Should Every Patient Be Screened for Cannabis Use Disorder?

By Pat Anson, PNN Editor

With the federal government on the verge of rescheduling cannabis as a less dangerous drug, and 38 states and the District of Columbia already allowing its medical and/or recreational use, it seems likely we’ll be hearing a lot more about cannabis use disorder.

A case in point is a large study, recently published in JAMA Network Open, that calls on primary care physicians to start screening all patients for cannabis use disorder (CUD).  It’s estimated that about 14.2 million Americans have CUD, a number that’s expected to grow as legal cannabis becomes more widely available.

The study found that 17% of primary care patients reported using cannabis in the last three months, usually to manage pain and other symptoms. Researchers say over a third of them (34.7%) used cannabis so frequently they were at moderate to high risk of CUD.

"Given the high rates of cannabis use, especially for symptom management, and the high levels of disordered use, it is essential that health care systems implement routine screening of primary care patients," wrote lead author Lillian Gelberg, MD, from the UCLA David Geffen School of Medicine.

“This group could benefit from a primary care clinician–based brief intervention to prevent those at moderate risk for cannabis use disorders from developing more serious CUD and to evaluate and refer high-risk users for possible addiction treatment.”

What is cannabis use disorder and how is it assessed? For the UCLA study, researchers used a screening tool known as ASSIST (Alcohol, Smoking and Substance Involvement Screening Test) that was originally developed by the World Health Organization and then modified to include cannabis.

Patients were asked if they’ve used cannabis in the last three months. If they said “yes,” five more questions were asked to assess why they use cannabis; how often they use it; if they’ve experienced tolerance or withdrawal; if they’ve tried unsuccessfully to reduce or stop using cannabis; and if it has interfered with any aspect of their lives.

Answer “yes” to one or two of those additional questions and a patient could then be diagnosed with CUD, even if they’ve used cannabis safely and responsibly for years. Their doctor could then select from dozens of diagnostic codes for CUD, ranging from cannabis dependence and intoxication to psychosis and hallucinations. All of the codes are billable for the doctor, so there is an incentive to use them.

Critics say this way of diagnosing people with CUD is fraught with problems, not unlike the way many pain patients have been diagnosed with opioid use disorder and forced into addiction treatment.

“This is my take too,” says Paul Armentano, Deputy Director of NORML, which advocates for full marijuana legalization. “Given that more than three-quarters of the (UCLA) cohort acknowledged consuming cannabis products ‘to manage symptoms,’ it’s hardly surprising that many if not all of these respondents would also report long-term regular use of the substance, as well as other criteria that overlap with signs of so-called cannabis use disorder.”

Armentano says several studies have documented declines in CUD, even after states legalized cannabis use.  

“To date, not a single legalization state has ever repealed or even rolled back their marijuana laws. This speaks to the reality that these regulations are working largely as intended and that the majority of those who consume cannabis do so in a responsible manner that poses little risk to either themselves or to others,” Armentano said in an email. 

In Washington State, one of the first states to legalize recreational cannabis, a recent study estimated that one in every five primary care patients had CUD, with 6.5% having moderate to severe CUD. Like the UCLA study, researchers said their findings underscore “the importance of assessing patient cannabis use in clinical settings.” 

“Knowledge of patient use provides an opportunity to discuss risks and limited benefits of cannabis use and potentially safer treatment alternatives for those using cannabis for medical reasons. For patients with higher risk cannabis use (eg, daily), psychometrically valid brief assessments for (diagnostic) symptoms of CUD can identify and gauge CUD severity,” they concluded. 

CUD Medications in the Pipeline

Treatments for CUD are currently limited to counseling and cognitive behavioral therapies such as meditation. Unlike opioid use disorder, there are no FDA-approved pharmaceutical treatments for CUD. That could soon be changing, as more drug companies recognize the potential value of CUD medication to their bottom lines.  

Indivior, the maker of Suboxone and Subutex for treatment of opioid use disorder, is conducting clinic trials on a synthetic drug -- called AEF0117 – that is designed to treat CUD by inhibiting a cannabinoid receptor in the brain that makes people feel “high.”

Indivior bought the worldwide rights to AEF0117 from a French pharmaceutical company for $100 million — which tells you how much value they think the drug could have. Indivior executives call AEF0117 “a unique opportunity to address a growing unmet public health need.”

“We have tested over a dozen potential treatment medications in our Cannabis Research Laboratory, and this is the first to decrease both the positive mood effects of cannabis and the decision to use cannabis by daily smokers,” said Margaret Haney, PhD, a professor of neurobiology at Columbia University who supervised the trials for Indivior.

According to ClincalTrials.gov, over a hundred clinical trials are currently underway or recruiting participants for a variety of potential CUD therapies. Most are treatments that already exist for other conditions and would be repurposed for CUD. One is gabapentin, a nerve drug currently used to treat seizures, shingles and pain. Other treatments being tested for CUD include transcranial magnetic stimulation, high blood pressure medication, and drugs used to help people stop smoking tobacco. 

Another anecdotal sign about the growing awareness of CUD can be found in the Federal Register, which has received over 17,000 comments so far about the Justice Department’s proposal to reclassify marijuana as a less restrictive Schedule III substance.

Nearly 700 of the comments mention CUD, with many containing boilerplate language claiming that “1 in 3 past year marijuana users met the clinical criteria for Cannabis Use Disorder.”

That theme is widely promoted by the addiction treatment industry, which maintains there is no clinical evidence “that the therapeutic benefits of medical cannabis or medical marijuana outweigh the health risks.”

There are currently no established medical guidelines or a “standard of care” that specifically address how to screen for CUD. But with cannabis use growing and healthcare providers coming under scrutiny for how they deal with substance abuse issues, future guidelines that require doctors to screen for CUD may be inevitable.

“How much longer will clients, families, social workers, and other mental health clinicians continue to be shortchanged by this situation? The time is well overdue to undertake formal cannabis use screening with well-established instruments during the mental health intake evaluation process, especially with adolescents and young adults,” wrote Jerrold Pollak, PhD, a clinical neuropsychologist, in Social Work Today.

One of the biggest hurdles for routine CUD screening may be patient reluctance to discuss their cannabis use. A survey of older U.S. adults found that less than 40% had discussed their cannabis use with a healthcare provider. Many fear being dropped by their doctor or being cut off from medication if they disclose that they’re using cannabis.

Lack of Testing Raises Risk of Bird Flu Pandemic

By Amy Maxmen and Arthur Allen, KFF Health News

Stanford University infectious disease doctor Abraar Karan has seen a lot of patients with runny noses, fevers, and irritated eyes lately. Such symptoms could signal allergies, covid, or a cold. This year, there’s another suspect, bird flu — but there’s no way for most doctors to know.

If the government doesn’t prepare to ramp up H5N1 bird flu testing, he and other researchers warn, the United States could be caught off guard again by a pandemic.

“We’re making the same mistakes today that we made with covid,” Deborah Birx, who served as former President Donald Trump’s coronavirus response coordinator, said June 4 on CNN.

To become a pandemic, the H5N1 bird flu virus would need to spread from person to person. The best way to keep tabs on that possibility is by testing people.

Scientifically speaking, many diagnostic laboratories could detect the virus. However, red tape, billing issues, and minimal investment are barriers to quickly ramping up widespread availability of testing. At the moment, the Food and Drug Administration has authorized only the Centers for Disease Control and Prevention’s bird flu test, which is used only for people who work closely with livestock.

State and federal authorities have detected bird flu in dairy cattle in 12 states. Three people who work on separate dairy farms tested positive, and it is presumed they caught the virus from cows. Yet researchers agree that number is an undercount given the CDC has tested only about 40 people for the disease.

“It’s important to know if this is contained on farms, but we have no information because we aren’t looking,” said Helen Chu, an infectious disease specialist at the University of Washington in Seattle who alerted the country to covid’s spread in 2020 by testing people more broadly.

Reports of untested sick farmworkers — as well as a maternity worker who had flu symptoms — in the areas with H5N1 outbreaks among cattle in Texas suggest the numbers are higher. And the mild symptoms of those who tested positive — a cough and eye inflammation, without a fever — are such that infected people might not bother seeking medical care and, therefore, wouldn’t be tested.

