Can Risk Scores Help Predict if Chronic Pain Will Spread?

By Pat Anson, PNN Editor

The term “biopsychosocial” is a bit of a dirty word in the pain community. Many patients feel that studying the biological, psychological and social factors involved in chronic pain trivializes their physical pain by linking it to anxiety, fatigue, trauma and other stressful life experiences – suggesting the pain is “all in your head.”

But researchers at McGill University in Montreal think biopsychosocial risk factors play a key role in determining the severity and spread of chronic pain to other parts of the body. And that could lead to better ways of treating and preventing pain.   

"By identifying common biopsychosocial factors associated with chronic pain, health care professionals could better personalize treatment plans and improve patient outcomes," said co-author Etienne Vachon-Presseau, PhD, Assistant Professor in the Faculty of Dental Medicine and Oral Health Sciences at McGill University.

Using data from the UK Biobank, a large biomedical database in the United Kingdom, McGill researchers analyzed nine years of health data for nearly 50,000 people who reported a common pain condition such as osteoarthritis, migraine, fibromyalgia and spinal disc degeneration. By the end of the study period, nearly half of the participants (44%) reported their pain had spread to more than one body site.

Why did some people develop chronic overlapping pain conditions (COPCs), while others did not?

To find out, the research team dug deeper into the data, using machine learning algorithms to study 99 different physical, psychological, demographic and sociological factors about the participants, such as their education, mental health, substance use, and socioeconomic status.

The study findings, published in Nature Medicine, identified the biggest risk factors associated with COPC: depression/anxiety, insomnia, neuroticism (feeling fed-up), fatigue, stressful life events, and a body mass index (BMI) above 30.

“Our findings suggest that the biopsychosocial model not only shapes pain experience and maintenance, but also predisposes the development of new pain sites, a phenomenon we refer to as the ‘spreading’ of pain sites,” researchers reported. “Furthermore, we found that the pain site co-occurrence was not random, with a strong dependence between proximal pain sites, shown from either acute or chronic pain sites and from correlations between pain intensity ratings. Thus, biopsychosocial risk scores developed for headache will also moderately predict knee pain and vice versa.”

Based on those findings, the McGill team developed a pain risk score that utilizes six simple questions:

Risk of Pain Spreading Screen

1. Do you have difficulty falling asleep at night or do you wake up in the middle of the night?

2. Do you often feel ‘fed-up’?

3. Over the past 2 weeks, how often have you felt tired or had little energy?

4. Have you ever seen a GP or psychiatrist for nerves, anxiety, tension or depression?

5. In the last two years, have you experienced a serious illness, assault, death of a spouse/partner or close relative, separation/divorce, or financial difficulties?

6. Is your BMI over 30?

McGill researchers say their questionnaire will help providers quickly assess the risk of a pain patient developing more severe pain and how the pain might spread across their body.

“Our model predicted chronic pain spreading across multiple body sites in nearly 50,000 out-of-sample individuals,” researchers said. “We showed that high sensitivity and specificity could still be obtained for certain chronic pain conditions using only six questions. The ability to predict chronic pain, particularly COPCs and its severe forms, with minimal effort has the potential to benefit both research and clinical practice.”

Ice Packs and Tylenol: Why a New Study on Post-Operative Pain Falls Flat

By Pat Anson, PNN Editor

The prescribing of opioids to patients recovering from surgery is a hot topic these days. Fearing that patients may become addicted, a growing number of U.S. hospitals now send their surgery patients home with non-opioid analgesics like Tylenol. According to a recent study, the number of opioid pills prescribed to patients for post-operative pain has been cut in half since 2017.

Reducing the use of opioids has led to complaints from patients that their post-operative pain is poorly treated. It may have even led to a tragic mass shooting. Police say the patient who killed four people – including his surgeon – at a Tulsa hospital this month was angry about “the ongoing pain that came from the surgery” he had 13 days earlier.

A new study by researchers at McGill University in Montreal is likely to add further fuel to the debate over opioids. In a meta-analysis of 47 clinical trials – a study of studies – researchers concluded that opioids don’t work well for post-operative pain, and cause more harm than good.

“The study results indicate that prescribing opioids to manage postoperative pain after discharge is not only unnecessary, but harmful in many surgical settings. These findings… fill a critical gap in knowledge about how pain should be managed at home after surgery,” is how a McGill University press release summarized the findings.

