More Lackluster Results for Non-Opioid Pain Reliever

By Pat Anson

New questions are being raised about the effectiveness of an experimental analgesic and whether it can be a viable alternative to opioid pain medication.

Results from Vertex Pharmaceuticals’ Phase 2 clinical trial show that suzetrigine is essentially no more effective than a placebo in relieving back and hip pain caused by lumbosacral radiculopathy (LSR).

After 12 weeks of treatment with suzetrigine, patients with LSR had a 2.02 average reduction in their pain scores on a rating scale of zero to 10. That compares to an average reduction of 1.98 for patients who received a placebo or sham treatment.

Although the difference between 2.02 and 1.98 is statistically meaningless, Vertex claimed the overall findings were “statistically significant and clinically meaningful” in a press release. The company blamed the lackluster results on the placebo effect and the difficulty of treating lumbosacral radiculopathy.

“Suzetrigine has again demonstrated its potential to fill an important unmet need in the treatment of pain,” said Carmen Bozic, MD, Executive Vice President and Chief Medical Officer at Vertex. “We did not see separation between the suzetrigine and the placebo arms. Yet our post-hoc analyses suggest that this could be due to the high placebo response in this study.”

Despite the disappointing results, Vertex still plans to go ahead with a Phase 3 study of suzetrigine for LSR, while changing the study design to minimize the impact of the placebo.

“Managing the placebo response in pain trials is a complex challenge. We look forward to innovating in clinical trial design, including for the pivotal study, with the aim of bringing a potentially safe and effective treatment to patients suffering from LSR," said Christine Sang, MD, co-chair of Vertex’s Peripheral Neuropathic Pain steering committee and principal investigator of the study.

Suzetrigine is already under consideration by the FDA as a treatment for acute pain, with a decision expected in late January. If approved, suzetrigine would be the first new medication for acute pain in over two decades.

Unlike opioids, suzetrigine blocks pain signals in the peripheral nervous system before they reach the brain. That means it won’t have the “liking” effect that opioids can have in some patients or be as addictive.

Although suzetrigine has been touted as a novel painkiller that "could bring relief to millions” without the risk of addiction, findings from earlier studies have also been mixed. In a Phase 3 trial of patients recovering from minimally invasive surgery, suzetrigine was no more effective than a low dose combination of hydrocodone and acetaminophen, more commonly known as Vicodin.

Although Vertex downplayed the results from the Phase 2 study, shares of the company lost about 15% of their value after last week’s announcement. Wall Street analysts said the Phase 2 findings were “very messy” and "raise considerable risk around suzetrigine's potential.”

Ultimately, it will be up to the FDA to decide whether suzetrigine should be allowed on the market. The agency is under pressure to approve new non-opioid analgesics, so it may look past the disappointing clinical trial findings. If approval is granted in January, it will coincide with implementation of the NOPAIN Act, which will make non-opioid analgesics in outpatient surgical settings eligible for higher Medicare reimbursement rates.  

In addition to acute pain and lumbosacral radiculopathy, Vertex is also studying suzetrigine as a treatment for diabetic peripheral neuropathy.

Survey Finds Patients and Doctors Unsatisfied with Treatments for Acute Pain

By Pat Anson

Nine out of ten (89%) patients who recently had short-term acute pain say it caused a major disruption in their lives, limiting their ability to sleep, exercise and enjoy leisure activity, according to a new survey. Many patients also expressed dissatisfaction with the pain medication they received and want to try a new one if their pain returns.

The survey was conducted by Vertex Pharmaceuticals, which is awaiting FDA approval of suzetrigine, its experimental non-opioid medication for acute pain. Vertex surveyed 1,001 adults and 547 doctors who were treated for or who treated acute pain. The company also commissioned a survey by the American Academy of Orthopaedic Surgeons (AAOS), which asked similar questions of 49 of its members who treated patients with moderate-to-severe pain from surgery.

The resulting report, “The State of Pain in America,” is obviously intended to drum up support for suzetrigine by showcasing dissatisfaction with current treatment options for acute pain. But the surveys also provide some interesting insights into what patients and doctors think about opioids and pain care in general.

“The Vertex and AAOS surveys underscore that treating acute pain in today’s health care landscape can be complex, as are the complexities that patients and health care providers have when personalizing pain management, highlighting the unmet need in this therapeutic area for more options,” Vertex said.

About 80 million adults receive treatment for acute pain in the U.S. each year, about half of whom receive an opioid, according to Vertex. Many also take acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) for pain relief.

Nearly a third of patients (31%) said they stopped taking analgesics before their acute pain resolved and 77% said they would be interested in trying a different medication – clear indications of dissatisfaction with their pain care.

Patients were also concerned with how acute pain impacted their lives:

• 70% Limited their ability to walk and exercise

• 69% Limited their sleep

• 65% Limited their hobby or leisure activity

• 65% Made them feel irritable or emotionally drained

• Missed an average of 19 work days annually

The surveys also found that both patients and doctors were worried about the risk of opioid addiction:

• 49% of patients concerned about opioid addiction

• 78% of doctors concerned about patients becoming addicted to opioids

• 88% of doctors believe patients prefer to manage pain without opioids

• 67% of patients said they would request a non-opioid medication in the future

• 52% of patients want a pain medication with fewer side effects

In addition, 83% of providers and 74% of AAOS surgeons said there was a high need for a new class of non-opioid pain medication.