The CDC has asked farmworkers with flu symptoms to get tested, but researchers are concerned about a lack of outreach and incentives to encourage testing among people with limited job security and access to health care. Further, by testing only on dairy farms, the agency likely would miss evidence of wider spread.

“It’s hard to not compare this to covid, where early on we only tested people who had traveled,” said Benjamin Pinsky, medical director of the clinical virology laboratory at Stanford University. “That left us open to not immediately recognizing that it was transmitting among the community.”

In the early months of covid, the rollout of testing in the United States was catastrophically slow. Although the World Health Organization had validated a test and other groups had developed their own using basic molecular biology techniques, the CDC at first insisted on creating and relying on its own test. Adding to delays, the first version it shipped to state health labs didn’t work.

The FDA lagged, too. It didn’t authorize tests from diagnostic laboratories outside of the CDC until late February 2020.

On Feb. 27, 2020, Chu’s research lab detected covid in a teenager who didn’t meet the CDC’s narrow testing criteria. This case sounded an alarm that covid had spread below the radar. Scaling up to meet demand took time: Months passed before anyone who needed a covid test could get one.

Chu notes this isn’t 2020 — not by a long shot. Hospitals aren’t overflowing with bird flu patients. Also, the country has the tools to do much better this time around, she said, if there’s political will.

‘We Should Absolutely Get Prepared’

For starters, tests that detect the broad category of influenzas that H5N1 belongs to, called influenza A, are FDA-approved and ubiquitous. These are routinely run in the “flu season,” from November to February. An unusual number of positives from these garden-variety flu tests this spring and summer could alert researchers that something is awry.

Doctors, however, are unlikely to request influenza A tests for patients with respiratory symptoms outside of flu season, in part because health insurers may not cover them except in limited circumstances, said Alex Greninger, assistant director of the clinical virology laboratory at the University of Washington.

That’s a solvable problem, he added. At the peak of the covid pandemic, the government overcame billing issues by mandating that insurance companies cover tests, and set a lucrative price to make it worthwhile for manufacturers. “You ran into a testing booth on every other block in Manhattan because companies got $100 every time they stuck a swab in someone’s nose,” Greninger said.

Another obstacle is that the FDA has yet to allow companies to run their influenza A tests using eye swabs, although the CDC and public health labs are permitted to do so. Notably, the bird flu virus was detected only in an eye swab from one farmworker infected this year — and not in samples drawn from the nose or throat.

Overcoming such barriers is essential, Chu said, to ramp up influenza A testing in regions with livestock. “The biggest bang for the buck is making sure that these tests are routine at clinics that serve farmworker communities,” she said, and suggested pop-up testing at state fairs, too.

In the meantime, novel tests that detect the H5N1 virus, specifically, could be brought up to speed. The CDC’s current test isn’t very sensitive or simple to use, researchers said.

Stanford, the University of Washington, the Mayo Clinic, and other diagnostic laboratories that serve hospital systems have developed alternatives to detecting the virus circulating now. However, their reach is limited, and researchers stress a need to jump-start additional capacity for testing before a crisis is underway.

“How can we make sure that if this becomes a public health emergency we aren’t stuck in the early days of covid, where things couldn’t move quickly?” Pinsky said.

A recent rule that gives the FDA more oversight of lab-developed tests may bog down authorization. In a statement to KFF Health News, the FDA said that, for now, it may allow tests to proceed without a full approval process. The CDC did not respond to requests for comment.

But the American Clinical Laboratory Association has asked the FDA and the CDC for clarity on the new rule. “It’s slowing things down because it’s adding to the confusion about what is allowable,” said Susan Van Meter, president of the diagnostic laboratory trade group.

Labcorp, Quest Diagnostics, and other major testing companies are in the best position to manage a surge in testing demand because they can process hundreds per day, rather than dozens. But that would require adapting testing processes for their specialized equipment, a process that consumes time and money, said Matthew Binnicker, director of clinical virology at the Mayo Clinic.

“There’s only been a handful of H5N1 cases in humans the last few years,” he said, “so it’s hard for them to invest millions when we don’t know the future.”

The government could provide funding to underwrite its research, or commit to buying tests in bulk, much as Operation Warp Speed did to advance covid vaccine development.

“If we need to move to scale this, there would need to be an infusion of money,” said Kelly Wroblewski, director of infectious disease programs at the Association of Public Health Laboratories. Like an insurance policy, the upfront expense would be slight compared with the economic blow of another pandemic.

Other means of tracking the H5N1 virus are critical, too. Detecting antibodies against the bird flu in farmworkers would help reveal whether more people have been infected and recovered. And analyzing wastewater for the virus could indicate an uptick in infections in people, birds, or cattle.

As with all pandemic preparedness efforts, the difficulty lies in stressing the need to act before a crisis strikes, Greninger said.

“We should absolutely get prepared,” he said, “but until the government insures some of the risk here, it’s hard to make a move in that direction.”

KFF Health News is a national newsroom that produces in-depth journalism about health issues. 

Seniors Surprisingly Eager To Try Virtual Reality Therapy for Pain

By Pat Anson, PNN Editor

When it comes to using new technology or acquiring new skills, older people have a reputation for being a little slow on the uptake. A Baby Boomer nearing 70, for example, might not rush out to buy the latest iPhone, while someone from GenZ or a Millennial would.

A new study of virtual reality (VR) therapy is proving how misguided that assumption is. Older people can indeed learn new things and benefit from them.

In a secondary analysis of a placebo controlled clinical trial, people over 65 were significantly more likely to use RelieVRx, a virtual reality program that distracts patients with back pain by immersing them in a “virtual” environment where they can swim with dolphins, play games or enjoy beautiful scenery.   

A demographically diverse group of over 1,000 patients with chronic low back pain participated in the 8-week trial, with the goal of spending a few minutes at home each day watching a RelieVRx program.

By the end of the study, pain scores were reduced by an average of 2 points on a zero to 10 pain scale.

The positive results were across the board, regardless of a person’s age, sex, ethnicity, income or education.

What stood out to researchers is that seniors were significantly more likely to use the devices daily – 47 times on average – compared to those under age 65 (37.6 times)

APPLIEDVR IMAGE

“We had the opportunity to do a deeper dive, and really see how the results were unfolding in younger adults versus older adults, and really found very good engagement with older adults 65 or older,” says Beth Darnall, PhD, Chief Science Advisor for AppliedVR, which makes the RelieVRx headset and programming. 

“What's important about this study and also interesting is that it challenges a very common misperception about older adults. That older people are low tech, disinterested in engaging with newer innovations. We actually saw great engagement among the older adults, as well as a great reduction in symptoms. It suggests that older adults are much more receptive to this type of an approach and that it's also very effective in this population.” 

There are a few caveats to the findings. Many older people are retired and have more time on their hands to participate in a home-based study like this. And since all the patients were recruited online, they may have already been tech savvy enough to wear the VR headset and make it work for them.

RelieVRx is currently being used in hundreds of hospitals and in the Veterans Affairs (VA) system. Patients who’ve tried VR seem to like it, regardless of their backgrounds.

“The VA patients are generally pretty different than the rest of the civilian populations,” says Josh Sackman, president and co-founder of AppliedVR. “The usage is fairly consistent, even with a VA patient prescribed by a doctor who has no exposure to what VR is ahead of time.” 

VR therapy is a form of mindfulness or cognitive behavioral therapy. It doesn’t cure or relieve physical pain, but distracts patients long enough that their symptoms seem less severe. A 2022 study found that VR therapy has long-lasting benefits up to six months after treatment stopped.

The FDA has authorized the marketing of EaseVRx for chronic low back pain in adults, the first medical device of its kind to receive that designation. EaseVRx is only available by prescription and can’t be purchased directly by consumers.

In the coming months, AppliedVR hopes to expand coverage of the device through Medicare, Medicaid, and at least one large commercial insurer.

Research Suggests Chronic Pain Should be Treated Differently in Men and Women

By Pat Anson, PNN Editor

Why are women more likely than men to suffer from fibromyalgia, osteoarthritis, irritable bowel syndrome, and other chronic pain conditions?  

