Category: Pain Management

Categories : Cardiovascular Disease Pain ManagementTags :

Researchers Quantify Risk Factors for Oral Diclofenac

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Safety concerns related to the widely used analgesic diclofenac may be tied to a little-studied drug-metabolising enzyme which can vary as much as 3000 times across individuals, according to new research published in the journal Clinical Pharmacology & Therapeutics.

The findings could be used to develop ways to identify those at risk of serious side effects from the drug. They may help determine safer dosing standards for specific populations, including women, young children and people of certain ethnicities.

Used to treat arthritis-associated pain and inflammation, diclofenac was available over-the-counter in the US until 2013, when the Food and Drug Administration restricted it to prescription-only use following reports of the drug causing heart damage. More than 10 million prescriptions per year are written for it in the US. It is also one of the most widely used non-steroidal anti-inflammatory drugs worldwide, and is still over-the-counter in many countries. 

“Most patients who are using diclofenac have arthritis, and many of them are at risk of heart disease,” senior author Bhagwat Prasad, an associate professor at Washington State University. “So there is a concern that taking diclofenac may be putting them at even greater risk of cardiovascular events such as heart attack and stroke.”

Previous findings by the WSU team had found a high degree of variability in the expression of UGT2B17, an enzyme that is a known player in diclofenac metabolism. They found that the enzyme is present at much lower levels in women than in men, which could explain the increased risk of heart damage seen in women taking diclofenac. The enzyme was also mostly absent in children under age 9 and discovered large ethnicity-based differences in the number of people who lack the gene for the enzyme altogether, which ranges from around 20% of Caucasians up to around 90% of Japanese people.

In this new study, the WSU researchers used human liver and intestinal samples along with computer modelling to quantify the degree to which this enzyme contributes to diclofenac metabolism relative to other related enzymes. They found it to be a major player, supporting the idea that low levels of the UGT2B17 enzyme may be the cause of heart damage tied to diclofenac use.

“No one knew why this heart toxicity is happening in some individuals,” said first author Deepak Ahire, a graduate student in the WSU College of Pharmacy and Pharmaceutical Sciences. “Our study showed, for the first time, that UGT2B17 is important in diclofenac metabolism and suggests that differences in UGT2B17 expression are what makes people’s response to diclofenac so variable, leading to toxicity in some whereas for others the drug simply does not work.”

Ahire said that their study found that this enzyme metabolises diclofenac mainly in the intestine, unlike other related enzymes that are active mostly in the liver. Thus the observed effects are limited to diclofenac tablets taken by mouth, which provides for the quickest absorption and pain relief.

The findings suggest genetic testing could help healthcare providers evaluate safety risks before prescribing diclofenac. Prasad also noted that drug regulatory authorities in countries where diclofenac is still available over the counter should consider doing efficacy testing to determine the optimal dose of the drug for their local market.

The WSU researchers are currently in the process of confirming their findings in a pilot clinical trial. Their next step would be to pursue collaborations with large hospitals to study the connection between diclofenac and heart damage in patients’ electronic medical records.

Source: Washington State University

Categories : Pain ManagementTags :

Scientists Probe Links Between Chronic Alcohol Use and Pain Sensitivity

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The links between alcohol and pain are complex. Research published in the British Journal of Pharmacology suggests that chronic alcohol consumption may increase drinkers’ pain sensitivity through two different molecular mechanisms – the first driven by alcohol intake and the second by alcohol withdrawal.

The research also suggests potential new drug targets for treating alcohol-associated chronic pain and hypersensitivity.

“There is an urgent need to better understand the two-way street between chronic pain and alcohol dependence,” says senior author Marisa Roberto, PhD, the Schimmel Family Chair of Molecular Medicine, and a professor of neuroscience at Scripps Research. “Pain is both a widespread symptom in patients suffering from alcohol dependence, as well as a reason why people are driven to drink again.”

