzing reviewed three years of his medical records.

“The government made an argument that basically disproved itself,” she said. “If you’ve got 3 years of records and in those 3 years of records you cannot point to one example of death, overdose, bodily injury or diversion, then that disproves the fact that any of the danger based on those things is imminent. If for three years you have a track record of it never happening, then how can it be imminent to happen now?”  

Bockoff is pursuing another legal avenue by appealing his suspension to a DEA Administrative Law Judge, who will begin hearings in Washington DC on January 19. That hearing process is expected to take nine days. A final decision on the suspension could be weeks or months after that.

Gabapentin Won’t Cure the Opioid Crisis

By Pat Anson, PNN Editor

The risk of prescribing gabapentin (Neurontin) off-label for pain management may finally be sinking into the medical community. The latest sign is an op/ed published in JAMA Internal Medicine, which warns that gabapentin is often ineffective for pain, may raise the risk of overdose, and “will not cure the opioid crisis”    

Gabapentin is a non-opioid medication that was originally developed as an anticonvulsant to treat epileptic seizures. In recent years, gabapentin prescribing has grown 5-fold, with a growing number of physicians prescribing it “off-label” for both acute and chronic pain. Some do it as an alternative to opioids, while others prescribe it in conjunction with opioids.

“Gabapentin is often thought of as a safe alternative for pain management and may be initially enticing as a nonopioid medication, though the evidence for its efficacy in pain control is limited,” wrote lead author Raegan Durant, MD, a Professor at University of Alabama at Birmingham School of Medicine and Associate Editor at JAMA.

“With more restrictive opioid prescribing guidelines, physicians may be struggling to treat pain effectively and more frequently turning to gabapentin as a nonopioid option. However, avoidance of opioids at the expense of either more frequent use of gabapentin or concurrent gabapentin and opioids simply exposes patients to similar risks for harm often without improving the likelihood of actual pain relief.”

The warning from Durant and JAMA Associate Editor Audrey Han, MD, stems from a recent study about the “alarming upward trajectory” of gabapentin being co-prescribed with opioids.  From 2006 to 2018, overlapping prescriptions for the two medications rose by 344 percent, with many of the prescriptions being written by pain specialists.

Gabapentin is only approved by the Food and Drug Administration to treat partial seizures, nerve pain from shingles and restless leg syndrome, but is also widely prescribed off-label for fibromyalgia, neuropathy, migraine and other pain conditions – despite little evidence supporting its use.  

In addition to poor pain relief, many patients who take gabapentin report side effects such as dizziness, confusion, drowsiness, mood swings and weight gain. A 2019 study linked gabapentin to a growing number of attempted suicides.

Gabapentin may cause euphoria, feelings of intoxication, and enhance the effects of opioids and other drugs. The FDA has warned that gabapentin may cause serious breathing problems and respiratory depression, especially in older adults. A recent study found gabapentin raises the risk of delirium in seniors recovering from surgery.

Stopping Rx Opioid Therapy Raises Risk of Overdose

By Pat Anson, PNN Editor

Discontinuing opioid therapy for people with chronic pain raises the risk of a patient dying from an overdose, according to a new Canadian study that calls for better guidance for healthcare providers on the risks associated with abrupt tapering.

Researchers analyzed the medical histories of over 14,000 pain patients in British Columbia who were on long term opioid therapy from 2014 to 2018 – a period when physicians in Canada and the United States were being urged to restrict opioid prescriptions due to a worsening overdose crisis. The vast majority of patients studied were either tapered to a lower dose or their opioid treatment was discontinued, regardless of whether they showed signs of opioid use disorder (OUD).  

The study findings, published in PLOS Medicine, show that discontinuing opioid therapy for pain was associated with increased overdose risk. The association was even stronger for the small minority of patients diagnosed with OUD. In total, 530 people in the study (3.8%) experienced either a fatal or non-fatal overdose, with 120 of them dying.