Various theories have been proposed over the years, such as gender bias in healthcare, the lingering effects of childhood trauma, and women “catastrophizing” about their pain more than men.

Now there’s a new theory, which could radically change how men and women are treated for pain.

In a groundbreaking study published in the journal BRAIN, researchers at University of Arizona Health Sciences identified two substances – prolactin and orexin B – that appear to make mice, monkeys and humans more sensitized to pain. Prolactin is a hormone that promotes breast development and lactation in females; while orexin B is a neurotransmitter that helps keep us awake and stimulates appetite.

Both males and females have prolactin and orexin, but females have much higher levels of prolaction and males have more orexin.  In addition to promoting lactation and wakefulness, both substances also appear to play a role in regulating nociceptors, specialized nerve cells near the spinal cord that produce pain when they are activated by a disease or injury.

“Until now, the assumption has been that the driving mechanisms that produce pain are the same in men and women,” says Frank Porreca, PhD, research director of the Comprehensive Center for Pain & Addiction at UA Health Sciences. “What we found is that the basic, underlying mechanisms that result in the perception of pain are different in male and female mice, in male and female nonhuman primates, and in male and female humans.”

Porreca and his colleagues made their discovery while researching the relationship between chronic pain and sleep.  Using tissue samples from male and female mice, rhesus monkeys and humans, they found that prolactin only sensitizes nociceptors in females, regardless of species, while orexin B only sensitizes the nociceptors of males.

The research team then tried blocking prolactin and orexin B signaling, and found that blocking prolactin reduced nociceptor activation only in female cells, while blocking orexin B only affected the nerve cells of males. In effect, they found that there are distinctive “male” and “female” nociceptors.  

“The nociceptor is actually different in men and women, different in male and female rodents, and different in male and female non human primates. That’s a remarkable concept, because what it's really telling us is that the things that promote nociceptive sensitization in a man or a woman could be totally different,” Porreca told PNN. “These are two mechanisms that we identified, but there are likely to be many, many more that have yet to be identified.”

Once such mechanism could be calcitonin gene-related peptides (CGRPs), a protein that binds to nerve receptors in the brain and trigger migraine pain. In a recent study, Porreca suggested that sexual differences may be the reason why migraine drugs that block CGRPs are effective in treating migraine pain in women, but are far less effective in men.  

Until these differences are more fully understood, Porreca says clinical trials should be designed to have an equal number of men and women. That way differences between the sexes could be more easily recognized and applied in clinical practice.

For example, therapies that block prolactin may be an effective way to treat fibromyalgia in women, while drugs that block orexin B might be a better way to treat certain pain conditions in men.

“We have an opportunity to develop therapies that could be more effective in treating pain in a man or in a woman than the generalized kinds of therapies that we use now,” said Porreca. ‘I think it's critically important that these pain syndromes really be taken very seriously. And that we find better ways of treating female pain and also male pain.” 

A Pained Life: Build a Better Mousetrap

By Carol Levy, PNN Columnist

I was watching an old TV series – “Diagnosis Murder” -- about a doctor who also solves mysteries. In one episode, Dr. Mark Sloan (Dick Van Dyke) was in a patient's room with her family. He told them their mother was in the early stages of Alzheimer's.

Her son asked, in a tremulous voice, “What can we do?”

Dr. Sloan smiles and said there was good news, along with the bad.

“It's a terrible disease, but on the positive side there are new drugs being developed all the time,” he said.

That got me mad. And it seemed as if every commercial I saw during and after the show was touting new medications, for everything from cancer to erectile dysfunction. Listening to them made me ever madder.

According to the National Cancer Institute, about 40% of us will be diagnosed with cancer at some point in our lives. Developing new cancer treatments, especially ones that are less harmful and painful to patients, is a necessity. After all, cancer kills.

Studies have found that erectile dysfunction affects about 18% of men. ED is a troublesome and embarrassing problem to have, but you won’t die from it.

Why do they spend so much time and money developing new drugs (and commercials) for medical conditions? Simple answer: the drugs make a lot of money for the pharmaceutical industry, even when a relatively small number of people may benefit from them.

Chronic pain may not kill in the typical sense, although many deaths can be traced back to poorly treated pain as an ancillary cause. According to a recent study, there are more new cases of chronic pain among U.S. adults than diabetes, depression and high blood pressure.

Given that the number of people with chronic pain is larger than many other conditions for which they are developing new drugs, why are we left out?

Many of us have had the experience of a doctor taking us off opioids or significantly reducing the dose, even when we’ve taken them safely and responsibly for years. The government has created fear among medical providers, especially those who specialize in pain management, making them uncomfortable prescribing opioids.

So, the question arises: Why isn't more being done to research and develop new non-opioid treatments for pain?

What comes to mind are mousetraps. Until they build a better mousetrap, until they create new and effective pain medications that are not opioid-based, we're stuck with what we have. Build a better mousetrap and the world will beat a path to a pharmaceutical company's door.

There is big money to be made in finding new pain medications. And there are plenty of mice. Why not build a better mousetrap?

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. 

New Drug Shows Promise in Treating Sjogren's Disease

By Pat Anson, PNN Editor

Sjogren's disease – also known as Sjogren's syndrome – is one of the most frustrating and painful autoimmune conditions. Often accompanied by rheumatoid arthritis, lupus and other immune system disorders, Sjogren's usually begins with dry eyes and a dry mouth, and then slowly progresses to a chronic illness that causes fatigue, muscle and joint pain, and organ damage.

Most frustrating of all is that there are few ways to stop Sjogren's progression and complications that can result in an early death. Eyes drops, anti-inflammatory drugs and pain medication only mask the symptoms temporarily.

“There are currently no disease-modifying therapies for Sjogren's, so current treatment is usually aimed at reducing symptoms," says E. William St. Clair, MD, a Professor in the Division of Rheumatology and Immunology at Duke University School of Medicine.

That could be changing, thanks to a new drug being developed by Amgen and an international research team. In a Phase 2 randomized clinical trial, 183 adult patients with moderate-to-severe Sjogren's received intravenous infusions of dazodalibep (DAZ), a drug that blocks the signals that drive the autoimmune reaction to Sjogren's.

The study findings, published this month in the journal Nature Medicine, show that patients who received DAZ therapy had a significant reduction in disease activity. They also had reduced symptoms of dryness, fatigue and pain.

"This is hopeful news for people with Sjögren's," says Clair, the study’s lead author. "DAZ is the first new drug under development for the treatment of Sjögren's to reduce both systemic disease activity and an unacceptable symptom burden.”

DAZ therapy was generally safe and well tolerated, with mild adverse events such as diarrhea, dizziness, respiratory tract infection, fatigue and hypertension.

Phase 2 studies are only meant to test a drug’s safety and efficacy. Amgen is currently recruiting about 1,000 patients with moderate-to-severe Sjögren's for two larger Phase 3 studies of DAZ therapy. Both are expected to take about two years to complete.  

Dazodalibep is also binge studied as a therapy for rheumatoid arthritis and glomerulosclerosis, a rare kidney disease. The drug was originally developed by Horizon Therapeutics, which Amgen purchased last year for $27.8 billion.

‘Misplaced and Dangerous’ Opioid Study Debunked by Critics

By Pat Anson, PNN Editor

Nearly a year after publishing a controversial study that questioned the effectiveness of opioid pain medication, The Lancet medical journal has published two rebuttal letters that challenge the study’s design and conclusions.

The blinded, placebo-controlled clinical trial – known as the OPAL study -- found that a 6-week course of low-dose oxycodone worked no better than a placebo in treating patients with recent mild-to-moderate back and neck pain. Based on that finding, Australian researchers recommended that opioids should not be used to treat acute back and neck pain, and that medical guidelines should be changed to reflect that view.

“Opioids should not be recommended for acute back and neck pain, full stop,” said lead investigator Christine Lin, PhD, a professor in the School of Public Health at University of Sydney.

“This recommendation is an extraordinary, misplaced, and dangerous conclusion, considering the authors studied the effects of only one type of slow-release opioid not indicated for acute pain and that guidelines should not be changed on the basis of a single randomized trial,” said Asaf Weisman, Dr. Youssef Masharawi and Dr. James Eubanks in their rebuttal letter. 