Over time, alcohol use disorder (AUD) can trigger the development of numerous chronic diseases, including heart disease, stroke, liver disease and some cancers. Among the many impacts of long-term alcohol consumption is pain: more than half of people with AUD experience persistent pain of some type. This includes alcoholic neuropathy, which is nerve damage that causes chronic pain and other symptoms.

Studies have also found that AUD is associated with changes in how the brain processes pain signals, as well as changes to how immune system activation occurs. In turn, this pain can lead to increased alcohol consumption. Moreover, during withdrawal, people with AUD can experience allodynia, in which a harmless stimulus is perceived as painful.

Roberto and her colleagues were interested in learning the underlying causes of these different types of alcohol-related pain. In the new study, they compared three groups of adult mice: animals that were dependent on alcohol (excessive drinkers), animals that had limited access to alcohol and were not considered dependent (moderate drinkers), and those that had never been given alcohol.

In dependent mice, allodynia developed during alcohol withdrawal, and subsequent alcohol access significantly decreased pain sensitivity. Separately, about half of the mice that were not dependent on alcohol also showed signs of increased pain sensitivity during alcohol withdrawal but, unlike the dependent mice, this neuropathy was not reversed by re-exposure to alcohol.

When Roberto’s group then measured levels of inflammatory proteins in the animals, they discovered that while inflammation pathways were elevated in both dependent and non-dependent animals, specific molecules were only increased in dependent mice. This indicates that different molecular mechanisms may drive the two types of pain. It also suggests which inflammatory proteins may be useful as drug targets to combat alcohol-related pain.

“These two types of pain vary greatly, which is why it is important to be able to distinguish between them and develop different ways to treat each type,” says first author Vittoria Borgonetti, PhD, a postdoctoral associate at Scripps Research.

Roberto’s group is continuing studies on how these molecules might be used to diagnose or treat alcohol-related chronic pain conditions.

“Our goal is to unveil new potential molecular targets that can be used to distinguish these types of pain and potentially be used in the future for the development of therapies,” says co-senior author Nicoletta Galeotti, PhD, associate professor of preclinical pharmacology at the University of Florence.

Source: Scripps Research Institute

Categories : Genetics Pain ManagementTags :

Whether Hypnosis for Pain is Effective Depends on a Patient’s Genetics

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Studies have shown that hypnosis is an effective treatment for pain for many individuals – but it depends on the patient’s susceptibility to hypnosis. Testing for hypnotisability requires special training and in-person evaluation rarely available in the clinical setting. Now, investigators have developed a fast, point-of-care molecular diagnostic test that identifies a subset of individuals. Their study, published in The Journal of Molecular Diagnostics, also found that a subset of highly hypnotisable individuals may be more likely to experience high levels of postoperative pain.

“Since hypnotisability is a stable cognitive trait with a genetic basis, our goal was to create a molecular diagnostic tool for objectively identifying individuals who would benefit from hypnosis by determining ‘treatability’ at the point-of-care,” explained co-lead investigator Dana L. Cortade, a recently graduated PhD at Stanford University. “The advancement of nonpharmacological adjuvant treatments for pain is of the utmost importance in light of the opioid epidemic.”

Prior research established that the genetic basis for hypnotisability includes four specific single-nucleotide polymorphisms (SNPs), or genetic variations, found in the catechol-o-methyltransferase (COMT) gene for a brain enzyme responsible for dopamine metabolism in the prefrontal cortex. Although SNPs can contain valuable information on disease risk and treatment response, cost, complexity and time prevent widespread use.

The investigators developed a SNP genotyping assay on a giant magnetoresistive (GMR) biosensor array to detect the optimal combination of the COMT SNPs in patient DNA samples. GMR biosensor arrays are reliable, cheaper, sensitive, and can be easily deployed in point-of-care settings using saliva or blood samples.

