Using anti-inflammatory drugs and steroids to relieve pain could increase the chances of developing chronic pain, according to researchers from McGill University and colleagues in Italy. Their research puts into question conventional practices used to alleviate pain. Normal recovery from a painful injury involves inflammation and blocking that inflammation with drugs could lead to harder-to-treat pain.

“For many decades it’s been standard medical practice to treat pain with anti-inflammatory drugs. But we found that this short-term fix could lead to longer-term problems,” says Jeffrey Mogil, a Professor in the Department of Psychology at McGill University and E. P. Taylor Chair in Pain Studies.

The difference between people who get better and don’t

In the study published in Science Translational Medicine, the researchers examined the mechanisms of pain in both humans and mice. They found that neutrophils – a type of white blood cell that helps the body fight infection – play a key role in resolving pain.

“In analyzing the genes of people suffering from lower back pain, we observed active changes in genes over time in people whose pain went away. Changes in the blood cells and their activity seemed to be the most important factor, especially in cells called neutrophils,” says Luda Diatchenko a Professor in the Faculty of Medicine, Faculty of Dentistry, and Canada Excellence Research Chair in Human Pain Genetics.

Inflammation plays a key role in resolving pain

“Neutrophils dominate the early stages of inflammation and set the stage for repair of tissue damage. Inflammation occurs for a reason, and it looks like it’s dangerous to interfere with it,” says Professor Mogil, who is also a member of the Alan Edwards Centre for Research on Pain along with Professor Diatchenko.

Experimentally blocking neutrophils in mice prolonged the pain up to ten times the normal duration. Treating the pain with anti-inflammatory drugs and steroids like dexamethasone and diclofenac also produced the same result, although they were effective against pain early on.

Thesefindings are also supported by a separate analysis of 500,000 people in the United Kingdom that showed that those taking anti-inflammatory drugs to treat their pain were more likely to have pain two to ten years later, an effect not seen in people taking acetaminophen or anti-depressants.

Reconsidering standard medical treatment of acute pain

“Our findings suggest it may be time to reconsider the way we treat acute pain. Luckily pain can be killed in other ways that don’t involve interfering with inflammation,” says Massimo Allegri, a Physician at the Policlinico of Monza Hospital in Italy and Ensemble Hospitalier de la Cote in Switzerland.

“We discovered that pain resolution is actually an active biological process,” says Professor Diatchenko. These findings should be followed up by clinical trials directly comparing anti-inflammatory drugs to other pain killers that relieve aches and pains but don’t disrupt inflammation.”

A new study is the first to investigate brain connectivity patterns at rest in veterans with both chronic pain and trauma, finding three unique brain subtypes potentially indicating high, medium, and low susceptibility to pain and trauma symptoms. The findings provide an objective measurement of pain and trauma susceptibility and could pave the way for personalized treatments and new therapies based on neural connectivity patterns.  

Chronic pain and trauma often co-occur. However, most previous research investigated them in isolation and using subjective measures such as surveys, leading to an incomplete picture. A new study in Frontiers in Pain Research has filled in some of the blanks. It found three unique brain connectivity signatures that appear to indicate veteran susceptibility or resilience to pain and trauma, regardless of their diagnostic or combat history. The study could pave the way for more objective measurements of pain and trauma, leading to targeted and personalized treatments.

Chronic pain and trauma are linked but not studied together

“Chronic pain is a major public health concern, especially among veterans,” said first author Prof Irina Strigo of the San Francisco Veterans Affairs Health Care Center. “Moreover, chronic pain sufferers almost never present with a single disorder but often with multiple co-morbidities, such as trauma, posttraumatic stress, and depression.”

Researchers already understand that both pain and trauma can affect connections in our brains, but no-one had studied this in the context of co-occurring trauma and pain. Much pain and trauma research also relies on subjective measurements, such as questionnaires, rather than objective measurements, such as brain scans.

Identifying brain connectivity signatures of pain and trauma

Taking a different approach, the researchers behind this new research studied a group of 57 veterans with both chronic back pain and trauma. The group had quite varied symptoms in terms of pain and trauma severity. By scanning the veterans’ brains using functional magnetic resonance imaging, the researchers identified the strength of connections between brain regions involved in pain and trauma. They then used a statistical technique to automatically group the veterans based on their brain connection signatures, regardless of their self-reported pain and trauma levels.

Based on the veterans’ brain activity, the computer automatically divided them into three groups. Strikingly, these divisions were comparable to the severity of the veterans’ symptoms, and they fell into a low, medium, or high symptom group.

The researchers hypothesized that the pattern of brain connections found in the low symptom group allowed veterans to avoid some of the emotional fallout from pain and trauma, and also included natural pain reduction capabilities. Conversely, the high symptom group demonstrated brain connection patterns that may have increased their chances of anxiety and catastrophizing when experiencing pain.