Weisman is a physiotherapist and spine researcher at Tel Aviv University, Masharawi is a professor of physical therapy at Tel Aviv University, and Eubanks is an assistant professor at the Medical University of South Carolina.    

“Relief of pain is one of the obligations of medical doctors. Despite the documented risks, which cannot be understated, opioids are indispensable for pain management, particularly in cases in which other forms of treatment are ineffective or inadequate,” they wrote. 

The second rebuttal letter noted that the OPAL study had an “extremely high” dropout rate and nearly a quarter of patients in the placebo group were taking opioids when the study began – two factors that confound and weaken the study’s findings. 

“We should be careful when drawing decisive conclusions based on this trial,” wrote Dr. Yu Toda, a palliative care specialist at Japan’s National Cancer Center Hospital. 

In reply to the letters, Lin and her co-authors defended the design of the OPAL study, but agreed the conclusions may have been too broad.

“We agree that we cannot generalize our results to all opioids. There are different opioid classes with different pharmacological profiles,” said Lin. “We agree that the OPAL results might not be generalizable to all patients with acute low back and neck pain, including those experiencing hyperacute pain requiring immediate pain relief in the emergency department.” 

Other critics found additional flaws in the OPAL study, pointing out that the daily dose of oxycodone was relatively low – ranging from 15 to 30 MME (morphine milligram equivalents) -- and that the oxycodone was combined with naloxone, a medication that blocks the effects of opioids. In clinical practice, a slow-release formulation of oxycodone is usually not prescribed for short-term pain and is never combined with naloxone,

Publishing rebuttal letters is a common practice for medical journals, but – until now -- The Lancet has not shared with its readers any counterpoints to the OPAL study

“The Lancet received submitted replies criticizing the OPAL Trial’s authors’ over-generalized conclusion within a month of the study’s online publication. Given evidence for patient harms from excessively rapid dose reductions or discontinuation of opioid therapy, waiting almost a year to publish these criticisms seems recklessly irresponsible,” said Dr. Chad Kollas, a palliative care physician and pain policy expert, whose rebuttal letter was rejected several months ago by The Lancet’s editors.

‘Many Patients Have Been Hurt’

The OPAL study received a fair amount of media attention when it came out and was even hailed as a “Landmark Trial” by some news outlets. But like many news stories dealing with opioids, they conveyed the simplistic message that all opioids are risky and ineffective, regardless of a patient’s condition, pain level or need.

“The Great Opioid Lie: Addictive painkillers do NOT reduce lower back or neck pain,” was the headline used by the Daily Mail. “Opioids might actually worsen pain in the long-run while increasing the odds of becoming addicted.”  

The OPAL study was even cited by U.S. Sens. Ed Markey (D-MA) and Joe Manchin (D-WV) in a letter to the FDA urging the agency not to conduct studies on the efficacy of opioids. Further studies are not needed, they claimed, and would only lead to the approval of new opioid medication.

“A recent randomized placebo-controlled study found that prolonged opioid use was ineffective for acute back and neck pain,” Sens. Markey and Manchin wrote. “For too long, drug manufacturers have been given the benefit of the doubt in developing and marketing a drug that unleashed a widespread, decades-long epidemic. Using a study model that risks continued bias in favor of approval is unacceptable.”

Weisman and his two colleagues say “opioid phobia” in the U.S. has led to pain patients around the world being denied appropriate treatment, causing unnecessary suffering.  

“Unfortunately, the opioid epidemic in the USA has led to many countries adopting strict umbrella policies and led to so-called opioid phobia among clinicians, and many patients worldwide have been hurt due to these processes,” they wrote.

I Was Kicked Out of a Support Group for Having Chronic Pain

By Ann Marie Gaudon, PNN Columnist

Recently, after the death of my mother, I registered to participate in a grief support group. The group met in the evening, which is good for able-bodied day workers, but a very poor time for me as far as chronic pain goes.

After working and the efforts of the day, my body is tired and worn down; which is a terrific setting for pain and other symptoms to come visit. I knew the group’s meeting time would be difficult, but was determined to do my best – and let me be very clear, I did just that.

The problem was, I proved to be all-too-human and they proved to be all too discriminatory.

By the 6-week mark, I had missed two meetings. Both times it was due to pain. I couldn’t get in or out of my car and was in no shape to stand for two hours. The furniture was too large for me to sit in with my back against the chair and my feet on the floor. No support is a no-go for my back, so I must stand in most places I attend. It’s nobody’s fault (well, maybe furniture makers) and I’ve adapted my life to it. Last time I checked, I was 157 cm tall (5’2”) and don’t have the height to sit properly in standard-sized chairs.

Anyone who knows me well knows that I have multiple pain conditions. It all started when I was 19 years old and much more has come my way as I age.

Anyhow, back to my sins of being human. The morning after I missed the second meeting, I received a telephone call to tell me that I had missed too much time and it would have a negative effect on the group’s bonding. I could not return. That was their policy.

At the time of the call, I had just gotten out of bed, my head was brain-fogged, and I wasn’t really registering the message. It took a little bit for my brain to kick-in and realize I had been kicked out! I was hurt and angry. but mostly I really wanted to advocate for everyone in pain. So I decided to send them an email.

“By telling me I was no longer welcome, you chose not only to dismiss my grief, but also to dismiss me because I am not an able-bodied person. These dismissals are not only unkind and quite the opposite of support, but also inflict moral injury to a person who is already suffering,” I wrote in my email.

I also said that I didn’t want or expect a reply. However, someone took the time to write back an extremely ignorant and dismissive email. I would gladly share it with you, but curiously the email ends with this legal disclaimer:

“This communication may contain confidential & privileged material for the sole use of the intended recipient. Any unauthorized review, use or distribution by others is strictly prohibited. If you have received this message by mistake, please advise the sender by reply email & delete the message. Thank you.”

I was so utterly shocked at being kicked out of a “support” group for having an invisible disability that I needed to speak with someone who knows about these things. Now I really needed support!

I was grateful for the opportunity to explain my experience with Kattlynne Grant, who is working on her second Masters and a PhD in Disability Studies at Brock University in Ontario. In addition to studying disability, Ms. Grant also lives with an invisible disability. I found her to be a great support for all of us:

“Just by the fact that someone responded to you when asked not to, it seems that they were more concerned about defending themselves and not hearing you as a person,” she told me. “By telling you that this happens to everyone who misses two sessions shows they really miss the mark of the implicit bias built into that policy – where it favours a certain type of embodiment over others because it assumes/expects a ‘normal’ level of function.  It is very exclusionary to those with disabilities, as it means that those who may struggle to keep with normative embodied expectations will not have access to their services.”

Someone within the support group organization took the time to shift the blame onto me and argue that I was in the wrong for not making them aware. Aware of what, my disability? What would they have done with that information? 

We all signed an agreement that we would do our best to attend all eight sessions. I did so wholeheartedly and meant it. I was never not committed to the group.

The facilitator said they realize that sometimes “life happens” and if we must miss a session, to just call ahead and let them know, which I did.  Nobody said two strikes and you’re out – not that it would have made it right. I’m only saying this because it was not even part of the conversation.

I was wholly offended to get a finger pointed back at me with passive aggressive statements such as “all we ask for is commitment” – which is all that I gave. I felt like I had been swept back to a time when disabled people were seen as a scourge on society, with no ethical or legal rights.

It was all very upsetting and offensive. I am upset to even have to share this with you, but it is what I need to do. I am being totally honest when I tell you that I was blind-sided when I was kicked out.

Ms. Grant had more to say about to these types of experiences.

“This move of shifting blame truly exposes how deeply that the ‘ideology of ability’ is ingrained within their practices,” she said. “The marginalized are often made responsible for their own adversity and exclusion, rather than acknowledging their role in this and the need for structural change.”

The Law Commission of Ontario describes ableism this way:

“A belief system, analogous to racism, sexism, or ageism, that sees persons with disabilities as being less worthy of respect and consideration, less able to contribute and participate, and of less inherent value than others. Ableism may be conscious or unconscious, and may be embedded in institutions, systems or the broader culture of a society.” 