Whether suzetrigine is a solution to these issues is an open question. Unlike opioids, which act on pain receptors in the brain, suzetrigine is designed to block pain in the peripheral nervous system. That means it won’t have the same “liking” effects of opioids or be addictive.

But in clinical studies, suzetrigine was not more effective than a low dose of Vicodin in treating acute pain in patients recovering from minimally invasive surgeries.

The risk of a surgery patient misusing opioids or becoming addicted is actually quite low – less than one percent. One study even found that patients who received no opioids during surgery were more likely to have post-operative pain and require opioids during recovery.

Vertex hopes suzetrigine will be approved by the FDA in January for post-operative acute pain.  The company is also studying the drug as a treatment for pain caused by diabetic peripheral neuropathy and for lumbosacral radiculopathy.  

Guideline: Pediatricians Can Prescribe Opioids to Children as Needed

By Pat Anson

Fears about children becoming addicted and overdosing on opioid medication have led to the undertreatment of acute pain in pediatric patients, according to a new clinical guideline by the American Academy of Pediatrics (AAP).

The AAP guideline – the organization’s first to address opioid prescribing to children and adolescents -- urges pediatricians to start with non-opioid medication when treating mild to moderate acute pain. Opioids can be prescribed if a child is in severe pain or doesn’t respond to non-opioid treatment.

“There’s been a big pendulum swing in the practice of medicine over the last two decades—first with opioid-overprescribing, then with a huge cutback in opioid prescribing, likely leaving some children’s pain undertreated,” said lead author Scott Hadland, MD, Chief of Adolescent Medicine at Massachusetts General Hospital and an Associate Professor of Pediatrics at Harvard Medical School

“We want pediatricians to prescribe opioids when they’re needed because untreated pain can lead to distress and psychological harm. At the same time, physicians need to take steps that reduce the long-term risk for addiction.”

The guideline recommends that immediate release opioids be used, starting with a low dose and an initial supply of five days or less. Opioids can be prescribed for longer periods if a child is recovering from trauma or surgery and the pain is expected to last longer than 5 days. Every prescription for opioids should also include a prescription for naloxone, an overdose reversal drug.

The AAP warns that codeine or tramadol should not be prescribed to patients younger than 12 years; adolescents 12 to 18 years of age who have obesity, sleep apnea, or severe lung disease; or when treating surgical pain after a tonsillectomy or adenoidectomy.

“For a patient with mild to moderate pain, doctors should always start nonopioid medications and treatment,” said guideline co-author Rita Agarwal, MD, a Pediatric Anesthesiologist and Professor at Stanford Medicine. “Opioids do remain an important tool for acute pain relief.  But there are times when acetaminophen and ibuprofen may be equally effective with fewer side effects, such as in procedures such as tonsillectomy, wisdom teeth removal, and fractures.”

The AAP’s guideline is based on a review of 11 clinical studies involving pediatric outpatients being treated for acute pain. Hundreds of other studies were excluded from the analysis because they involved adults or hospitalized patients.

The use of opioids by children and adolescents has been a contentious issue for many years. Opioids were once commonly prescribed after wisdom teeth removal, a practice that is now discouraged.

The AAP’s guideline review committee found that most children prescribed opioids do not become addicted or have an overdose. The risk of a child developing opioid use disorder or experiencing an overdose one year after a prescription ranged from 0.3% to 5.8%.

The World Health Organization (WHO) released a guideline in 2021 recommending that opioids only be given to children who are dying or seriously ill and not expected to recover. The WHO guideline found that “evidence of the effectiveness and safety of opioids is completely lacking in children.”  

Dogs Can Help Us Feel Less Pain

By Pat Anson

If you’re a dog lover like me, you know how beneficial a pet dog can be. Dogs give us unconditional love and companionship, and help us reduce stress, stay active and be socially connected.

What you may not know is that our four-legged friends can also help us feel less pain. In fact, according to a new study, they’re better at it than humans.

A team of European researchers conducted an unusual experiment to see if people experience less pain when their dog was nearby or when they were with a close friend.

They recruited 124 healthy female pet owners to immerse their hands in cold water (about 36°F) for up to five minutes to induce pain. The so-called “cold pressor task” is a common way for researchers to induce acute pain in clinical studies.

For this study, the cold water test was performed in a laboratory while the participants had either their pet dog or a same-sex friend nearby. Some of the women took the test while alone and served as a control group. The interaction of the participants, dogs, and their friends was monitored by video camera.   

The study findings, recently published in the journal Acta Psychologica, suggest that dogs can help people cope with painful situations better than humans can.

“Participants reported and showed less pain and they felt less helpless in the dog condition compared to the alone condition,” wrote lead researcher Heidi Mauersberger, a Research Assistant in the Department of Psychology at Humboldt University in Berlin.

“Participants accompanied by their dog reported less pain and showed lower physiological pain reactions, greater pain tolerance, and less intense facial displays of pain as well as felt less helpless than participants…accompanied by their friends.”

Being with a friend was better than being alone, but Mauersberger says the presence of another human being -- even a close friend -- made the women feel like they were being judged or evaluated.

“In contrast to the presence of pet dogs, the mere presence of close friends may have triggered social demands and social-evaluative threat in the painful situation. In fact, the increased eye contact frequency between participants and friends compared to participants and dogs may be a reason for the heightened threat perceptions in the friend compared to the dog condition.”

To test their theory further, researchers conducted a second test, this time immersing the participants’ hands in cold water while they were with a complete stranger or a dog they were unfamiliar with.