The study investigated the association between COMT diplotypes and hypnotisability using a clinical hypnotisability scale called the Hypnotic Induction Profile (HIP) in individuals who had participated in one of the three previous clinical trials in which an HIP was administered. An additional exploratory study of the association between perioperative pain, COMT genotypes, and HIP scores was conducted with the patients in the third cohort, who had undergone total knee arthroplasty (TKA). DNA was extracted from blood samples previously collected in the first cohort, and saliva samples were collected by mail from participants in the other two trials. Participants were considered treatable by hypnosis if they had HIP scores of 3 or higher on a scale of zero to 10.

For participants identified with the optimal COMT diplotypes by the GMR biosensor array, 89.5% scored highly on the HIP, which identified 40.5% of the treatable population. The optimal COMT group mean HIP score was significantly higher than that in the suboptimal COMT group. Interestingly, further analysis revealed that the difference was observed only in women.

“Although we had expected some difference in effect between females and males, the association between hypnotisability and COMT genotypes was strongest in the females in the cohort,” said co-lead investigator Jessie Markovits, MD, Department of Internal Medicine, Stanford School of Medicine, Stanford, CA, USA. “The difference may be due to lower numbers of males in the cohort, or because COMT is known to have interactions with oestrogen and to differ in activity by sex. Additional gene targets including COMT, with stratification by sex, could be the focus of future study.”

In the exploratory analysis of the relationship between COMT genotypes and pain after TKA surgery, the same optimal COMT individuals had significantly higher postoperative pain scores than the suboptimal group, indicating a greater need for treatment. “This supports the body of evidence that COMT genotypes impact pain, and it is also known that COMT genotypes affect opioid use after surgery. Pain researchers can use this technology to correlate genetic predisposition to pain sensitivity and opioid use with response to an evidence-based, alternative remedy: hypnosis,” Dr Cortade said.

COMT SNPs alone are not a complete biomarker for identifying all individuals who will score highly on a hypnotisability scale and experience high pain sensitivity. The GMR sensor nanoarray can accommodate up to 80 SNPs, and it is possible that other SNPs, such as those for dopamine receptors, are needed to further stratify individuals.

The investigators observe that this study highlights the utility and potential of the evolving applications of precision medicine. “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,” Dr Markovits said. “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.”

Source: Elsevier

Categories : Pain ManagementTags :

Spinal Degeneration Pain may Result from Damaged, Stiffened Ligaments

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From back pain to achy joints, musculoskeletal pain, while common, can be life-changing and debilitating. A recent study published by the Journal of Biomechanical Engineering reveals that, in spinal degeneration, stiffening ligaments can alter mechanical loading on joints resulting in facet joint pain. This research may help to develop new treatments for musculoskeletal pain.

“Our goal is to understand the degeneration process of musculoskeletal tissues, including cartilage, ligaments, and intervertebral discs, using advanced mechanics techniques,” says Jill Middendorf, an assistant professor of mechanical engineering at Johns Hopkins University. “If we understand why this process is happening, we hope to translate our findings into new methods to repair damaged tissues and prevent more pain,”

Middendorf and collaborators sought to understand how the soft tissues of the spine change as spinal discs break down, or degenerate, over time.

Specifically, they looked at the facet capsular ligament, a soft tissue that holds the two sides of the facet joint together and is thought to be a common cause of lower back pain. Previous studies suggest this could be related to mechanical changes that occur in this ligament during spinal degeneration, though it’s not clear exactly why, Middendorf says.

To find out, the team extracted facet capsular ligaments from cadaver spines and ran experiments to measure the ligament’s mechanical properties, like stress and strain, under different loading conditions. By comparing MRI images of the spine and their experimental results, the team discovered that the tissues in the ligament became stiffer as the spine degenerated.

The researchers think this increased stiffness causes altered loading in surrounding tissues, and may explain why some people experience facet joint pain.

“Here we show that there is a correlation between the mechanics of the ligament and spine degeneration, which brings us even closer to being able determine if this ligament is causing pain or if it’s some other part of the spine,” Middendorf says.