Here is how the Ontario Human Rights Commission defines systemic discrimination:

“Systemic or institutional discrimination consists of attitudes, patterns of behaviour, policies or practices that are part of the social or administrative structures of an organization or sector, and that create or perpetuate a position of relative disadvantage for people with disabilities. The attitudes, behaviour, policies or practices appear neutral on the surface but nevertheless have an adverse effect or exclusionary impact on people with disabilities.”

Bringing awareness to the ways that we unintentionally reinforce systems of privilege and exclusion should be important to any organization, but especially for a support group. It would be a way to reduce the pain and grief of future members, not just add to them. 

Ann Marie Gaudon is a registered social worker and psychotherapist in the Waterloo region of Ontario, Canada with a specialty in chronic pain management.  She has been a chronic pain patient for over 30 years and works part-time as her health allows. For more information about Ann Marie's counseling services, visit her website.  

Illegal Online Pharmacies Still Advertise on Facebook

By Pat Anson, PNN Editor

At least two illegal online pharmacies are advertising on Facebook, offering to sell opioids and other controlled substances to people without a prescription and without visiting a doctor. The ads appear to be a direct violation of Facebook’s own policies and may be illegal.

“29 common medications, delivered fast and privately. No prescription required,” says one ad displaying an image of Adderall and Xanax tablets.

“Don’t leave your home, stay safe with us,” says another ad offering to sell Xanax. “Get our delivery services and we will have everything you need.”  

Of course, there’s nothing “safe” about the sale of medication – real or counterfeit -- by sketchy companies over the internet.

In addition to Adderall and Xanax, Canadian Online Pharmacy and BestPharm also offer home delivery of opioids, muscle relaxers, weight loss, anti-anxiety, and erectile dysfunction drugs – many of them brand name medications sold at inflated prices.  

I was surprised to see the ads in my Facebook feed. I’ve been covering pain management for over a decade and frequently interact with PNN readers over Facebook, so it’s likely the ads are using Facebook algorithms and user history to selectively target me and my readers – many of them chronically ill -- even though Facebook and its parent company Meta have strict policies about pharmaceutical advertising.

“Promoting prescription drugs is not allowed without prior written permission from Meta,” Facebook states on its website, directing advertisers to an online application form that requires they first be registered and certified by LegitScript. Facebook and other e-commerce platforms use LegitScript to make sure they’re doing business with reputable companies that can pay them for advertising.

However, unlike other internet companies, Facebook does not use LegitScript to proactively monitor and screen ads to make sure they don’t promote questionable products or engage in illicit activity.

If they did, they would quickly learn that LegitScript classifies Canadian Online Pharmacy as a “rogue” pharmacy that uses fraudulent or deceptive business practices.  

“LegitScript has reviewed this Internet pharmacy and determined that it does not meet LegitScript Internet pharmacy verification standards,” LegitScript states on a webpage that anyone can use to check the URLs of online pharmacies to see if they are legitimate.  

“Additionally, LegitScript has determined that this pharmacy website meets our definition of a Rogue Internet Pharmacy.”

BESTPHARM FACEBOOK AD

BestPharm isn’t even listed in LegitScript’s database, which means Facebook shouldn’t be running their ads, according to its own policies.

Facebook and Meta did not respond to requests from PNN for comment on this story.

“Facebook has a role to play in enforcing their advertising policy and, in this case, their policy is not meeting their own expectations,” says Libby Baney, senior advisor to the Alliance for Safe Online Pharmacies, a trade group that estimates there are 35,000 active online pharmacies worldwide, about 95% of them operating illegally or engaged in fraud.     

“A number of years ago, the social media platforms were admonished by the FDA to try to do more to prevent this type of advertising or content to consumers. And many, including Facebook, made commitments or pledges to government and public health officials to do more to screen their ads for this type of content,” Baney told PNN.

“I was quite surprised actually to see how blatant the advertisements were that you found and I don't have a real explanation for it, other than they’re falling through the cracks of the advertising policy standards that many of these companies, including Facebook, have in place.”

‘How Can This Be Legal?’

Fortunately, many Facebook users who saw the same ads I did questioned whether the pharmacies are legitimate. They showed their skepticism in the comment section of the ads.

“Xanax being promoted on Facebook? Profits must be low,” wrote one poster who saw an ad that featured a hand holding about 20 Xanax tablets.

“Wow, that’s enough to sedate an entire neighborhood. Way to make yourselves look legit, LOL!” said another poster.

“Your Prices are INSANE.......... cheaper to buy from the dude slinging drugs on the corner,” wrote another Facebook poster.

“How can this be legal?” asked another.

Remember, these ads are deliberately targeting people with chronic pain and other illnesses, who often have trouble getting their medications. There are currently record shortages of prescription drugs and many pharmacies are out of stock or rationing medications in short supply.

CANADIAN ONLINE PHARMACY FACEBOOK AD

In a recent PNN survey, 90% of patients with an opioid prescription said they had trouble getting it filled.

Desperate people do desperate things. We’ll never know many Facebook users clicked the button to “Learn more,” which takes them directly to the advertiser’s website where they can place an order for drugs.

“It could be a total scam, meaning your credit card and personal information are stolen. Or it could be a partial scam that could endanger your health, which is you get something dangerous laced with fentanyl,” says Baney. “You're putting your life in the hands of some anonymous advertiser on the internet.”

‘No Prescriptions Needed’ 

A close look at an online pharmacy’s website may provide a clue to their legitimacy. Canadian Online Pharmacy, for example, bills itself as an “international” pharmacy that ships medications around the world.

“Your Global Source for Quality Medicines! No prescriptions needed, no awkward doctor visits! Enjoy convenience, privacy, and savings on top-notch medications, all delivered to your doorstep,” the website claims.

Where is the Canadian Online Pharmacy based? The company lists an address in Wheeling, West Virginia that is shared with dozens of other online companies, selling everything from pillows and audio equipment to cameras and pizza. The telephone that’s listed has a Washington DC area code.

BestPharm doesn’t provide a physical address or telephone number, but does share the names and pictures of several people who supposedly run the company in its “About Us” section. Their names and images appear to be fictitious or stolen off the internet.

The picture for Chief Operating Officer Jessica Pearson, for example, is the same one used by over a dozen other women online, only their names are Emma, Emily and Ella.

Emma is particularly notable. Her Linkedin page claims she works for Google on special projects involving artificial intelligence, and that she’s a graduate of the Massachusetts Institute of Technology, where she studied “the toggled self-assembly of colloidal suspensions in binary systems.”

BESTPHARM

LINKEDIN

All of this might be funny, if it wasn’t for the fact that people are getting ripped off and risking their lives by buying drugs from fake pharmacies.

“I hear about these types of incidents or patient experiences from parents who've lost loved ones, who have purchased counterfeit products online after seeing ads that are clearly in violation of U.S. law,” Baney said.

According to The Wall Street Journal, Meta is under investigation by federal prosecutors for its role in the illicit sale of drugs online. A grand jury has been convened to look into whether the company’s social-media platforms are facilitating and profiting from illicit drug sales. No criminal charges have been filed.

“The sale of illicit drugs is against our policies and we work to find and remove this content from our services,” a spokesman for Meta said in a statement to the newspaper.

‘When Are You Going to Take Down These Posts?’

In 2018, Meta CEO Mark Zuckerberg was grilled during a congressional hearing about Facebook publishing posts and ads for illegal online pharmacies.

“Your platform is still being used to circumvent the law, and allow people to buy highly addictive drugs without a prescription,” said Rep. David McKinley (R-WV). “When are you going to take down these posts that are done with illegal, digital pharmacies?”

“Right now when people report the posts to us, we will take them down and have people review,” Zuckerberg replied. “I agree that this is a terrible issue, and respectfully, when there are tens of billion pieces of content that are shared every day, even 20,000 people reviewing it can’t look at everything.” 

Six years have passed and illegal online pharmacies are still advertising on Facebook. The company heavily relies on artificial intelligence (AI) to screen the millions of advertisements it runs every year.

But clever advertisers find ways to outsmart AI. There’s even a tutorial on YouTube to help cannabis companies get around Facebook restrictions on cannabis advertising. The key is to avoid using certain keywords like “THC” or getting “high,” which could get an ad rejected by AI. It’s better to use emojis, images and vague terms to get your point across.