It’s important to read the fine print here. The McGill study, published in The Lancet, has three major limitations that the press release either ignores or downplays.

First, most of the clinical trials that were studied were for dental procedures such as tooth extractions or for minor surgeries conducted in a physician’s office, such as removal of a skin lesion. None of the surgeries involved patients having major operations in a hospital, such as a cesarean section or appendectomy.

Second, much of the data was “largely derived from low-quality trials,” according to the authors.

Third, the primary goal of the study was to assess the pain relief provided by opioids and non-opioid analgesics for one day -- “on day 1 after discharge” – which hardly fills the “critical gap in knowledge” about post-operative pain that McGill claims to have been filled. What about the next 5 or 10 days a patient might need to recover from surgery? What about 13 days?

Despite these glaring limits on the quality of their analysis, McGill researchers came to some broad conclusions.

"We found that prescribing opioids had no impact on patient-reported postoperative pain compared to simple over-the-counter analgesics, but it significantly increased the risk of adverse events, such as nausea, vomiting, constipation, dizziness and drowsiness," said lead author Julio Fiore Jr., PhD, a non-practicing “surgical scientist” at McGill University Health Centre.

"Prescribing opioid-free analgesia may prevent these adverse effects, improve patients' recovery experience, and also help mitigate the opioid crisis by reducing the risk of postoperative opioid misuse, addiction and diversion."

Study Methodology Questioned

But critics of the study’s methodology point out that most patients had only modest pain scores and received very low doses of opioids. The median daily dose of 27 morphine milligram equivalents (MME) is far below cautionary levels recommended by the CDC — and hardly reflective of what a patient might need after a major surgery.

“Most of the surgeries were minor and probably required minimal post-op analgesia,” said Stephen Nadeau, MD, a professor of Neurology at the University of Florida College of Medicine. “In short, the generalization of their findings to all opioid treatment of post-operative pain goes far beyond what the data will support. The reviewers and Lancet editor should have taken them to task about this.”

Over $80,000 in taxpayer funding for the McGill study came from the Canadian Institutes of Health Research, which is Canada's federal agency for healthcare research.

“This is typical of the research that we have seen from Canadian researchers that have put Canadians in such a bad state. Their methods and reasons are suspect and the use of data mining continues to come up with false premises,” said Barry Ulmer, Executive Director of the Chronic Pain Association of Canada. “It is shocking and McGill should be ashamed, as should The Lancet. What is also shocking is the Canadian government continues to fund many of these over the wall studies.”

In a preview of the McGill study published in 2020, Fiore and his colleagues said they would exclude from their analysis any studies that evaluated the effectiveness of analgesia for chronic postoperative pain. In other words, they excluded studies of pain relievers that had outcomes running counter to their narrative. If a surgery patient developed chronic pain after their acute pain was only treated with Tylenol, they didn’t want to hear about it.   

"The quality of the selected studies was variable, and none of them addressed non-opioid analgesia during discharge from major or major-complex surgery," acknowledged co-author Charbel El-Kefraoui, a non-practicing “research trainee” at McGill University. "It will therefore be important to conduct studies on different surgical procedures and on different postoperative pain management regimens, including pharmacologic and non-pharmacologic interventions like expectation setting, relaxation and ice packs."

Good luck with that. Ice packs and Tylenol are probably a good way to recover from a toothache, which is basically what the McGill study looked at. They are not a good way to treat acute pain from a major surgery. Or a way to avoid future tragedies like the one in Tulsa.

A Gut Feeling About Fibromyalgia

By Pat Anson, PNN Editor

Over the years there’s been a lot of speculation about what causes fibromyalgia – everything from gluten and genetics to childhood trauma, spinal fractures and a weakened immune system.

About 5 million Americans suffer from fibromyalgia, a poorly understood disorder characterized by deep tissue pain, fatigue, mood swings and insomnia. It can take years for a patient to be diagnosed and treatments are often ineffective – in part because of uncertainty about what actually causes fibromyalgia.

For the first time, researchers at McGill University Health Centre in Montreal have found an association between gut bacteria and fibromyalgia. It’s not clear whether the microbes cause fibromyalgia or if they are a symptom, but the discovery opens the door to new forms of treatment and diagnosis. The findings are being reported in the journal Pain.