“Our findings underscore the need for healthcare providers and policymakers to carefully consider potential unintended adverse effects of discontinuing opioid treatment for chronic pain when developing prescribing interventions and making practice decisions,” wrote lead author Mary Clare Kennedy, PhD, a Research Scientist with the BC Centre on Substance Use and a Research Fellow at the University of British Columbia.

“Given the harms of opioid treatment discontinuation identified in this and past studies, non-consensual and abrupt discontinuation of opioid treatment for pain is contraindicated in almost all instances.”

Kennedy and her colleagues were unable to determine what substances were involved in the overdoses, but they believe some patients who had their opioid therapy stopped may have resorted to illicit fentanyl and other street drugs to manage their pain, withdrawal and other symptoms. Over 73% of the overdose deaths that occurred in British Columbia during the study period involved fentanyl.

Previous studies have also found that opioid tapering raises the risk of an overdose and mental health crisis. A study published last year in JAMA found that tapered patients were 68% more likely to be treated for opioid withdrawal, drug overdose or alcohol intoxication, and they were twice as likely to experience depression, anxiety or a suicide attempt.

The FDA warned in 2019 that rapid tapering or abrupt discontinuation of opioids could result in serious harm to patients, including withdrawal, uncontrolled pain, psychological distress and suicide.

‘Reckless Mistreatment of Patients’

Despite this growing body of evidence, forced tapering and opioid discontinuation continues – some of it caused by the heavy-handed tactics of law enforcement. Over 200 pain patients were recently cut off from opioids after their California doctor had his DEA license suspended without warning. One patient and his wife died by suicide within a week of the DEA’s action.

“Not only are we collectively causing harm, we are failing to stop causing harm even when we agree that we're causing it, which is actually worse,” says Stefan Kertesz, MD, an associate professor at the University of Alabama at Birmingham, who is leading a study of pain patient suicides.

Kertesz says regulators, insurers, journalists and law enforcement have misinterpreted overdose studies to suggest that opioid prescribing, particularly at higher doses, was the root cause of the overdose crisis.  

“Many clinicians and policymakers engaged in aggressive extrapolation that went far beyond the data. Many journalists and legal plaintiffs described the prescriptions in a way that aggravated matters. They made dose into a fetish, a performance metric, and a threshold for law enforcement,” Kertesz told PNN. “Dose based quality metrics, payor standards and legal investigation thresholds incentivize reckless mistreatment of patients.

“My ultimate question is when will agencies like the National Committee for Quality Assurance, the Office of Inspector General, and law enforcement actually come to appreciate the evidence in play?”

It took six years, but the CDC recently revised its 2016 opioid guideline to include specific language warning of the dangers of tapering or discontinuing opioids.

“Clinicians should avoid abrupt discontinuation of opioids, especially for patients receiving high dosages of opioids, should avoid dismissing patients from care, and should ensure appropriate care for patients with pain and patients with complications from opioid use,” the revised guideline states.

Deaths of Intractable Pain Patients Often Mistaken as Overdoses

By Dr. Forest Tennant, PNN Columnist

Unexpected and sudden death commonly occur in persons who have poorly controlled pain caused by Intractable Pain Syndrome (IPS). Many persons with IPS who have died unexpectedly have been falsely accused of an “overdose” because drugs were found in their body fluids at autopsy. In reality, the cause was almost always cardiac arrest, hypoglycemia or adrenal failure.

Cardiac Arrest

Pain flares during cardiac arrest may cause the adrenal glands to pump out so much adrenalin that their blood pressure and pulse rate jump up dramatically. This causes blood vessels, including the coronary arteries and those in the brain, to constrict and shut off blood flow. The result may be a heart attack, stroke or arrhythmia.

Chronic, recurrent coronary constriction may cause heart pain called “angina.” A person with IPS who has their medications, usually opioids or benzodiazepines, reduced too rapidly is very prone to cardiac arrhythmia and cardiac arrest.