With insights gathered from their tissue experiments, researchers in Middendorf’s lab plan to work next on furthering our understanding of spinal degeneration and creating engineered musculoskeletal tissue that can be implanted to replace damaged or diseased tissue.

However, when it comes to pain, answers aren’t always easy to find.

“‘One of the challenges associated with diagnosing and treating spine pain is determining the source of the pain,” Middendorf says. “But we can understand more about the causes and mechanisms of tissue damage, and that means we will someday be able to reverse engineer a solution.”

Source: Johns Hopkins

Categories : Ageing Pain ManagementTags :

The Impacts of Persistent Pain in Older Adults

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Woman holding an old man's hand
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In a study of 5589 US adults aged 65 years and older, persistent pain was common and was linked to meaningful declines in physical function and well-being over 7 years. Reporting in the Journal of the American Geriatrics Society, investigators found that 38.7% of participants reported persistent pain, and 27.8% reported intermittent pain. (“Persistent pain” was defined as being bothered by pain in the last month in two consecutive annual interviews and “intermittent” pain was defined as bothersome pain in one interview only.)  

More than one-third of participants described pain in five or more sites. Over the subsequent 7 years, participants with persistent pain were more likely to experience declines in physical function (64% persistent pain, 59% intermittent pain, 57% no bothersome pain) and well-being (48% persistent pain, 45% intermittent pain, 44% no bothersome pain), but were not more likely to experience cognitive decline (25% persistent pain, 24% intermittent pain, 23% no bothersome pain).

“The findings from this study point to the importance of access to effective treatment for persistent pain in older adults and the need for additional research in chronic pain to optimise quality of life,” said lead author Christine Ritchie, MD, MSPH, of Massachusetts General Hospital.

Source: Wiley

Categories : Pain ManagementTags :

Paracetamol and NSAIDs Best Non-opioid Drugs for Low Back Pain

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Acute low back pain is a common cause of disability, and while opioid drugs are effective at controlling pain, excessive use creates a great potential for substance abuse. An analysis in the Journal of Orthopaedic Research examined which non-opioid drugs are best for relieving this pain.

The analysis, which included all randomised controlled trials published to date (18 studies with 3478 patients), showed that muscle relaxants and non-steroidal anti-inflammatory drugs (NSAIDs) could effectively and rapidly reduce symptoms.

The combination of NSAIDs and paracetamol was associated with a greater improvement than NSAIDs alone.

“This is a first step towards the optimisation of the management of acute low back pain. However, specific patient characteristics such as having allergies and comorbidities must always be taken into consideration,” said lead author Alice Baroncini, MD, PhD, of RWTH University Hospital in Germany. “Further research will need to focus on the identification of the type of drugs that not only offer the best and quickest pain relief, but also show the lowest rate of symptom recurrence.”

Source: Wiley

Categories : Pain ManagementTags :

Brain Structures Predict Risk of Awareness under Anaesthesia

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Awareness during anaesthesia is an extremely rare but horrific risk for patients. Now, for the first time, neuroscientists have identified brain structures which could predict an individual’s predisposition this phenomenon. The findings, just published in the journal Human Brain Mapping, could help identify patients who need larger anaesthetic doses.

Although anaesthesia has been used in clinical medicine for over 150 years, scientists do not fully understand why its effect on people is so varied. One in four patients presumed to be unconscious during general anaesthesia may in fact have subjective experiences, such as dreaming. Estimated to occur in 1:1000 to 1:20 000 cases, some patients may have awareness under general anaesthetic. These experiences may range from hearing sounds to the pain of surgery combined with the sensation of suffocation and paralysis in the setting of neuromuscular blockade.

The researchers from Trinity College Dublin found that one in three participants were unaffected by moderate propofol sedation in their response times, thus thwarting a key aim of anaesthesia – the suppression of behavioural responsiveness.