"We found that fibromyalgia and the symptoms of fibromyalgia — pain, fatigue and cognitive difficulties — contribute more than any of the other factors to the variations we see in the microbiomes of those with the disease,” said lead author Amir Minerbi, MD, of the Alan Edwards Pain Management Unit at McGill University Health Centre. 

“We also saw that the severity of a patient's symptoms was directly correlated with an increased presence or a more pronounced absence of certain bacteria - something which has never been reported before."

Minerbi and his colleagues enrolled 156 women in their study – about half had fibromyalgia and the rest were a healthy control group. Participants were interviewed and gave stool, blood, saliva and urine samples, which were then compared.

Researchers found that the two groups had strikingly different types and amounts of gut bacteria. Nineteen different species of bacteria were found in either greater or lesser quantities in the gut microbiomes of fibromyalgia patients than in the healthy control group.

For example, Faecalibacterium prausnitzii, one of the most abundant and well-studied bacteria in the human gut, was found to be depleted in fibromyalgia patients. It is believed to block pain and inflammation in the intestines.

Other bacteria associated with irritable bowel syndrome, chronic fatigue syndrome and interstitial cystitis were found to be abundant in the fibromyalgia patients, but not in the healthy control group.  

The bacterial differences don’t appear to be related to diets, lifestyles or genetics, since some of the healthy participants lived in the same house as the fibromyalgia patients or were their parents, offspring or siblings.

"We used a range of techniques, including Artificial Intelligence, to confirm that the changes we saw in the microbiomes of fibromyalgia patients were not caused by factors such as diet, medication, physical activity, age, and so on, which are known to affect the microbiome," says Minerbi.

Researchers say it's not clear whether the changes in gut bacteria seen in fibromyalgia patients are simply markers of the disease or whether they play a role in causing it. Because fibromyalgia involves a cluster of symptoms, the next step will be to investigate whether there are similar changes in the gut microbiome of patients with other types of chronic pain, such as back pain, headaches and neuropathic pain.

“This is the first evidence, at least in humans, that the microbiome could have an effect on diffuse pain, and we really need new ways to look at chronic pain." said senior author Yoram Shir, MD, Director of the Alan Edwards Pain Management Unit

If their findings are confirmed, researchers think their discovery could speed up the process of diagnosing fibromyalgia.

"By using machine learning, our computer was able to make a diagnosis of fibromyalgia, based only on the composition of the microbiome, with an accuracy of 87 per cent. As we build on this first discovery with more research, we hope to improve upon this accuracy, potentially creating a step-change in diagnosis," says Emmanuel Gonzalez, PhD, Canadian Center for Computational Genomics and the Department of Human Genetics at McGill University.

Several previous studies have suggested an association between diet and fibromyalgia. Donna Gregory Burch says her fibromyalgia symptoms improved when she went on a gluten-free diet. Studies show that consuming food additives such as monosodium glutamate (MSG) can worsen symptoms, while foods rich in Vitamin D can help reduce joint and muscle pain.

Rats, Depression and Chronic Pain

By Pat Anson, Editor

An unusual study involving rats, depression and chronic pain is making headlines – the latest in a long line of flawed research studies being used to debunk the effectiveness of opioid pain medication.

“NIH study suggests opioid therapy not effective against chronic pain,” is the headline in UPI.

“Pain-induced changes in the brain explain the limited effectiveness of opioid therapy,” is how the Tech Explorist put it.

At issue is a small study by the National Institutes of Health (NIH) and McGill University in Montreal on pain-induced changes in 17 laboratory rats. That's right, 17 rats. The study findings, published in the journal Pain, concluded that chronic pain reduced the number of opioid receptors – the molecules that opioids bind to -- in the rats’ brains. In theory at least, that would make the rats less responsive to opioid pain medication.

Note that the research did not include any people, the rats were not given any opioids, and the effectiveness of opioids wasn't even measured in the rats. But that didn’t stop the NIH from drawing some sweeping conclusions.

“These results provide insights into why we see limited effectiveness of opioid therapy in chronic pain and the mechanism of the depression that may accompany it,” said David Shurtleff, PhD, acting director at the National Center for Complementary and Integrative Health (NCCIH).