Hypoglycemia

Insulin is normally made and secreted by the pancreas to lower blood sugar in order to digest food and stabilize metabolism. In times of pain, cortisol and blood sugar are raised. When this occurs, insulin is pumped out by the pancreas to heal injured or damaged tissues. Too much insulin caused by a pain flare can force blood sugar to drop to such a low level – a condition known as hypoglycemia -- that death may occur.

The long-term effect of constant pain on the pancreas is an insulin deficiency, so high blood sugar levels (diabetes) are regularly found in persons with IPS.

Adrenal Failure

Uncontrolled constant pain may exhaust the adrenal glands to a point that the hormone cortisol drops too low, causing Addison’s disease or adrenal insufficiency. Symptoms such as darkened skin, abdominal pain and weakness usually appear slowly, but if there’s rapid onset of symptoms it could lead to adrenal failure and death.

Addison’s Disease is named after Dr. Thomas Addison, who described 11 cases of adrenal failure in 1855. About half his cases had histories of severe pain. Persons who die of adrenal failure often do so in their sleep.

Many persons with IPS have unexpectedly and suddenly died and have been falsely accused of drug overdose. To prevent sudden death, persons with IPS must be in a pain treatment program that is balanced and doesn’t rely just on just one or two medications.

Forest Tennant, MD, DrPH, is retired from clinical practice but continues his research on the treatment of intractable pain and arachnoiditis. This column is adapted from a bulletin recently issued by the Intractable Pain Syndrome Research and Education Project.

The Tennant Foundation gives financial support to Pain News Network and sponsors PNN’s Patient Resources section.   

California Medical Board Urged to End Bias Against Rx Opioids

By Pat Anson, PNN Editor

The Medical Board of California got an earful from doctors, patients and their advocates during a public hearing Thursday on proposed changes to the board’s guideline for prescribing opioids and other controlled substances. Most speakers praised changes to the guideline that give physicians more flexibility in prescribing higher doses of opioids, but said they don’t go far enough.

“It continues to reflect pervasive bias that we find just about everywhere against the use of opioid pain medication,” said Kristen Ogden of Families for Intractable Pain Relief, a patient advocacy group. “There seems to be an underlying assumption that opioids are bad. Risks vs. benefit is often mentioned, but potential benefits receive very little attention in the draft. It’s kind of like a form of subliminal messaging.”

The board’s draft proposal continues to maintain that opioids “should not be the first line of treatment” for patients with chronic non-cancer pain and recommends that physicians “use extra precautions” when increasing doses above 50 morphine milligram equivalents (MME). Urine drug tests and pill counts are also strongly recommended for patients on long-term opioid therapy. Forced or rapid tapering of patients is discouraged, and doctors are urged to give patients at least 30 days’ notice before discharging them.   

“Opioid prescribing has been a major hot button issue for several years,” said board member Richard Thorp, MD, former president of the California Medical Association. “Our concern primarily is patient safety, and part of that patient safety is being able to prescribe to those patients that critically need these medications (in) a safe and viable environment.”

Thorp headed a task force that reviewed the medical board’s policies, which like many others around the country are modeled after the CDC’s 2016 opioid guideline.

“Unfortunately, many agencies, health plans and other kinds of oversight agencies took the guidelines as very strict guidelines,” said Thorp. “As result, many people who were on larger doses of opioid medications for chronic conditions that were intractable were significantly disadvantaged. Maybe that’s an extreme understatement. Many of them were really harmed by rapid tapering off of medications. Many primary care physicians, in particular, on which this burden had fallen basically backed out of the arena in prescribing chronic narcotics.”

The CDC has acknowledged the harm its opioid guideline has caused, but has been slow in revising it. An updated guideline is not expected to be finalized until late this year, nearly seven years after the original guideline was released.