The results were largely the same. The pet owners felt more comfortable and coped better with pain around dogs they had not bonded with. Individuals with positive attitudes about dogs experienced the most pain relief.

“Participants demonstrated better adaptation to pain, exhibited less pain behavior, reported reduced helplessness and higher self-efficacy as well as experienced more positive affect when suffering pain in the presence of unfamiliar dogs compared to the presence of unfamiliar human companions,” said Mauersberger.

To be clear, this experiment wasn’t designed to come up with another wacky treatment for chronic pain. People with chronic pain or taking prescription medication were excluded from the study.

The research was conducted to help demonstrate the value of therapy dogs, which have long been known to provide psychological benefits to people suffering from stress, anxiety or loneliness.

A 2020 study helped explain how that happens. People being treated for fibromyalgia who interacted with a therapy dog had a significant increase in levels of oxytocin – a hormone released by the pituitary gland that’s known as the “cuddle hormone” or “love hormone.” They were also more relaxed, their heart rates slowed, and they had more positive thoughts and feelings.  

Do you have a dog, cat or pet of any kind that helps you feel better? 

Weak Evidence Antidepressants Treat Pain in Older Adults

By Crystal Lindell

New research shows that there’s not much evidence that antidepressants actually work at treating pain in people over 65 years old. 

The study, which comes out of the University of Sydney in Australia, is concerning because older adults with chronic pain are often prescribed antidepressants instead of pain medication. 

However, in a frustrating conclusion, the authors still do not recommend the one medication that is proven to treat pain in older adults: Opioids. 

Instead, they suggest that doctors use a “multidimensional approach using non-pharmacological strategies, such as physical exercise and cognitive behavior therapy.” 

In other words, they essentially conclude that pain patients should get no medication.

However, I am glad that more research is coming out to expose how ineffective antidepressants usually are at treating pain. That class of medication has long been held up as an opioid alternative, despite the fact that many patients don’t get much relief from them. 

The researchers found that international guidelines that recommend antidepressants for chronic pain are heavily based on studies that either exclude older adults or include only a small number of them.  

The researchers found that in the last 40 years there have been just 15 clinical trials globally that focused on the use of antidepressants for pain in older people. And many of them were industry-funded trials with fewer than 100 participants.

The authors say their research fills a much-needed information gap, by bringing together the data from these trials to look at the efficacy and adverse effects of antidepressants for acute and chronic pain in older adults..

They found a lack of evidence to support the use of antidepressants for most pain conditions – despite the fact that they are often recommended in clinical guidelines. And none of the research they analyzed looked at the effectiveness of antidepressants for acute pain, such as shingles or muscular pain.

“These medicines are being prescribed to remedy patients' pain, despite the lack of evidence to adequately inform their use,” said co-author Dr. Christina Abdel Shaheed, an Associate Professor at the University of Sydney’s Institute for Musculoskeletal Health.

The findings mirror those of a recent study in the United Kingdom, which found that there is “no reliable evidence for the long‐term efficacy of any antidepressant, and no reliable evidence for the safety of antidepressants for chronic pain at any time point." 

Withdrawal and Other Side Effects

Shaheed says the potential harms of antidepressants in older people are well documented, and should be factored into any decisions about prescribing the medications. The study found that people taking antidepressants experienced more side effects effects, such as falling, dizziness, and a higher risk of being injured. The potential withdrawal if patients abruptly stop taking antidepressants can also be severe.

The study found that duloxetine, which is sold under that brand names Cymbalta and Yentreve, was able to relieve osteoarthritis knee pain in older adults during the intermediate term, but not short-term or long-term.

As a patient who often shares my health issues publicly, I often get messages and questions from readers who are also dealing with chronic pain. Anytime they mention Cymbalta, I pause. 

I had a horrible experience trying to come off Cymbalta, and I don’t think it even helped much with my pain when I was on it. Plus, my columns about the withdrawal experience apparently resonated, because they are among the most-read, liked and commented on articles I’ve ever written. In other words, it’s not just me. 

If Cymbalta or another antidepressant does help someone, I think they should take it. But I don’t think doctors are fully transparent about how bad the withdrawal can be or how little evidence there is that they even help with pain in the first place. 

“For clinicians and patients who might be using or considering duloxetine for knee osteoarthritis, the message is clear: benefits may be seen with a little persistence, but the effects may be small and need to be weighed up against the risk,” said lead author Dr. Sujita Narayan, an Academic Fellow at the Institute for Musculoskeletal Health.

Again, I’m glad the authors are drawing attention to the problems with prescribing antidepressants for pain management. I just find it alarming that they don’t even bother to mention any alternative medications, and instead suggest non-pharmacological treatments. 

Looking back, I guess I took for granted in the early days of opioid-phobia that most people in the medical field at least recognized that giving zero medication for pain was inhumane. That often meant doctors went from prescribing opioids to prescribing antidepressants. It came with a lot of downsides for patients, but at least it was something. 

If the next stage of opioid-phobia really is just “all medications are bad at treating pain,” then things are worse than I thought. And a lot of people are going to be suffering unnecessarily. 

We already have effective treatments, we just need to use them.

Is the Hype About a New Non-Opioid Analgesic Justified?

By Carol Levy

In a previous column, I asked why pharmaceutical companies haven’t been able to “build a better mousetrap” by developing new and effective non-opioid medications for pain 

Every doctor I've seen about my chronic facial pain has only offered me opioids. As is true for many of us, I hate the way they make me feel. They also rarely help, outside of making me so cloudy-headed that I become less aware of the pain and have trouble thinking clearly.