“These basic research findings support NIH’s efforts to better understand chronic pain and comorbid symptoms and to develop better ways to help chronic pain patients effectively manage their pain.”

McGill University was more cautious, saying further studies were needed in humans to confirm the study findings.

“Although the study… was conducted in rats, and the results of animal studies may not be directly applicable to people, the findings provide new insights into how the brain may respond to pain and opioids,” a McGill press release states. “These findings, if confirmed in people, will enhance the understanding of the impact of chronic pain on the brain, its relation to depression, and the effects of opioids.”

Researchers have many theories about the origins and treatment of chronic pain, but conducting tests on humans to prove them is problematic. Laboratory animals are often used as an imperfect substitute.

In the NIH/McGill study, 17 rats had brain surgeries to produce a nerve injury that causes chronic pain, while another group of rats had sham surgeries (a similar procedure that did not cause chronic pain). Three months later, PET scan imaging showed opioid receptors had decreased in multiple regions of the brain in the nerve-injured rats, but no changes occurred in the sham-surgery rats.

These results suggest that pain itself, not treatment or pre-existing trauma, altered the brain’s opioid system. Other tests showed a weaker link between chronic pain and depression in the nerve-injured rats.

How did researchers determine the rats were depressed? 

When given a choice, healthy rats will normally drink water sweetened with sugar rather than plain water. But animals with a decreased ability to experience pleasure, a recognized symptom of depression, may not. The rats in the study with chronic pain showed a decreased preference for sugar water over plain water, while rats in the sham group still showed a preference for sweetened water. This, the researchers believe, was enough evidence to conclude the nerve-injured rates were depressed.

“It’s well known that there’s a link between chronic pain and depression,” explained co-author M. Catherine Bushnell, PhD, scientific director of NCCIH’s Division of Intramural Research.  “The results of this study indicate that pain-induced changes in the brain’s opioid system may play a role in this association. Animals with the greatest decrease in opioid receptor availability showed the greatest increase in depression-like symptoms after experiencing chronic pain.”

While intriguing, the results of this rat study are far from definitive and do not prove that opioids are an ineffective treatment for chronic pain in people. What they do show is that we need more and better research about opioids and chronic pain, not more misleading headlines and statements from the NIH.

Chronic Pain Changes Our Immune Systems

By Pat Anson, Editor

Scientists already know that chronic pain can change the way our brains work, but now there is new evidence that pain may also make lasting changes in our immune systems.

In studies on laboratory rats, researchers at McGill University in Montreal found that chronic pain alters the way genes work in the immune system. The discovery may help explain why pain can persist long after the initial injury.

"We found that chronic pain changes the way DNA is marked not only in the brain but also in T cells, a type of white blood cell essential for immunity,” said Moshe Szyf, a professor in the Faculty of Medicine at McGill. "Our findings highlight the devastating impact of chronic pain on other important parts of the body such as the immune system."

McGill researchers examined DNA from the brains and white blood cells of rats nine months after a nerve injury. They found a “stunning” number of changes in DNA methylation – which regulates how genes function. Chronic pain appeared to reprogram how the genes work.

"We were surprised by the sheer number of genes that were marked by the chronic pain -- hundreds to thousands of different genes were changed," adds Szyf. "We can now consider the implications that chronic pain might have on other systems in the body that we don't normally associate with pain."

Many of the genes that were altered are associated with depression, anxiety, and loss of cognition, which are some of the negative side effects of chronic pain.  The findings could open new avenues to diagnosing and treating chronic pain in humans, as some of the genes affected by chronic pain could represent new targets for pain medications.

“These findings reveal potential new avenues for the development of novel therapeutics directed at either the molecular regulation of methylation or at key genes or pathways dysregulated in chronic pain,” the study found.  “This work also provides a possible mechanistic explanation for commonly observed comorbidities observed in chronic pain (i.e anxiety, depression). Finally, the sheer magnitude of the impact of chronic pain, particularly in the prefrontal cortex, illustrates the profound impact that living with chronic pain exerts on an individual.”

The McGill study is published in the journal Scientific Reports.

A recent study at Northwestern University found that chronic pain “rewires” a part of the brain that controls whether we feel happy or sad.  Researchers found that a group of neurons thought to be responsible for negative emotions became hyper-excitable within days of an injury that triggers chronic pain.