‘It Has Killed People’

The medical board heard from several patients and physicians who are critical of its past efforts to rein in opioid prescribing, such as the board’s controversial “Death Certificate Project,” which resulted in hundreds of letters threatening disciplinary action being sent to doctors who prescribed opioids to patients who later overdosed. A study found that overdose deaths doubled in California after the project was launched, with many of the deaths linked to street drugs, not prescription opioids.

“It has killed people. My son is one of those people,” said Rosie Arthur, who said her son was abruptly taken off opioids after 24 years and put on antidepressants, which led to his death. “I don’t want to see anybody else die needlessly.”

Doctors told the board its enforcement efforts have had a chilling effect on pain management across the state.

“Some of our physicians are under investigation for compliance with these guidelines, which are resulting in serious unintended consequences,” said Lee Snook, Jr., MD, a pain management specialist in Sacramento. “Our physicians specializing in pain management have stopped taking new referrals, leaving patients and their primary physicians without local accessible options for complex pain management. One of these physicians announced his retirement last week.”   

“We have found it impossible to find pain consultants. There is nobody to refer our pain patients to, particularly patients who are on public programs. There is nobody in our community who will manage chronic medical pain,” said Aaron Roland, MD, a family physician in Burlingame. “Unfortunately, one of our clinicians recently had to leave us, leave our practice, because she had to devote herself full time to defending herself in a case brought by the Medical Board of California for opiate prescribing.”

“In the minds of our primary care docs, they really don’t want to have anything to do with any level of pain management for fear they will lose their license and lose their job,” said Michael Conroy, MD, chief medical officer for a large primary care practice in Sacramento. Conroy pointed out the board’s draft guideline uses the word “should” 44 times and the word “must” seven times.

“Very few of these statements are backed by much in the way of hard science,” he said. “The use of this language can be viewed as signaling an intent to use these statements to discipline doctors who aren’t perfect. Nobody is ever going to be perfect in documenting or attending to 51 separate things on a simple visit with a chronic pain patient.”

Conroy urged the board to modify its draft guideline to indicate that most of its recommendations are based on opinion and should not be used for disciplinary purposes or viewed as hard requirements.

Opioid Tapering Raises Risk of Overdose and Mental Health Crisis

By Pat Anson, PNN Editor

Tapering patients to lower doses of opioid pain medication significantly raises the risk of opioid withdrawal, drug overdose and a mental health crisis such as depression, anxiety or suicide attempt, according to a large new study. For most patients, the risk remains elevated up to two years after their doses were reduced.

Opioid prescribing has fallen dramatically in the United States over the past decade, particularly after the release of the CDC’s controversial opioid guideline in 2016. Although millions of patients were affected, few efforts were made to study patient outcomes or what happens to those who have their opioid doses reduced or even stopped.

To address this knowledge gap, researchers at the University of California Davis School of Medicine analyzed health data for over 19,300 patients on long-term opioid therapy who had their doses reduced by at least 15 percent. In addition to medical and pharmacy claims, researchers looked at emergency room visits and hospital admissions for overdose, withdrawal or mental health crisis, both before and after tapering.

"We used an innovative observational study design to understand the patients' experience before and after opioid dose reduction. We compared outcome rates in pre- and post-taper periods with patients serving as their own controls," said co-author Daniel Tancredi, PhD, a pediatrics professor at UC Davis Health.

"While patients may struggle during the early tapering period, we reasoned that many may stabilize with longer-term follow-up and have lower rates of overdose and mental health crisis once a lower opioid dose is achieved," said lead author Joshua Fenton, MD, professor and vice chair of research at UC Davis School of Medicine.

But Fenton and his colleagues found patients continued to struggle long after their doses were cut. Their findings, published in JAMA Network Open, show a 57% increase in overdose or withdrawal incidents and a 52% increase in mental health crises 12 to 24 months after doses were lowered.