The research also showed, for the first time, that the participants who were resistant to anaesthesia had fundamental differences in the function and structures of the fronto-parietal regions of the brain to those who remained fully unconscious. Crucially, these brain differences could be predicted prior to sedation.

Lorina Naci, Associate Professor of Psychology, Trinity who lead the research said:

“The detection of a person’s responsiveness to anaesthesia prior to sedation has important implications for patient safety and wellbeing. Our results highlight new markers for improving the monitoring of awareness during clinical anaesthesia. Although rare, accidental awareness during an operation can be very traumatic and lead to negative long-term health outcomes, such as post-traumatic stress disorder, as well as clinical depression or phobias.”

“Our results suggest that individuals with larger grey matter volume in the frontal regions and stronger functional connectivity within fronto-parietal brain networks, may require higher doses of propofol to become nonresponsive compared to individuals with weaker connectivity and smaller grey matter volume in these regions.”

The research, conducted in Ireland and Canada, investigated 17 healthy individuals who were sedated with propofol, the most common clinical anaesthetic agent. The participants’ response time to detect a simple sound was measured when they were awake and as they became sedated. Brain activity of 25 participants as they listened to a simple story in both states was also measured.

Source: Trinity College Dublin

Categories : Diseases, Syndromes and Conditions Pain ManagementTags :

Cluster Headaches are Linked to other Medical Conditions

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People with cluster headaches may be more than three times more likely to have other medical conditions such as heart disease, mental disorders and other neurologic diseases, according to a study published in Neurology.

Cluster headaches are short but extremely painful headaches that can occur many days, or even weeks, in a row. The headaches can last anywhere from 15 minutes to three hours.

“Around the world, headaches have an incredibly negative impact on people’s quality of life, both economically and socially,” said study author Caroline Ran, PhD, of the Karolinska Institutet in Stockholm, Sweden. “Our results show that people with cluster headaches not only have an increased risk of other illnesses, those with at least one additional illness missed four times as many days of work due to sickness and disability than those with just cluster headaches. They also have a higher chance of a long-term absence from work.”

The study involved 3240 people with cluster headaches ages 16–64 in Sweden who were compared to 16 200 matched controls. The majority were men, typical of cluster headache.

Researchers looked at work records and disability benefits to determine how many days during a year people were absent from work due to sickness and disability.

Among those with cluster headaches, 92%, or 2977 people, had at least one additional illness. Of those without cluster headaches, 78%, or 12 575 people, had two or more illnesses.

Of those with cluster headaches, more women had additional illnesses than men, 96% and 90% respectively.

The average number of days a person was absent due to sickness and disability was nearly twice as high among people with cluster headaches with 63 days compared to those without cluster headaches with 34 days.

People with cluster headaches and at least one additional illness had four times as many absence days compared to people with cluster headaches who did not have an additional illness.

“Increasing our understanding of the other conditions that affect people with cluster headache and how they impact their ability to work is very important,” added Ran. “This information can help us as we make decisions on treatments, prevention and prognoses.”

A limitation of the study was that information on personal data, such as smoking, alcohol consumption and BMI, which could affect the occurrence of diseases, was not available.

Source: American Academy of Neurology

Categories : Implants and Prostheses Pain ManagementTags : 1 Comment

Do Spinal Cord Stimulators Live up to Pain Relief Expectations?

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A comparison of spinal cord stimulators (SCS) revealed that the implants only offer a notable benefit within the first year of use, while also being associated with a high risk of adverse effects – nearly one in five, and a similar number requiring device revision or removal.

In this propensity-matched comparative effectiveness research analysis of 7560 insured individuals published in JAMA Neurology, treatment with SCS was not associated with a reduction in use of opioids, pain injections, radiofrequency ablation, or spine surgery at two years.

The study used administrative claims data, including longitudinal medical and pharmacy claims, from 2020–2021. Patients with incident diagnosis codes for failed back surgery syndrome, complex regional pain syndrome, chronic pain syndrome, and other chronic postsurgical back and extremity pain were included in this study.