“The goal is not to try to break the rules, but to see where you can bend the rules. Be a little bit creative,” says Aaron Nosbisch, CEO and Founder of Brez, a cannabis-infused drink.

“My ads are saying you’ll experience euphoria, feelings of relief, and be a great alternative to alcohol. Promote the ideas of what the products do for people (without mentioning) THC and CBD. People are looking to feel good. People are looking to have a good night and have a good time. Sell that.”

What can Facebook do to stop advertisers from exploiting cracks in its screening system?

“Enforce their own policy,” says Baney. “We look forward to Facebook addressing these issues that they've committed to in public forums with government officials.”

A Compound Found in Cannabis Could Make Opioids Safer

By Pat Anson, PNN Editor

What gives the cannabis sativa plant it’s pain-relieving properties?

Most people will tell you it’s cannabidiol (CBD) and/or tetrahydrocannabinol (THC), the two most well-known chemical compounds found in cannabis.  

But researchers at University of Arizona Health Sciences say terpenes -- aromatic compounds that give cannabis its distinctive “skunky” smell – have analgesic effects as well. In fact, in a new study published in the journal PAIN, they report that cannabis terpenes are just as effective as morphine in reducing neuropathic pain in laboratory animals.

“A question that we’ve been very interested in is could terpenes be used to manage chronic pain?” lead researcher John Streicher, PhD, a Pharmacology Professor at UA’s College of Medicine in Tucson, said in a press release. “What we found is that terpenes are really good at relieving a specific type of chronic pain with side effects that are low and manageable.”

Terpenes are found in all plants and are the main component of essential oils. Terpenes give lavender, sage and eucalyptus oils their distinctive smells, which are used to promote relaxation or even reduce pain and inflammation. In nature, terpenes help plants attract pollinators such as bees or to protect themselves from predators.

Most plants have only two dominant terpenes, but cannabis has up to 150 terpenes. Streicher and his colleagues tested five of the cannabis terpenes by injecting them into mice with chemotherapy-induced neuropathic pain.

They found that each of the five terpenes reduced nerve pain significantly, at levels similar to or even better than morphine. And when combined with morphine, the analgesic effects were enhanced even further.

Perhaps the most striking discovery is that the mice showed no signs of euphoria or “liking” terpenes – a sign that they may not have abuse potential.

“We looked at other aspects of the terpenes, such as: Does this cause reward? Is this going to be addictive? Is it going to make you feel awful?” Streicher said. “What we found was yes, terpenes do relieve pain, and they also have a pretty good side effect profile.”

In addition to injections, researchers also administered terpenes to the mice orally and through inhalation from a vaporizer. The results were the same. The mice had significant pain relief with no side effects or signs of addiction.

More research is needed, but some cannabis companies are already incorporating terpenes into their products. Lemon Kush, for example, is a marijuana strain that contains limonene, a terpene that smells like lemon, while the hybrid Blue Dream has a terpene that’s also found in blueberries.

“A lot of people vape or smoke terpenes as part of cannabis extracts that are available commercially in states where cannabis use is legal,” Streicher said “We were surprised to find that the inhalation route didn’t have an impact in this study, because there are a lot of at least anecdotal reports saying that you can get the effects of terpenes whether taken orally or inhaled.”

The next step for Streicher and his research team is to study whether terpenes can block the abuse potential of opioids, while at the same time enhancing their analgesic effects.

“This brings up the idea that you could have a combination therapy, an opioid with a high level of terpene, that could actually make the pain relief better while blocking the addiction potential of opioids,” Streicher said.

Animals Have Long Used Plants to Treat Pain and Heal Wounds

By Adrienne Mayor

When a wild orangutan in Sumatra recently suffered a facial wound, apparently after fighting with another male, he did something that caught the attention of the scientists observing him.

The animal chewed the leaves of a liana vine – a plant not normally eaten by apes. Over several days, the orangutan carefully applied the juice to its wound, then covered it with a paste of chewed-up liana. The wound healed with only a faint scar. The tropical plant he selected has antibacterial and antioxidant properties and is known to alleviate pain, fever, bleeding and inflammation.

The striking story was picked up by media worldwide. In interviews and in their research paper, the scientists stated that this is “the first systematically documented case of active wound treatment by a wild animal” with a biologically active plant. The discovery will “provide new insights into the origins of human wound care.”

To me, the behavior of the orangutan sounded familiar. As a historian of ancient science who investigates what Greeks and Romans knew about plants and animals, I was reminded of similar cases reported by Aristotle, Pliny the Elder, Aelian and other naturalists from antiquity.

A remarkable body of accounts from ancient to medieval times describes self-medication by many different animals. The animals used plants to treat illness, repel parasites, neutralize poisons and heal wounds.

The term zoopharmacognosy – “animal medicine knowledge” – was invented in 1987. But as the Roman natural historian Pliny pointed out 2,000 years ago, many animals have made medical discoveries useful for humans. Indeed, a large number of medicinal plants used in modern drugs were first discovered by Indigenous peoples and past cultures who observed animals employing plants and emulated them.

What We Learned by Watching Animals

Some of the earliest written examples of animal self-medication appear in Aristotle’s “History of Animals” from the fourth century BCE, such as the well-known habit of dogs to eat grass when ill, probably for purging and deworming.

Aristotle also noted that after hibernation, bears seek wild garlic as their first food. It is rich in vitamin C, iron and magnesium, healthful nutrients after a long winter’s nap. The Latin name reflects this folk belief: Allium ursinum translates to “bear lily,” and the common name in many other languages refers to bears.

Pliny explained how the use of dittany, also known as wild oregano, to treat arrow wounds arose from watching wounded stags grazing on the herb. Aristotle and Dioscorides credited wild goats with the discovery. Vergil, Cicero, Plutarch, Solinus, Celsus and Galen claimed that dittany has the ability to expel an arrowhead and close the wound. Among dittany’s many known phytochemical properties are antiseptic, anti-inflammatory and coagulating effects.

According to Pliny, deer also knew an antidote for toxic plants: wild artichokes. The leaves relieve nausea and stomach cramps and protect the liver. To cure themselves of spider bites, Pliny wrote, deer ate crabs washed up on the beach, and sick goats did the same. Notably, crab shells contain chitosan, which boosts the immune system.

When elephants accidentally swallowed chameleons hidden on green foliage, they ate olive leaves, a natural antibiotic to combat salmonella harbored by lizards. Pliny said ravens eat chameleons, but then ingest bay leaves to counter the lizards’ toxicity. Antibacterial bay leaves relieve diarrhea and gastrointestinal distress. Pliny noted that blackbirds, partridges, jays and pigeons also eat bay leaves for digestive problems.

Weasels were said to roll in the evergreen plant rue to counter wounds and snakebites. Fresh rue is toxic. Its medical value is unclear, but the dried plant is included in many traditional folk medicines. Swallows collect another toxic plant, celandine, to make a poultice for their chicks’ eyes. Snakes emerging from hibernation rub their eyes on fennel. Fennel bulbs contain compounds that promote tissue repair and immunity.

According to the naturalist Aelian, who lived in the third century BCE, the Egyptians traced much of their medical knowledge to the wisdom of animals. Aelian described elephants treating spear wounds with olive flowers and oil. He also mentioned storks, partridges and turtledoves crushing oregano leaves and applying the paste to wounds.

The study of animals’ remedies continued in the Middle Ages. An example from the 12th-century English compendium of animal lore, the Aberdeen Bestiary, tells of bears coating sores with mullein. Folk medicine prescribes this flowering plant to soothe pain and heal burns and wounds, thanks to its anti-inflammatory chemicals.

Ibn al-Durayhim’s 14th-century manuscript “The Usefulness of Animals” reported that swallows healed nestlings’ eyes with turmeric, another anti-inflammatory. He also noted that wild goats chew and apply sphagnum moss to wounds, just as the Sumatran orangutan did with liana. Sphagnum moss dressings neutralize bacteria and combat infection.