For every 100 patients during pre-tapering, there was an average of 3.5 overdose or withdrawal events and 3 mental health crises. After tapering, there were 5.4 overdose/withdrawal events and 4.4 mental health crises for every 100 patients. The risks associated with tapering were greatest in patients with the highest doses.

"Our findings suggest that, for most tapering patients, elevated risks of overdose and mental health crisis persist for up to two years after taper initiation," said Fenton. "We hope this work will inform a more cautious approach to decisions around opioid dose tapering."

An earlier study at UC Davis found that tapered patients were 68% more likely to be treated at a hospital for opioid withdrawal, overdose or alcohol intoxication, and were twice as likely to have a mental health crisis.

‘I Was Cut Off Cold Turkey’

The FDA warned in 2019 that rapid tapering or abrupt discontinuation was causing serious harm to patients. The CDC Director also pledged that year to evaluate the impact of the agency’s opioid guideline on patients and to “clarify its recommendations.”

Three years later, not a word of the CDC guideline has changed and the agency is slow walking efforts to revise it. A revised guideline draft, which cautions doctors to avoid rapid tapering or discontinuation, is not expected to be finalized until late this year. In the meantime, many doctors continue to taper patients – even those who’ve taken opioids safely and responsibly for years.

“Yesterday, I was cut off of one of my opioid medications, cold turkey. I've been given one last 30-day supply of the other, after 19 years of chronic pain treatment with opioid medication. I am bedridden,” a patient told us in a recent PNN survey on the impact of the 2016 guideline.

“Currently my pain management doctor is tapering everyone from schedule II (opioid) medications, even with years of good results and no side effects. This is dangerous when people are dealing with real pain,” said another patient.

“Before the guidelines, my pain was controlled with fentanyl patches and Vicodin for breakthrough pain. I was able to work, care for my home and family. That's all been taken away and now I spend my time either in bed or on my couch, in pain. Tapering down was 7 months of hell in my bedroom. It was cruel and unnecessary to take away medicine that allowed me to enjoy and participate in my life,” another patient wrote.

In an editorial also published in JAMA Network Open, two University of Alabama at Birmingham researchers who are studying the role of tapering in patient suicides urged doctors to be more cautious.

“Our view is that opioid dose reduction is likely to offer benefit for some, while harming others. The harms may include worsening pain, distress, or death,” wrote Stefan Kertesz, MD, and Allyson Varley, PhD. “Given this uncertain balance of harm and benefit, it would be wise for health systems to stop promoting this change to care. A policy of tapering all patients to doses lower than a specified threshold cannot be supported from available evidence.”

Kertesz and Varley are currently recruiting family and friends of patients who died by suicide to participate in a pilot study about the impact of opioid tapering on their loved ones. To participate in their study, click here to take an online survey or call 1-866-283-7223.

What Are the Long-Term Risks of Prescription Opioids?

By Roger Chriss, PNN Columnist

A standard critique of prescription opioids is the absence of good long-term data on safety and efficacy. Clinical trials are generally short-term and last only a few weeks, so questions about cumulative long-term risks, including addiction and overdose, remain unclear.

Clinical trials that run for a year or more are complex and costly. Attrition may be high and outcomes may be muddied by the inevitable effects of aging, disease progression, and life events. There are also ethical issues involved with subjecting patients to long-term trials where they may receive nothing more than a placebo.

In other words, launching new trials is often impractical. Fortunately, there are a few other ways to answer questions about long-term opioid risk.

Compare Outcomes

First, we can compare outcomes among patients whose key difference is opioid dosage. In a recent Canadian study, researchers looked at over 2 million individuals in Ontario given an opioid prescription between 2013 and 2016 for pain. They identified 1,121 patients who had a fatal or non-fatal overdose – a minuscule overdose rate of 0.0055 percent.

But when compared to patients getting relatively low daily doses of 20 morphine milligram equivalents (MME), those who received 200 MME or more had a “high hazard of overdose.”  