That is the exact opposite of what the drug is supposed to do. It's supposed to make me feel better, and therefore better able to work, play, and do regular activities — which is exactly what the cloudiness stops me from doing. That's not a workable trade-off.

When I protest, “There must be something other than an opioid,” the reply from doctors is always the same: “There is nothing else.”

Now there may be. The FDA is giving priority review to a new drug application for suzetrigine, an experimental non-opioid analgesic developed by Vertex Pharmaceuticals. The drug has previously been granted “Fast Track” and “Breakthrough Therapy” designations by the agency for the treatment of moderate-to-severe acute pain. Final approval could come in January, which would make suzetrigine the first new class of medication for pain in over two decades.

The upside to suzetrigine is that it’s not an opioid. That would address the lie that we are responsible for the opioid crisis, and should be held captive by doctors who fear being raided by the DEA and don’t prescribe opioids anymore.

The downside is that suzetrigine is being considered as a treatment for acute pain and perhaps chronic neuropathy. My pain is neuropathic in nature -- trigeminal neuralgia and anaesthesia dolorosa (phantom pain) --- so I was at first exhilarated, and then deflated to see that suzetrigine is only being studied as a treatment for diabetic peripheral neuropathy. I had hoped this would be something for all of us.

I Google searched for other non-opioid analgesics, hoping there might be some new ones in the process of testing or even FDA fast-tracked. I couldn't find any.

As I researched further, I began to feel dejected. All drugs have downsides. That is expected. But I had hoped the FDA’s priority review meant the research was very positive about suzetrigine. Instead, I found there are many questions as to whether the drug is any better than what is already out there.

So why is the FDA fast-tracking it? Are they so eager to approve non-opioids that anything that might work will be considered? Maybe. The breakthrough therapy and fast-track designations may be geared more towards appeasing the FDA’s critics than anything else.

The headlines sounded so promising. “New Painkiller Could Bring Relief to Millions” and “A New Class of Medicine for Pain Relief On The Horizon.”

When I found out about this drug my heart leaped. Now I am not so sure. I hope it's not just another false flag. 

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 Non-Opioid Analgesic Gets Priority Review from FDA

By Pat Anson

The Food and Drug Administration could approve an experimental non-opioid analgesic early next year, potentially making it the first new medication for acute pain in over two decades.

Vertex Pharmaceuticals says the FDA has accepted its New Drug Application for suzetrigine, giving the drug a priority review with a target action date of January 30, 2025. Suzetrigine has previously been granted FDA Fast Track and Breakthrough Therapy designations for the treatment of moderate-to-severe acute pain.

“Today’s FDA filing acceptance for suzetrigine marks a critical milestone toward bringing this new, transformative non-opioid analgesic to the millions of patients,” Nia Tatsis, PhD, an Executive Vice President and Chief Regulatory and Quality Officer for Vertex, said in a statement.

“The FDA’s granting of a priority review further reinforces the high unmet need in treating acute pain, and the filing brings us one step closer to our objective of filling the gap between medicines with good tolerability but limited efficacy and opioid medicines with therapeutic efficacy but known risks, including addictive potential.”

Suzetrigine is designed to block pain in the peripheral nervous system, rather than the brain. That means it won’t have the “liking” effects of opioids or be as addictive.  

In Phase 3 clinical studies, suzetrigine was more effective in reducing post-operative pain than a placebo after minimally invasive surgeries.  Over 80% of patients rated suzetrigine as good or excellent in treating acute pain, but it was not more effective than a combination of the opioid hydrocodone and acetaminophen, more commonly known as Vicodin.

Vertex hopes suzetrigine will eventually be approved for a variety of pain conditions, not just post-operative pain.  The company has been studying the drug as a treatment for pain caused by diabetic peripheral neuropathy.

“In my 24 years practicing medicine, I have seen firsthand the desperate need for new non-opioid therapies for treating pain. Too many people today are either undertreated, dealing with negative side effects of currently available therapies or foregoing pain medications altogether for fear of becoming dependent on opioids,” said Scott Weiner, MD, a Vertex consultant and Associate Professor of Emergency Medicine at Harvard Medical School.

The Biden Administration has been under pressure from lobbyists, politicians and anti-opioid activists to have the FDA approve more non-opioid medications like suzetrigine. The new analgesics are expected to be far more expensive than opioids and other older pain relievers.

If the FDA approves suzetrigine in January, it will coincide with implementation of the NOPAIN Act, which will expand access to non-opioid analgesics in outpatient surgical settings by making them eligible for higher Medicare reimbursement rates.

There’s Little Evidence That Massage Therapy Helps With Pain

By Crystal Lindell

It’s often touted as an alternative pain treatment, but it turns out there’s not much evidence showing that massage therapy actually helps with either chronic or acute pain. 

That’s according to new research published in JAMA Network Open that analyzed hundreds of clinical studies of massage therapy for pain. In a systematic review of those studies, the authors found little evidence that massage therapy actually helps relieve pain. In fact, most of the studies concluded that the certainty of evidence was low or very low. 

Notably, the researchers looked at studies involving many different types of pain, including cancer-related pain, chronic and acute back pain, chronic neck pain, fibromyalgia, labor pain, myofascial pain, plantar fasciitis, postpartum pain, postoperative pain, and pain experienced during palliative care. 

“There is a large literature of original randomized clinical trials and systematic reviews of randomized clinical trials of massage therapy as a treatment for pain,” wrote lead author Selene Mak, PhD, a researcher and program manager at the VA’s Greater Los Angeles Healthcare System. 