Nature’s Pharmacopoeia

Of course, these premodern observations were folk knowledge, not formal science. But the stories reveal long-term observation and imitation of diverse animal species self-doctoring with bioactive plants. Just as traditional Indigenous ethnobotany is leading to lifesaving drugs today, scientific testing of the ancient and medieval claims could lead to discoveries of new therapeutic plants.

Animal self-medication has become a rapidly growing scientific discipline. Observers report observations of animals, from birds and rats to porcupines and chimpanzees, deliberately employing an impressive repertoire of medicinal substances. One surprising observation is that finches and sparrows collect cigarette butts. The nicotine kills mites in bird nests. Some veterinarians even allow ailing dogs, horses and other domestic animals to choose their own prescriptions by sniffing various botanical compounds.

Mysteries remain. No one knows how animals sense which plants cure sickness, heal wounds, repel parasites or otherwise promote health. Are they intentionally responding to particular health crises? And how is their knowledge transmitted? What we do know is that we humans have been learning healing secrets by watching animals self-medicate for millennia.

Adrienne Mayor is a research scholar in the Classics Department and History and Philosophy of Science Program at Stanford University. She studies the history of "folk science" in ancient myths and oral traditions.

This article originally appeared in The Conversation and is republished with permission.

How Anesthesia Drugs Work in the Brain

By Dr. Adam Hines   

Over 350 million surgeries are performed globally each year. For most of us, it’s likely at some point in our lives we’ll have to undergo a procedure that needs general anaesthesia.

Even though it is one of the safest medical practices, we still don’t have a complete, thorough understanding of precisely how anaesthetic drugs work in the brain. In fact, it has largely remained a mystery since general anaesthesia was introduced into medicine over 180 years ago.

Our study published in The Journal of Neuroscience provides new clues on the intricacies of the process. General anaesthetic drugs seem to only affect specific parts of the brain responsible for keeping us alert and awake.

In a study using fruit flies, we found a potential way that allows anaesthetic drugs to interact with specific types of neurons (brain cells), and it’s all to do with proteins. Your brain has around 86 billion neurons and not all of them are the same – it’s these differences that allow general anaesthesia to be effective.

To be clear, we’re not completely in the dark on how anaesthetic drugs affect us. We know why general anaesthetics are able to make us lose consciousness so quickly, thanks to a landmark discovery made in 1994.

But to better understand the fine details, we first have to look to the minute differences between the cells in our brains. Broadly speaking, there are two main categories of neurons in the brain.

The first are what we call “excitatory” neurons, generally responsible for keeping us alert and awake. The second are “inhibitory” neurons – their job is to regulate and control the excitatory ones.

In our day-to-day lives, excitatory and inhibitory neurons are constantly working and balancing one another.

When we fall asleep, there are inhibitory neurons in the brain that “silence” the excitatory ones keeping us awake. This happens gradually over time, which is why you may feel progressively more tired through the day.

General anaesthetics speed up this process by directly silencing these excitatory neurons without any action from the inhibitory ones. This is why your anaesthetist will tell you that they’ll “put you to sleep” for the procedure: it’s essentially the same process.

A Different Kind of Sleep

While we know why anaesthetics put us to sleep, the question then becomes: “Why do we stay asleep during surgery?” If you went to bed tonight, fell asleep and somebody tried to do surgery on you, you’d wake up with quite a shock.

To date, there is no strong consensus in the field as to why general anaesthesia causes people to remain unconscious during surgery.

Over the last couple of decades, researchers have proposed several potential explanations, but they all seem to point to one root cause. Neurons stop talking to each other when exposed to general anaesthetics.

While the idea of “cells talking to each other” may sound a little strange, it’s a fundamental concept in neuroscience. Without this communication, our brains wouldn’t be able to function at all. And it allows the brain to know what’s happening throughout the body.

Our new study shows that general anaesthetics appear to stop excitatory neurons from communicating, but not inhibitory ones. This concept isn’t new, but we found some compelling evidence as to why only excitatory neurons are affected.

For neurons to communicate, proteins have to get involved. One of the jobs these proteins have is to get neurons to release molecules called neurotransmitters. These chemical messengers are what gets signals across from one neuron to another: dopamine, adrenaline and serotonin are all neurotransmitters, for example.

We found that general anaesthetics impair the ability of these proteins to release neurotransmitters, but only in excitatory neurons. To test this, we used Drosophila melanogaster fruit flies and super resolution microscopy to directly see what effects a general anaesthetic was having on these proteins at a molecular scale.

Part of what makes excitatory and inhibitory neurons different from each other is that they express different types of the same protein. This is kind of like having two cars of the same make and model, but one is green and has a sports package, while the other is just standard and red. They both do the same thing, but one’s just a little bit different.

Neurotransmitter release is a complex process involving lots of different proteins. If one piece of the puzzle isn’t exactly right, then general anaesthetics won’t be able to do their job.

As a next research step, we will need to figure out which piece of the puzzle is different, to understand why general anaesthetics only stop excitatory communication.

Ultimately, our results hint that the drugs used in general anaesthetics cause massive global inhibition in the brain. By silencing excitability in two ways, these drugs put us to sleep and keep it that way.

Adam Hines, PhD, is a Research Fellow at Queensland Brain Institute at The University of Queensland in Australia. His research focuses on combining neuroscience and artificial intelligence to develop “bio-inspired robotics.”

This article originally appeared in The Conversation and is republished with permission.

Cannabis Oil Provides ‘Modest’ Pain Relief

By Pat Anson, PNN Editor

Cannabis can be consumed in many different forms for pain relief. You can smoke or vape cannabis flowers, rub cannabis-infused lotions and ointments on your skin, or ingest edibles and beverages containing cannabidiol (CBD) and/or tetrahydrocannabinol (THC), the active ingredients in cannabis.

But it’s cannabis oil that is increasingly cited in research as providing the most benefit for pain sufferers.

The latest study was conducted in Israel, involving about 200 middle-aged adults with chronic pain who were treated by a specialist for at least one year without satisfactory pain relief before trying cannabis. Participants suffered from a variety of pain conditions, including nerve pain, joint pain and headaches. Their average pain level at the start of the study was 7.9 on a zero-to-10 pain scale.

For 6 months, participants ingested cannabis oil extracts daily in a variety of different THC and CBD concentrations, all prescribed by a physician, which were consumed sublingually under the tongue. The doses were considerably lower than what you’d get from smoking or vaping.

By the end of the study, the average pain level among participants had dropped from 7.9 to 6.6, equivalent to a 14% reduction in pain, with similar improvements in sleep, anxiety, depression, disability, and quality of life.

“All these effects are modest in size but are rather consistent and congruent with those found in additional cohorts. Hence, cannabis seems to have an impact on the ‘disease burden’ of chronic pain rather than being a potent analgesic per se,” lead author Dorit Pud, PhD, a Nursing Professor at the University of Haifa, reported in the journal Pain Reports.

‘Taken together, these observational cohorts suggest that in practice, much lower doses of oil extracts of cannabis are used compared with inflorescence (smoking or vaping). It therefore seems that oil extracts may be advantageous over inflorescence as they allow more precise dosing, lower THC dose consumption, and comparable analgesia.”

The number of patients consuming opioids decreased over the course of the study, but because the doses were low and only a minority were taking them, researchers were reluctant to draw conclusions about the opioid-sparing effects of cannabis.

The research team noted that about a quarter of the patients had a 30% or more reduction in pain, but they were unable to determine why these “responders” had better results than others. About half the participants had an adverse side effect from cannabis oil, such as dizziness or confusion, but those symptoms usually declined after the first month.

Previous studies have also found cannabis oil effective in treating pain. Researchers in Columbia say 92% of patients reported less pain after consuming a proprietary formulation of oil containing CBD and THC. Similar findings were reported in a recent study in Australia. Other studies have found cannabis oil effective in treating fibromyalgia and migraine.

Little Evidence That Antidepressants Work for Chronic Pain

By Drs. Hollie Birkinshaw and Tamar Pincus

About one in five people globally live with chronic pain, and it is a common reason for seeing a doctor, accounting for one in five GP appointments in the UK.

With growing caution around prescribing opioids – given their potential for addiction – many doctors are looking to prescribe other drugs, “off-label”, to treat long-term pain. A popular option is antidepressants.