A dose of 200 MME may be an extreme example, since Canadian guidelines recommend that initial doses be limited to no more than 50 MME. But researchers said their study proves the value of guidelines. 

“Although the absolute risk of an opioid overdose within the first year of prescription opioid use is low, better alignment of opioid initiation practices with guidelines may reduce opioid-related harm,” they concluded. 

Compare Opioids 

Second, we can compare two opioids: oxycodone and hydrocodone. In a retrospective analysis of patients in Oregon between 2015 and 2017, researchers found that after an initial prescription in opioid-naive people, 0.3% experienced a fatal or non-fatal overdose and 2.8% refilled an opioid prescription at least six times, what the researchers considered “chronic opioid use.” 

Patients who received oxycodone were less likely to develop chronic use than those receiving hydrocodone, but the oxycodone patients had a slightly higher risk of overdose.  

Based on that finding, researchers concluded that “hydrocodone may be the favorable agent” when starting people on opioids. 

Compare Odds

We can also use statistical inference to estimate risks. In an analysis of 13,884 U.S. adults living with chronic pain between 1999 and 2004, epidemiologists found that 5% died from all causes within 3 years and 9% died within 5 years.  

Researchers found that chronic pain patients on opioids had a slightly higher risk of death – and calculated an odds ratio of 1.06 for them dying within three years and 1.03 at five years compared to those not taking opioids.  

It’s hard to infer much from a study like that, because researchers didn’t establish a causal relationship between opioids and death. Since chronic pain itself raises the risk of dying, the findings could simply mean that patients on opioids are sicker, in more pain, and closer to death.  

Despite this, researchers came to the sweeping conclusion that “chronic pain increased the risk of all-cause mortality through opioid prescriptions.” 

Compare Health Outcomes 

Last, we can look at health outcomes. An alarming, preliminary study from Taiwan evaluated chronic pain patients on long-term opioid therapy and found they have significantly higher risk for cancer compared to those not taking opioids. 

The overall hazard ratio for the opioid group was 2.66 – which means they have over twice the risk of having many different types of cancer. 

“Long-term opioid use might be a significant risk factor for breast, gastric, colorectal, ovarian, prostate, lung, pancreatic, head and neck, and esophageal cancers and HCC (hepatocellular carcinoma),” researchers concluded in their study, which has not yet been peer-reviewed. 

Risks of Other Drugs 

These findings help shed light on the long-term risks of prescription opioids, at least compared to healthy control subjects who do not take opioids. However, that is not the situation faced by most people with chronic illness, who are often on multiple medications to manage their pain and other symptoms.  

As a result, we need to know the risks of non-opioid pain management options. For instance, the consequences of cannabis addiction are low compared to opioids. But the cancer risk appears to be substantially higher. A major review in BMC Archives of Public Health found that “cannabinoids including THC and cannabidiol are important community carcinogens exceeding the effects of tobacco or alcohol.”

The risks of non-steroidal anti-inflammatory drugs (NSAIDs) are well-known. According to a 2011 review, “chronic NSAID use increases the risk of peptic ulcer disease, acute renal failure, and stroke/myocardial infarction. Moreover, chronic NSAID use can exacerbate a number of chronic diseases including heart failure and hypertension.” 

For other non-opioid medications, we lack long-term studies. For instance, a 2017 Cochrane review on gabapentin for chronic neuropathic pain notes that “study duration was typically four to 12 weeks.” Cochrane also notes that only short-term trials were conducted for serotonin and norepinephrine reuptake inhibitors like duloxetine for fibromyalgia.  

As for non-pharmacological options like spinal cord stimulators, the situation is similarly uncertain. A new Australian study in the Journal of Patient Safety found that for every 10 stimulators that were surgically implanted, four had to me removed for various reasons. That outcome went unnoticed in short-term studies and emphasizes the need for more careful patient selection and monitoring of outcomes.  