“Our systematic review found that despite this literature, there were only a few conditions for which authors of systematic reviews concluded that there was at least moderate-certainty evidence regarding health outcomes associated with massage therapy and pain. Most reviews reported low- or very low–certainty evidence.”

The results are especially concerning because massage therapy is often recommended as an nonopioid alternative for treating pain. In fact, in its revised 2022 opioid guideline, the CDC specifically mentions “massage” multiple times as a nonpharmacologic alternative. 

“Nonopioid therapies are preferred for subacute and chronic pain. Clinicians should maximize use of nonpharmacologic and nonopioid pharmacologic therapies as appropriate for the specific condition and patient,” the guideline says.

Researchers involved in the current study found that “massage therapy” was a poorly defined category of treatment, which made it more difficult to analyze. For example, in some studies, acupressure was considered massage therapy, but at other times it was classified as acupuncture. 

“Massage therapy is a broad term that is inclusive of many styles and techniques,” Mak wrote. “This highlights a fundamental issue with examining the evidence base of massage therapy for pain when there is ambiguity in defining what is considered massage therapy.”

Researchers also found that it was difficult to do placebo-controlled massage studies because it’s difficult to compare massage with a sham or placebo treatment. 

“Unlike a pharmaceutical placebo, sham massage therapy may not be truly inactive,” they wrote. “It is conceivable that even the light touch or touch with no clear criterion used in sham massage therapy may be associated with some positive outcomes.… Limitations of sham comparators raise the question of whether sham or placebo treatment is an appropriate comparison group in massage therapy trials.”

The researchers said it might be better to compare massage therapy with other treatments rather than a placebo. They also called for more high-quality research to look into exactly how helpful massage therapy is for pain. 

All of this doesn’t mean that massage therapy offers zero benefits, and patients who get something out of it should continue to use it.  However, medical professionals (and guideline authors) should be more cautious about recommending massage as a substitute for proven pain treatments, such as opioids. Because the last thing people in pain need is to be given ineffective treatments while being denied effective ones..

‘Smart Opioid’ Relieves Pain with Lower Risk of Overdose

By Pat Anson, PNN Editor

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

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

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

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

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

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

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

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

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

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

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

Patients Should Know the Health Benefits of Ketamine, Not Just the Risks

By Drs. Amber Borucki and Rakhi Dayal 

Recent headlines about the death of “Friends” actor Matthew Perry have pointed to ketamine as a contributing cause. Perry drowned in his hot tub last October, which the medical examiner’s office attributed to the “acute effects of ketamine,” as well as coronary artery disease and the opioid buprenorphine.

With this news, the public became more familiar with a medication they may never have heard of previously.  Ketamine is a classified by the Drug Enforcement Administration (DEA) as a “dissociative anesthetic,” meaning that it can cause the user to feel disconnected and alter their perceptions of sight or sound. 

Ketamine is used in hospital or surgical settings for anesthesia purposes, for acute pain management, in the emergency room or intensive care, and in some cases for chronic pain management. A form of ketamine (esketamine) is also used to treat mental health conditions. 

Appropriate monitoring and medical supervision are necessary for safe ketamine use. While it is important to recognize the risks of this medication when used improperly, it is also important to make sure that people don’t become overly fearful of a drug that serves an important role in patient care when delivered properly by trained healthcare providers. 

When the news broke that Michael Jackson’s death was attributed to propofol, patients were suddenly concerned about the use of this drug in their anesthesia treatment. As physicians, it is our responsibility to make sure patients understand the proper and improper uses of medications, and that we help alleviate concerns through education. As with any treatment, we need to strike the right balance between providing information on the risks, while also communicating the benefits. 

While ketamine is in the spotlight and more stories are published about its use, it is important that we take a moment to provide greater clarity about this medication.  

What Is Ketamine?  

Ketamine is an anesthetic agent that was originally developed in 1963 and gained approval from the Food and Drug Administration (FDA) as a general anesthetic in 1970. It is well established that ketamine has tremendous clinical value in providing sedation and pain relief when patients undergo anesthesia, and can also be beneficial as part of a comprehensive pain management plan. More recently, the FDA approved a form of ketamine in a nasal spray for treatment-resistant depression.   

Ketamine is used for a variety of indications, with some being FDA-approved and some being considered "off-label" uses.  

• General anesthesia (FDA-approved): Ketamine can be used as part of a general anesthetic given for surgery, and in certain clinical situations is one of the preferred medications.  When ketamine is given by a trained anesthesia provider, it is a safe and effective part of the anesthesia regimen.     

• Acute pain (off-label): Ketamine can be given to treat pain after surgery or for other significant acute pain conditions. This is commonly done by providing a low-dose infusion of ketamine through an IV while a patient recovers in the hospital. Although this is considered "off-label” use, there are joint guidelines issued in 2018 by the American Society of Regional Anesthesia and Pain Medicine (ASRA), the American Society of Anesthesiologists (ASA), and the American Academy of Pain Medicine (AAPM) to guide safe use for acute pain.

• Chronic pain management (off-label): Ketamine for chronic pain is also considered "off-label" use, but there are also consensus guidelines by the ASRA, ASA and AAPM that discuss chronic pain clinical scenarios where research found ketamine to be beneficial. 