Patients were an average age of 63.5 years and 59.3% were female. Among matched patients, during the first year, patients treated with SCSs had higher odds of chronic opioid use (adjusted odds ratio [aOR], 1.14) compared with patients treated with CMM but lower odds of epidural and facet corticosteroid injections (aOR, 0.44), radiofrequency ablation (aOR, 0.57), and spine surgery (aOR, 0.72).

During the second year, these beneficial effects disappeared. Compared to CMM there were no significant differences with SCS use in:

  • chronic opioid use (aOR, 1.06),
  • epidural and facet corticosteroid injections (aOR, 1.00)
  • radiofrequency ablation (aOR, 0.84)
  • spine surgery (aOR, 0.91)

Overall, 226 of 1260 patients (17.9%) treated with SCS experienced SCS-related complications within 2 years, and 279 of 1260 patients (22.1%) had device revisions and/or removals, which were not always for complications. Total costs of care in the first year were $39 000 higher with SCS than CMM and similar between SCS and CMM in the second year.

In an accompanying editorial, Prasad Shirvalkar, MD, PhD, and Lawrence Poree. MD, PhD, MPH conclude: “The findings appear to belie the popular belief that SCS may result in reduced opioid medication usage or overall fewer physician visits in the years immediately following device implant.”

They continue: “Notably, a formal cost-utility analysis was not done, and therefore caution is advised not to interpret these results as an argument against the therapeutic effectiveness of SCS for reducing symptoms or improving daily function. After all, there is surely some intrinsic social value to alleviating symptoms and improving individual function that may justify health care costs for chronic pain, just as in the practical treatment of cancer or heart disease.”

Categories : Pain ManagementTags :

Cannabis Medical Trials get Positive Media Coverage Despite Results

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In many trials testing cannabis for pain relief, there is no significant difference between placebo and the active cannabinoid substance. Still, these studies receive significant media coverage regardless of the clinical outcome, according to a study published in JAMA Network Open.

“We see that cannabis studies are often described in positive terms in the media regardless of their results,” says the study’s first author Filip Gedin, postdoc researcher at Karolinska Institutet. “This is problematic and can influence expectations when it comes to the effects of cannabis therapy on pain. The greater the benefit a treatment is assumed to have, the more potential harms can be tolerated.”

The study is based on an analysis of published clinical studies in which cannabis has been compared with placebo for the treatment of clinical pain. The change in pain intensity before and after treatment were the study’s primary outcome measurement.

The analysis drew on 20 studies published up to September 2021 involving almost 1500 individuals.

No difference between cannabis and placebo

The results of the study show that pain is rated as being significantly less intense after treatment with placebo, with a moderate to large effect. The researchers also observed no difference in pain reduction between cannabis and placebo, which corroborates results from another recently published meta-analysis. 

“There is a distinct and clinically relevant placebo response in studies of cannabis for pain,” says Dr Gedin.

The researchers also examined a possible connection between the magnitude of the therapeutic effect shown by the cannabis studies and the coverage they receive in the media and in academic journals. Media presence was measured through Altmetric, which is a method of evaluating mentions in the media, in blogs and on social media. Academic impact was measured in terms of citations by other researchers.

The analysis of media presence included a total of 136 news items in traditional media and in blogs and was categorised as positive, negative or neutral, depending on how the results were presented concerning the effectiveness of cannabis as a treatment for pain.

Lots of media attention

The researchers found that the cannabis studies received much greater media attention than other published studies. The coverage was substantial regardless of the magnitude of the placebo response and regardless of the therapeutic effect of cannabis. They also observed no link between the proportion of positively described news about a study and the effect it reported. 

The researchers add the caveat that their study combined trials of varying designs and quality and therefore the results should be interpreted with caution.

This research was financed by Riksbankens Jubileumsfond (Karin Jensen). The researchers report no potential conflicts of interest.

Source: Karolinska Institute