There are real risks to prescription opioids but it would be simplistic to dismiss them entirely. As pain physician Antje Barreveld notes in a recent STAT News op-ed: “Opioids do have a place in pain control and can be safely prescribed, even at high doses, by following best practices while monitoring for risks and side effects.” 

Understanding the long-term risks of prescription opioids will be important as the CDC finalizes its revised opioid guideline, and as regulators, insurers and clinicians decide how to act on them. But more generally, we need long-term studies of all pain management modalities so that we can better understand their risks.

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

Few Fatal Overdoses Found in Rx Opioid Study

By Pat Anson, PNN Editor

The odds of having an overdose are relatively small for most people after getting their first opioid prescription, but are significantly higher if patients are over age 75, insured by Medicaid or Medicare, and have a history of depression or substance use disorders, according to a large new study.

Researchers analyzed health claims for nearly 237,000 opioid “naïve” patients in Oregon from 2013 to 2018, and found that about 3 in 1,000 (0.3%) experienced an overdose within three years of their first prescription. The vast majority of the 667 reported overdoses were non-fatal, and researchers could not determine if they involved illicit opioids or the opioids that patients were prescribed.  

“There were relative few fatal overdoses - I believe it was less than 100. So we didn't look further than that because there wasn't statistical power,” said lead author Scott Weiner, MD, an emergency physician at Brigham and Women’s Hospital in Boston. “Unfortunately, it is not possible to ascertain if the overdose was from illicit or prescribed opioids from the data.”  

One of the more surprising aspects of the study is that there was little association found between overdoses and high dose prescriptions. The CDC says opioids prescribed at daily doses that exceed 90 MME (morphine milligram equivalent) raise the risk of overdose, but Weiner and his colleagues found little evidence to support that.  

“Incidence of overdose was not associated with varying levels of MME that were received in the first 6 months, which may indicate that patient factors may be more important than the strength of the opioids prescribed. These are both novel findings,” researchers reported in in JAMA Network Open.

The research team did find a higher risk of overdose when patients were prescribed long-acting opioids such as oxycodone, or used opioids concurrently with benzodiazepines, a class of anti-anxiety medication.  

Patients in the study who refilled an opioid prescription 6 or more times also had a higher overdose risk, as did those who got refills from three or more pharmacies. 

Patients with alcohol or substance use disorders had the highest risk of overdose, as did those with a history of depression or psychosis. 

Medicaid, Medicare and Elderly Patients at High Risk

Another high risk factor associated with overdose is insurance coverage. Patients covered by Medicaid had an overdose risk almost four times higher than those covered by a private insurer, while those insured by Medicare Advantage had an overdose risk nearly 8 times higher than commercially insured patients. 

The finding that patients over age 75 had an overdose risk nearly three times higher than other age groups is not surprising, according to one pain management expert.

“Obviously, this older age group has more comorbidities which is also associated with increased risk,” said Lynn Webster, MD, past president of the American Academy of Pain Medicine. “What we don’t know is why opioids were prescribed and if severity of pain or suicidality or denial to prescribe opioids for severe pain could be contributing factors for the higher risk of overdose with elderly patients.”

Weiner cautioned doctors against taking the findings too literally. For example, although African-Americans were found to have a higher risk of overdose compared to white patients, they make up only a small percentage of Oregon’s population, making the data for them statistically weak.

“I absolutely do not advocate for suboptimal pain control for any patient, regardless of their risk profile. However, I do want prescribers to be careful when prescribing opioids to any previously naive patient, and to be extra careful when prescribing to the higher risk groups,” Weiner told PNN in an email.

“For patients in the higher risk groups, particularly those with diagnosis of substance use disorders, I would counsel the patient and inform them of their elevated risk and come up with a game plan for safety. I am only unwilling to prescribe to anyone when I don't believe an opioid is indicated for their condition.”  