If a patient is considering the use of ketamine for chronic pain, it is important to understand what type of medical supervision is provided and by whom. Patients should consider seeking treatment from a physician who is board certified in pain medicine, as they have extra training in pain management. The use of ketamine for chronic pain should be part of a larger umbrella of comprehensive pain treatment strategies provided in a multidisciplinary care team model.

What Are the Risks of Ketamine?

Ketamine is classified a schedule III controlled substance by the DEA, and therefore has some addictive potential. Side effects include increased heart rate, high blood pressure, increased saliva production, blurry vision, dizziness, sedation, nausea, urinary symptoms, dissociation (out of body sensation) and respiratory depression. It can even cause hallucination at certain doses. 

Caution is advised when ketamine is used with other medications that have similar adverse effects, such as sedation, respiratory depression, confusion, and delirium. Medication interactions and overdose with ketamine can lead to unconsciousness, slowed breathing, and rare severe consequences such as death. 

The medical use of ketamine in general anesthesia under the medical supervision of a trained provider is generally considered safe. Off-label use of ketamine for acute and chronic pain also has established national guidelines for medical practitioners to follow. This treatment can provide pain relief to patients safely, when provided by a board-certified anesthesiologist or pain physician using proper monitoring and safety guidelines.

Unsupervised and non-medical use of ketamine, particularly when taken in combination with other sedating medications, can lead to adverse outcomes and even death, as we saw with Matthew Perry. We encourage patients to have conversations with providers about their treatment plan and to discuss any concerns they have about the medications they are prescribed.

Amber Borucki, MD, is an Associate Professor of Anesthesiology, Perioperative and Pain Medicine at Stanford University.

Rakhi Dayal, MD is Chair of the Pain Committee for the California Society of Anesthesiologists, and Program Director of Pain Medicine and Professor of Anesthesiology & Perioperative Care at University of California, Irvine.

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. 

Moderation – Not Prohibition – Is Key to Treating ER Patients With Opioids

By Pat Anson, PNN Editor

Over the years many people living with pain have told us that they avoid going emergency rooms because they fear their pain will be ignored and that they’ll be treated as an addict if they ask for opioids.  

“Going to the ER terrifies me and I am an RN,” one patient said. “I was recently there on 2 separate episodes for kidney stones. Over a three-day period they gave me absolutely nothing for pain!” 

“I can't and won't return to an ER even if I am dying because I won't accept being treated like an addict ever again,” said a 60-year-old disabled woman.  

“It took me 12 hours and a staged public fit to get any pain relief at my local ER when I went in with a pinched nerve,” another patient told us. 

“Called suicide hotline and was told to go to ER,” said a woman suffering from a severe flare from rheumatoid arthritis. “Well, that was a waste. Told I was drug seeking and received a hefty bill to pile on top of all the others.”

A new study suggests that moderation – not prohibition -- is the key to treating pain in the ER with opioids. Researchers in Canada found that half of patients discharged from an emergency department needed only a handful of opioid tablets to control their pain.

“Patients are often prescribed too many opioid tablets and that means unused tablets are available for misuse,” Raoul Daoust, MD, a professor of Family and Emergency at University of Montreal, said in a press release. “On the other hand, since the opioid crisis, the tendency in the USA is to not prescribe opioids at all, leaving some patient in agonising pain.

“With this research I wanted to provide a tailored approach to prescribing opioids so that patients have enough to manage their pain but almost no unused tablets available for misuse.”

Daoust and his colleagues surveyed 2,240 adult patients who were treated for acute pain at one of six hospital emergency departments in Canada. All were discharged with an opioid prescription and were asked to complete a pain diary for two weeks.

Their findings, presented over the weekend at the European Emergency Medicine Congress in Spain, showed five or fewer morphine tablets (5mg) were adequate for about half the patients. The rest needed more tablets, depending on their condition. For example, patients suffering from renal colic or abdominal pain needed eight tablets, while a patient with broken bones needed 24 tablets. 

Daoust says emergency room physicians need to recognize that morphine can be “very beneficial” for patients. The key is to individualize treatment and prescribe the right amount to minimize the risk of addiction.

“Our findings make it possible to adapt the quantity of opioids we prescribe according to patient need. We could ask the pharmacist to also provide opioids in small portions, such as five tablets initially, because for half of patients that would be enough to last them for two weeks,” said Daoust.

The researchers plan to apply their findings in a clinical setting to evaluate whether they can reduce the long-term use and misuse of opioids. 

“This study shows how opioid prescriptions could be adapted to specific acute pain conditions, and how they could be dispensed in relatively small numbers at the pharmacy to lower the chance of misuse. This research could provide a safer way to prescribe opioids that could be applied in emergency departments anywhere in the world,” said Youri Yordanov, MD, an emergency physician at Saint-Antoine Hospital in Paris, who was not involved in the research.

A large 2017 study found that the risk of long-term opioid use is lower for ER patients than it is for patients treated in other medical settings. Researchers found that only 1.1% percent of ER patients taking opioids for the first time progressed to long term use. That compares to 2% of patients in non-emergency settings.

Low Dose Opioids Ineffective for Acute Lower Back and Neck Pain

By Pat Anson, PNN Editor

A low dose of prescription opioids works no better than a placebo in relieving acute lower back or neck pain, according to a new study in Australia.  

The blinded, placebo-controlled trial was relatively small – just 345 participants – but was unusual because patients were followed for up to a year, a rarity for a clinical trial that studies pain.  Half the participants received a combination of oxycodone and naloxone for six weeks at a low daily dose of 20mg or about 30 morphine milligram equivalents (MME). The other half received placebo tablets that looked similar to oxycodone.   