Interestingly, based on self-reported pain and trauma symptoms, the medium symptom group was largely similar to the low symptom group. However, the medium symptom group showed differences in their brain connectivity signature, which suggested that they were better at focusing on other things when experiencing pain, reducing its impact.  

Putting the findings into future practice

“Despite the fact that the majority of subjects within each subgroup had a co-morbid diagnosis of pain and trauma, their brain connections differed,” said Strigo.

“In other words, despite demographic and diagnostic similarities, we found neurobiologically distinct groups with different mechanisms for managing pain and trauma. Neurobiological-based subgroups can provide insights into how these individuals will respond to brain stimulation and psychopharmacological treatments.”

So far, the researchers don’t know whether the neural hallmarks they found represent a vulnerability to trauma and pain or a consequence of these conditions. However, the technique is interesting, as it provides an objective and unbiased hallmark of pain and trauma susceptibility or resilience. It does not rely on subjective measures such as the surveys. In fact, subjective measurements of pain in this study would not differentiate between the low and medium groups.

Techniques that use objective measures, such as brain connectivity, appear more sensitive and could provide a clearer overall picture of someone’s resilience or susceptibility to pain and trauma, thereby guiding personalized treatment and paving the way for new treatments.

No condition gives more relief when treated sufficiently to both patient and physician than chronic pain. Every day, the problem of pain plagues millions of people in our society, pain decreases our productivity and our ability to enjoy life pain interferes with our sleep and our ability to manage the day to day tasks.

And some studies have shown that pain that interferes with daily life can also be associated with an increased risk of mortality. Traditional medicine will often treat pain with an anti-inflammatory or analgesic like acetaminophen. If these do not work often, the person has been prescribed a stronger anti-inflammatory medication.

And if the pain persists or does not respond to these medications, Prescribers often feel there is little choice, but to resort, to opioids like morphine, oxycodone and hydromorphone, all of these medications come with their own set of contraindications and possible drug interactions.

And none of them is without side effects. In the words of today’s guest pharmacist, Graham McKenzie, this has resulted in an opioid epidemic that has destroyed lives and shattered the public’s belief in the pharmaceutical system. This begs the question. What if there was another option?

Imanuel Lerman, MD, is an associate professor of anesthesiology and pain management specialist. CREDIT UC San Diego Health Sciences

Spinal cord stimulation (SCS) for chronic pain involves delivering low levels of electricity directly into the spinal cord using an implanted device, which modifies or blocks nerve activity to minimize the sensation of pain reaching the brain. The approach is most often used after nonsurgical pain treatment options have failed to provide sufficient relief.

The underlying mechanisms of how SCS works are not fully understood, but in a new paper published in the April 28, 2022 online issue of the journal Bioelectronic Medicine, a research team led by scientists at University of California San Diego School of Medicine report high-frequency SCS proved more effective at improving perceived pain reduction (PPR) than low-frequency SCS in patients studied, and that there was some variation in PPR between male and female patients.

Low-frequency SCS (50 Hz) was originally approved by the U.S. Food and Drug Administration (FDA) as a treatment for intractable back and leg pain in 1989. In 2015, the FDA approved high-frequency SCS (10,000 Hz), which delivers electrical stimulation pulses that are shorter in duration, lower in amplitude and do not induce paresthesia, the abnormal sensation of tingling or prickling.

The newly published retrospective study examined 237 patients who had received SCS treatment between 2004 and 2020: 94 patients (40 females, 54 males) who received HF-SCS and 143 patients (70 females and 73 males) who received LF-SCS. At three and six months post-implantation, the researchers found that PPR across all patients improved compared to baseline, but HF-SCS produced greater PPR than LF-SCS. HF-SCS was also associated with less subsequent use of opioids to mitigate pain.

However, there were differences in the findings between sexes:

• Male PPR, for example, was significantly better for HF-SCS at three and six months when compared to LF-SCS, while this was only true for females at the 6 month time point.
• LF-SCS males used more opioids post-implantation and at six months while females used more opioids post-implantation, at three, six and tended to use more opiates at the 12-month time-point.

“Our work was sparked by a growing literature that demonstrate sex specific immune pathways differentially contribute to chronic pain processes,” said senior author Imanuel Lerman, MD, an associate professor of anesthesiology, pain management specialist at UC San Diego Health, and an affiliate of the Qualcomm Institute. “The observed parameter-specific (high versus low frequency) sex-based differences in spinal cord stimulation efficacy and opiate use are definitely intriguing. 

“It’s a first step in the right direction, but clearly more work needs to be done to carefully characterize sex specific pain regulatory pathways that may prove responsive to specific types of neuromodulation and or pharmaceutical therapies.”