It’s Time to Talk About Fentanyls, Plural

By Roger Chriss, PNN Columnist

The U.S. overdose crisis saw over 100,000 deaths in the year ending May 2021, driven primarily by illicitly produced fentanyl. But fentanyl is both a specific drug and a class of drugs, a distinction that is not always appreciated or understood.

At a December 2 meeting of the House Energy and Commerce’s Subcommittee on Health, Rep. Anna Eshoo (D-CA) was puzzled by testimony calling for more research into fentanyl and its chemical cousins, known as analogues.

“I don’t quite understand the need to study fentanyl, we already know what it does. It is not clear to me. Everyone has stated how devastating fentanyl is,” said Eschoo. “What is it that we don’t know about this?”

In fact, a great deal is unknown about the fentanyls causing overdoses, including their potency and potential drug interactions. As the National Institute on Drug Abuse explains, there are 15 to 30 different fentanyl analogues, including acetylfentanil, carfentanil and furanofentanyl, each with its own potency.

Fentanyl itself was first synthesized in 1959 by Paul Janssen. It entered medical use in 1968 in the form of fentanyl citrate as a general anesthetic, and has since been used in chronic pain, palliative care and combat medicine.

The two other common pharmaceutical fentanyls are sufentanil and remifentanil. The former was first synthesized in 1974 and the latter was developed in the early 1990s. Sufentanil is the most potent prescription opioid currently available, and is the only one strong enough to displace buprenorphine and provide analgesia. Remifentanil, by contrast, has a faster onset and recovery time.

But these are not the fentanyls appearing in most drug deaths, which are known collectively as illicitly manufactured fentanyl (IMF) or clandestine fentanyl. Such drugs have a substantial chemical similarity to pharmaceutical fentanyls, going by names like 4-fluoroisobutyryl fentanyl, lofentanyl and valeryl fentanyl.

Each fentanyl has its own characteristics. For instance, a new study of 13 fatal overdoses in Michigan involving valeryl fentanyl found that blood samples from the same decedent tested both positive and negative for the drug. This indicates that valeryl fentanyl has unique pharmacokinetics, which could make it more difficult for medical examiners to detect in overdose cases.

Similarly, a recent study in Psychopharmacology on a fentanyl analog called cyclopropylfentanyl found that when the drug was given to rats it “displays much greater analgesic potency when compared to morphine, suggesting that cyclopropylfentanyl poses increased overdose risk for unsuspecting users.”

Fentanyl’s ‘Evil Cousin’

But in many cases, the lethal dose of an illicit fentanyl can only be guessed at. As Josh Bloom recently explained in the American Council on Science and Health, fentanyl’s “evil cousin” mefentanyl may be 35 times more potent than prescription fentanyl. Even worse, standard test strips for fentanyl are only modestly effective in detecting mefentanyl,

“It's a damn good thing that mefentanyl isn't one of the common fentanyls pouring into this country,” wrote Bloom. “Imagine if a much more potent analog of fentanyl (was) widely circulating in the US with no way to detect it preemptively. Nightmare.”

Further, how fentanyls combine with other drugs requires investigation. For instance, a recent report of a person smoking a drug mixture that combined a potent fentanyl analog with a psychostimulant suggests that drug traffickers are creating new designer drugs to reduce the risk of their customers dying from respiratory depression.

Some fentanyls are so potent and chemically complex that higher doses of the overdose reversing drug naloxone are needed. A new study in the International Journal of Pharmaceutics suggests that naloxone may have to be modified to work better against illicit fentanyls. The study authors are working on a derivative of naloxone named NX-90 that may have a better pharmacological profile.

So this is why the plural is essential. We need to know as much as possible about pharmaceutical fentanyl and its chemical cousins remifentanil and sufentanil in order to improve clinical care. And we need to know as much as possible about illicit fentanyls in order to detect them accurately and develop better overdose rescue drugs.

Last, we need to keep an eye out for new synthetic opioids like protonitazene and isotonitazene, which are emerging regularly and are even more potent than fentanyl.

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