It's important to note that the study only included people with mild or moderate pain of less than 12 weeks duration -- not the severe, long-term back and neck pain caused by degenerative disc disease, spinal injuries, arthritis, and other chronic conditions. Participants were excluded if they had that type of pain.  

The study findings, published in The Lancet, showed no significant difference in pain severity between the opioid and placebo groups. On a scale of zero to 10, the average pain score was 2.8 in the opioid group after six weeks, compared to 2.3 in the placebo group. After a year, the average pain score was 2.4 in the opioid group, versus 1.8 in the placebo group. 

Pain Severity Over 52 Weeks

THE LANCET

Researchers say patients who received opioids had a slightly higher risk of opioid misuse at the end of the study, a finding based on a mental health survey that screens patients for drug related behavior.

“Our findings show that even judicious, short-term use of an opioid conferred no benefits in pain reduction and led to a small increase in pain at the medium-term and long-term compared with placebo. The opioid group had worse quality-of-life mental health scores than the placebo group,” researchers reported. “Although no difference was found in overall time to recovery, more people in the placebo group recovered in the first 14 days compared with those in the opioid group.”

Most medical guidelines recommend exercise and over-the-counter pain relievers for short-term back or neck pain, with opioids only used as a last resort. The authors of the Lancet study say even that limited use is inappropriate.

“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. “Not even when other drug treatments are not able to be prescribed or have not been effective for a patient.”

The Lin study is somewhat similar to the 2018 Krebs study, which found that low doses of oxycodone were no more effective than over-the-counter pain relievers in treating chronic back and osteoarthritis pain. Critics say the Krebs study was biased from the start and this one is no better.

“They generalise enormously,” Michael Vagg, MD, Dean of Pain Medicine at the Australian and New Zealand College of Anaesthetists, told the Medical Republic. “They studied oxycodone and naloxone in a modified-release formulation. But modified-use opioids have never been on-label for use in acute pain and they are not recommended as such… to which I and everyone in pain medicine would say ‘We figured that out ages ago’. That’s not how you use opioids in acute pain.

“In layman’s terms, they’ve done a study where they tried to look at doing push-ups to help with back pain and then they’ve decided that all exercise is no good for the back pain.”

Lower back pain is the world’s leading cause of disability and neck pain is the fourth largest, but there is surprisingly little evidence about the best ways to treat them.

A previous study published in The Lancet by an international team of researchers found that lower back pain was often treated with bad advice, inappropriate tests, risky surgeries and painkillers. The authors said there was limited evidence to support the use of opioids for low back pain, and epidural steroid injections and acetaminophen (paracetamol) were not recommended at all. Most patients responded better to physical and psychological therapies that kept them active.

Hypnosis Works Better Than Prayer as Pain Reliever

By Pat Anson, PNN Editor

When it comes to relieving acute pain, praying to God for help isn’t nearly as effective as a single session of hypnosis or mindfulness meditation, according to an unusual new study.

Intrigued by research that found Muslim prayer rituals reduce pain, an international team of researchers recruited 232 healthy adults in Portugal to further study the effects of spirituality on pain.

Short-term acute pain was induced in all participants by wrapping their arms and hands in a cold compress for up to 5 minutes. After a rest period, participants listened to either a 20-minute recording of guided hypnosis, mindfulness meditation, or a passage from the New Testament followed by a short Christian prayer. A fourth group listened to a reading from a natural history book and served as a control group.

After listening to the recordings, acute pain was induced again with a cold compress, while participants had their pain intensity, pain tolerance, cardiac function and stress levels monitored.

The study findings, recently published in the Journal of Pain Research, show that hypnosis was effective in lowering pain intensity and raising pain tolerance, followed closely by mindfulness meditation. The benefits from Christian prayer (CP) were small and not considered statistically significant.

“The findings suggest that both single short-term hypnosis and mindfulness meditation training, but not biblical-based CP, may be viable options for effective acute pain self-management,” researchers reported. “The findings also suggest that hypnosis might be slightly more efficacious than mindfulness meditation, at least in the short-term, and perhaps especially among novice individuals with very limited hypnosis or meditation practice/training.”

The research team was somewhat surprised by the lack of results for Christian prayer, and think it may have been due to the complexity of the bible-based prayer. A shorter, simpler form of prayer may have worked better. Another factor was that only a third of the study participants described themselves as Christian, while a third said they were atheists or agnostics.

“It is therefore possible that the prayer used in this study might have had a larger beneficial effect among those describing themselves as Christian than those describing themselves as being in one of the non-Christian groups and have had little (or even opposite) effect on atheists and agnostics. For the latter, prayer might have been bothering or even distressing, leading the individuals to focus more on the pain and on the distress caused by prayer itself,” researchers said.

Could Hypnosis Replace Opioids?

Previous studies have found that hypnosis and mindfulness can reduce acute pain in hospitalized patients, and that hypnosis can relieve chronic pain for patients with irritable bowel syndrome (IBS), complex regional pain syndrome (CRPS) and other intractable pain conditions.

A new study published in The Journal of Molecular Diagnostics even suggests that hypnosis can be an alternative to opioids in relieving post-operative pain.

Researchers at Stanford University say genetics play a role in “hypnotizability” — the tendency of some people to respond to hypnosis more than others — and developed a molecular diagnostic tool to identify individuals who would benefit from hypnosis through their blood and saliva samples. They believe the tool could be used as a “point-of-care” test in a hospital setting to determine how patients are treated for pain. Depending on the test results, a patient recovering from surgery could get “hypnotic analgesia” as an adjunct or alternative to pain medication.