In the UK, doctors can prescribe the following antidepressants for “chronic primary pain” (pain without a known underlying cause): amitriptyline, citalopram, duloxetine, fluoxetine, paroxetine and sertraline. Amitriptyline and duloxetine are also recommended for nerve pain, such as sciatica.

However, our review of studies investigating the effectiveness of antidepressants at treating chronic pain found that there is only evidence for one of these drugs: duloxetine.

We found 178 relevant studies with a total of 28,664 participants. It is the largest-ever review of antidepressants for chronic pain and the first to include all antidepressants for all types of chronic pain.

Forty-three of the studies (11,608 people) investigated duloxetine (Cymbalta). We found that it moderately reduces pain and improves mobility. It is the only antidepressant that we are certain has an effect. We also found that a 60mg dose of duloxetine was equally effective in providing pain relief as a 120mg dose.

In comparison, while 43 studies also investigated amitriptyline (Elavil), the total number of participants was only 3,372, indicating that most of these studies are very small and susceptible to biased results.

The number of studies and participants for the other antidepressants are:

• Citalopram (Celexa): five studies with 209 participants

• Fluoxetine (Prozac): 11 studies with 622 participants

• Paroxetine (Paxil): nine studies with 960 participants

• Sertraline (Zoloft): three studies with 210 participants.

The evidence for amitriptyline, citalopram, fluoxetine, paroxetine and sertraline was very poor, and no conclusions could be drawn about their ability to relieve pain.

This is particularly important as UK prescribing data shows 15,784,225 prescriptions of amitriptyline in the last year. It is reasonable to assume that a large proportion of these may be for pain relief because amitriptyline is no longer recommended for treating depression.

This suggests that millions of people may be taking an antidepressant to treat pain even though there is no evidence for its usefulness. In comparison, 3,973,129 duloxetine prescriptions were issued during the same period, for a mixture of depression and pain.

In light of our findings, which were published in May 2023, the UK’s National Institute for Health and Care Excellence (Nice) recently updated its advice to doctors on how to treat chronic pain.

The updated Nice guidance now suggests 60mg of duloxetine to treat [chronic primary pain] and the same drug and dose to treat nerve pain.

Limited Treatments Options

GPs often report frustration at the limited options available to them to treat patients experiencing chronic pain. Amitriptyline is cheap to prescribe – only 66p per pack (US 82.5 cents) – which may explain the high number of prescriptions for this drug.

This is an example of how the gap between evidence and clinical practice could harm patients. Although our review was unable to establish the long-term safety of antidepressant use, previous research has highlighted the high rates of side-effects for amitriptyline, including dizziness, nausea, headaches and constipation.

It’s important to bear in mind, though, that pain is a very individual experience, and the evidence in our review is based on groups of people. We acknowledge that certain drugs may work for people even when the research evidence is inconclusive or unavailable. If you have any concerns about your pain medication, you should discuss this with your doctor.

Hollie Birkinshaw, PhD, is a Research Fellow at University of Southampton. She specializes in research involving chronic musculoskeletal pain, and the integration of psychology in pain and health services. Birkinshaw receives funding from the UK’s National Institute for Health and Care Research (NIHR).

Tamar Pincus, PhD, is a Professor of Health Psychology at University of Southampton. Her research focuses on the psychological aspects of chronic pain. Pincus receives funding from NIHR, Medical Research Council and Versus Arthritis.  

This article originally appeared in The Conversation and is republished with permission.

Public Comments Sought on Marijuana Rescheduling

By Pat Anson, PNN Editor

The U.S. public is finally getting a chance to comment on the federal government’s historic decision to reclassify marijuana from a Schedule I substance with a “high potential for abuse” to a less restrictive Schedule III drug with “moderate to low potential for physical and psychological dependence.”

After months of foot dragging, the Justice Department published a notice in the Federal Register today giving the public 60 days to comment on the proposed rescheduling. Written comments must be submitted or postmarked on or before July 22. Online comments can be made here.

Every step in this process has been fraught with delays. And there may be more.

The Food and Drug Administration completed a review last August – nearly a year after it was requested by President Biden -- finding “credible scientific support” for marijuana’s rescheduling. But the FDA report was not made public until January, after a lawsuit was filed by two pro-cannabis lawyers seeking its release when the agency didn’t respond to requests under the Freedom of Information Act (FOIA).

Another four months passed before the Justice Department, which oversees the Drug Enforcement Administration, submitted to the Federal Register a notice about the proposed rescheduling. Since the DEA is charged with enforcing the Controlled Substances Act (CSA) and determines how drugs are scheduled, public notices involving the CSA are almost always signed by the DEA administrator.

This one, however, is signed by Attorney General Merrick Garland, not DEA Administrator Anne Milgram – a sign that her agency is not yet on board with marijuana’s rescheduling.

“DEA has not yet made a determination as to its views of the appropriate schedule for marijuana,” Garland wrote. “The CSA vests the Attorney General with the authority to schedule, reschedule, or decontrol drugs… The Attorney General has delegated that authority to the DEA Administrator, but also retains the authority to schedule drugs under the CSA in the first instance.”

According to an Associated Press report, Milgram told her staff in March that marijuana’s rescheduling “had been taken over” by Garland and the DOJ. The DEA wanted more time for studies to determine whether marijuana has an accepted medical use, a request that was rejected.

Former DEA Administrator Tim Shea believes the rescheduling process was hijacked by DOJ for political reasons.

“If she (Milgram) had supported it she would have signed it and sent it in,” Shea told the AP. “DEA was opposed to this and the politics entered and overruled them. It’s demoralizing. Everybody from the agents in the streets to the leadership in DEA knows the dangers this brings.”   

Asked recently during a congressional hearing what her views are on marijuana. Milgram ducked the question.

“Since DEA is ultimately the decider of scheduling and rescheduling, and the DEA administrator is in that role, it would be inappropriate for me to make comments about this process or parts of that process,” Milgram said.

‘Evidence Supports Marijuana for Pain’

Reclassifying marijuana as a Schedule III substance – in the same category as codeine and ketamine – may be historic, but it’s not the full “legalization” that many cannabis supporters have been calling for.  

Under the CSA, legal access to Schedule III substances requires a prescription from a licensed doctor that is filled at a licensed pharmacy. Any new medical marijuana products would also have to go through a lengthy and costly clinical trial process to assess their safety and effectiveness. Even if they pass that test, they would likely only be approved by FDA for certain conditions.  

Garland’s notice in the Federal Register is largely based on the FDA’s 2023 review, which states there is good evidence that marijuana is helpful in treating chronic pain and mixed evidence it could be useful in relieving nausea, anxiety, epilepsy and PTSD.

“FDA’s review of the available information identified mixed findings of effectiveness across indications, ranging from data showing inconclusive findings to considerable evidence in favor of effectiveness, depending on the source. The largest evidence base for effectiveness exists for marijuana use within the pain indication (in particular, neuropathic pain). Numerous systematic reviews concluded that there exists some level of evidence supporting the use of marijuana for chronic pain,” Garland wrote.

As for marijuana’s potential for abuse, Garland cited findings that marijuana poses less of a health risk than illicit drugs and even some legal medications such as oxycodone and benzodiazepines.

“The rank order of the comparators in terms of greatest adverse consequences typically ranked heroin, benzodiazepines, and cocaine first or in immediately subsequent positions, with marijuana in a lower place in the ranking,” Garland wrote.

“For overdose deaths, marijuana is always in the lowest ranking among comparator drugs. These evaluations demonstrate that there is consistency across databases, across substances, and over time. HHS thus concluded that although abuse of marijuana produces clear evidence of a risk to public health, that risk is relatively lower than that posed by most other comparator drugs.”

The opening of a public comment period does not mark the end of the rescheduling process. The DEA/DOJ will need time to review and evaluate thousands of comments, which will be followed by an administrative hearing and a final ruling that is subject to presidential review. Even then, the final rule has to be published in the Federal Register, followed by a 30 or 60-day wait period before the rule takes effect. 

During that process, and until a final rule is published, marijuana remains a schedule I controlled substance that is illegal under federal law. About three-quarters of states have already legalized marijuana for medical or recreational purposes.