“It is a step towards enabling researchers and healthcare professionals to identify a subset of patients who are most likely to benefit from hypnotic analgesia,” said co-lead investigator Jessie Markovits, MD, Department of Internal Medicine, Stanford School of Medicine.

“Precision medicine has made great strides in identifying differences in drug metabolism that can impact medication decisions for perioperative pain. We hope to provide similar precision in offering hypnosis as an effective, non-pharmacological treatment that can improve patient comfort while reducing opioid use.”

Pain Sufferers Are Unfairly Stigmatized

By Marimée Godbout-Parent, University of Quebec

Imagine living with pain every day for months, or even years — pain that is so intrusive, it disrupts every day of your life. Unfortunately, this is the daily reality of millions of people living with chronic pain. And all too often, they find their condition being stigmatized or even denied outright.

As a doctoral student in the epidemiology of chronic pain, I have the opportunity to work with patient partners. Given the high prevalence and multiple impacts of this disease, it is high time we started working to change attitudes and confront the prejudices that surround it. 

Before discussing chronic pain, let’s start at the beginning. Is pain always a negative thing? Of course not. Pain is essential to our proper functioning. It acts as an alarm system to warn us of danger.

For example, if we were to accidentally put our hand on a hot stove top, a pain message would be sent to our brain. Before we even had time to think about it, we would remove our hand from the hot surface, avoiding an intense burn in the process. This pain provides us with the reflexes we need in order to avoid the worst situations.

Pain can also last a little longer. This is the case, for example, after an injury, an operation or an infection. This pain will often resolve itself after a normal healing cycle or disappear with the help of treatment. This is called acute pain. Short-term pain like this is perceived more as a symptom.

Chronic Pain Is a Disease

When pain persists beyond the normal healing time, it is no longer considered simply a symptom, but a disease in its own right. This is called chronic pain. Chronic pain is defined as pain that persists for a minimum of three months. Yet, for the vast majority of people living with this disease, the pain persists for several years.

In these people, the pain message is somehow missing. It is no longer present to warn us of dangers, but becomes a burden on its own. Chronic pain can occur as a result of cancer, an accident, or after surgery. Unfortunately, sometimes we are unable to find the cause. This makes it difficult to treat.

Although this disease is not widely recognized, it is estimated to affect about 20 per cent of the Canadian population. Considering that our population in 2022 is estimated to be close to 39 million, this would mean that approximately 7.5 million people are living with chronic pain. For the purpose of comparison, 7.5 million Canadians is equivalent to the entire population of Québec. It’s an impressive and worrisome number.

In addition to affecting a large portion of the population, chronic pain causes more than just physical pain. The disease affects the daily functioning, psychological well-being, quality of life, social life and work of the people afflicted by it.

Imagine having so much pain that it reduces your ability to work, play with your children, see your friends or concentrate and even affects your ability to carry out everyday tasks. Despite the person’s desire to stay active, the body just can’t keep up. So it’s not surprising that consequences such as fatigue, frustration, sadness, anxiety and depression follow. The constant overlap between physical, psychological and social difficulties creates deep distress in this population.

Facing Prejudice

Despite the significant impacts associated with it, chronic pain remains largely stigmatized. Indeed, negative attitudes and beliefs that people living with chronic pain have become dependent on their medications, that they are exaggerating the severity of their condition, are just lazy or do not want to help themselves are widespread.

Chronic pain is a very real disease.

So, knowing the multiple consequences and prevalence of chronic pain, why is there still so much prejudice and stigma towards those who suffer from it?

The question remains unanswered. For some, what we cannot see simply does not exist. Because pain is an experience that varies from person to person, because we don’t have a specific tool for detecting it or because we can’t necessarily see it, pain can seem invisible. We have a harder time feeling sympathy or understanding for things that cannot be explained medically with medical tests or X-rays.

So, despite the many explanations offered by patients, they often have to deal with prejudices from health professionals, their entourage or the general population. Many people living with chronic pain feel that their pain is not understood by their friends, family, employers or even their health-care professionals, which adds to their feelings of helplessness, sadness and anger. In addition to dealing with the difficulties that chronic pain brings, these comments place an inestimable burden on sufferers.

Francine, who has been living with chronic pain for 15 years, regularly receives these types of comments from her family and friends:

“Well, you’ve only been walking for 10 minutes, you can do more. Just try harder.”

Sylvie, who has lived with chronic pain for 17 years, has to deal with her doctor’s comments:

“You are the only patient I have not been able to relieve with cortisone shots in 40 years, so perhaps you should consult a psychologist instead.”

These phrases, which can sound harmless to some, are often loaded with meaning for those who hear them on a daily basis. Accepting chronic pain as a disease is an important and difficult step. It should not be coupled with such pejorative comments.

Without being experts in the field, we can all play a role, in one way or another, in the lives of these people. Offering an active and understanding ear, not making quick judgments and acknowledging their condition is already a huge step in the right direction.

Support and communication with those around you are elements that should not be neglected and can certainly make a positive difference.

Marimée Godbout-Parent is a doctoral student in health sciences research at the University of Quebec in Abitibi-Témiscamingue. She has received funding from the Canadian Institutes of Health Research.

This article was written in collaboration with Sylvie Beaudoin and Christian Bertrand, patient partners. It originally appeared in The Conversation and is republished with permission.