US Pharm. 2023;48(3):28-32.

Some Antidepressants Ineffective in Treating Chronic Pain

Many people are unaware that some antidepressants (medications used to treat people living with depression) are also being prescribed to treat certain chronic pain conditions.

Chronic pain affects between one-third and one-half of the UK population. The treatment of chronic pain is often suboptimal, with commonly used medicines having limited or unknown benefits and, sometimes, harmful side effects. Antidepressants are prescribed to help manage chronic pain, even when the person affected does not have a mood disorder such as depression. Their use has been increasing over time.

An international team of researchers, including academics from the University of Warwick, has found that some classes of antidepressants were effective in treating certain pain conditions in adults, but others either were not effective or the effectiveness was unknown. Published in The BMJ, the study reviewed the safety and effectiveness of antidepressants in the treatment of chronic pain, bringing together all of the existing evidence in one document.

The researchers say the results show that clinicians need to consider all the evidence before deciding to prescribe antidepressants for chronic pain management. Martin Underwood from the University of Warwick, a coauthor of the paper, said, “There is a role for antidepressants in helping people living with chronic pain, however, this is more limited than previously thought. Antidepressants may have unpleasant side effects that patients may wish to avoid. We need to work harder to help people manage their pain and live better, without relying on the prescription pad.”

The review examined 26 systematic reviews from 2012 to 2022 involving more than 25,000 participants and 150 clinical trials. This included data from eight antidepressant classes and 22 pain conditions, such as back pain, fibromyalgia, headaches, postoperative pain, and irritable bowel syndrome. Serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants such as duloxetine were found to be effective for the largest number of pain conditions, including back pain, knee osteoarthritis, postoperative pain, fibromyalgia, and neuropathic pain (nerve pain).

In contrast, tricyclic antidepressants, such as amitriptyline, are the most commonly used antidepressant to treat pain in clinical practice, but the review showed that it is unclear how well they work or whether they work at all for most pain conditions.

The use of antidepressants as a treatment for pain has recently gained attention globally. A 2021 guideline for chronic primary pain management published by the National Institute for Health and Care Excellence (NICE) recommends against using pain medicines, with the exception of antidepressants. The guideline recommends different types of antidepressants, such as amitriptyline, citalopram, duloxetine, fluoxetine, paroxetine, or sertraline, for adults living with chronic primary pain.

Lead author Giovanni Ferreira from The Institute for Musculoskeletal Health and Sydney Musculoskeletal Health at the University of Sydney, Australia, said a more nuanced approach to prescribing antidepressants for pain is needed. “Recommending a list of antidepressants without careful consideration of the evidence for each of those antidepressants for different pain conditions may mislead clinicians and patients into thinking that all antidepressants have the same effectiveness for pain conditions. We showed that is not the case.”

Coauthor Christina Abdel Shaheed from the School of Public Health and Sydney Musculoskeletal Health at the University of Sydney said, “The findings from this review will support both clinicians and patients to weigh up the benefits and harms of antidepressants for various pain conditions so that they can make informed decisions about whether and when to use them.”

Dr. Ferreira said that there are multiple treatment options for pain, and people should not rely solely on pain medicines for pain relief. “Some pain medicines may have a role in pain management, but they need to be considered as only part of the solution. For some pain conditions, exercise, physiotherapy, and lifestyle changes may also help. Speak to your health professional to learn more about what alternatives might be appropriate for you.”

Scientists Seek a Better Pain Killer

Research published in Cell provides a comprehensive structural framework that might help drug developers rationally design safer drugs to relieve severe pain. The work was spearheaded by the laboratory of Eric Xu, PhD, at the CAS Key Lab of Receptor Research in China in collaboration with the laboratory of Bryan L. Roth, MD, PhD, at the University of North Carolina (UNC) School of Medicine, where graduate student Jeff DiBerto led the pharmacologic experiments to understand the receptors’ signaling mechanisms.

Opioid drugs relieve pain by mimicking a naturally occurring pain-relief function within the nervous system. They are the best, strongest pain relievers we have. Unfortunately, they come with side effects, some severe—such as numbness, addiction, and respiratory depression—leading to overdose deaths.

Scientists have been trying for many years to overcome the side-effect problem in various ways, all involving one or more of four opioid receptors, to no avail. One avenue scientists continue to explore is the creation of peptide or peptide-inspired small molecule drugs.

Peptides are short chains of amino acids. Certain naturally occurring, or endogenous, peptides bind to opioid receptors on the surface of cells to create an analgesic effect, also known as pain relief. Analgesics, unlike anesthetics, do not “turn off” the nerves to numb the body or alter consciousness. The goal, therefore, is to create a peptide drug that has a strong analgesic effect without numbing nerves, altering consciousness, or causing digestive, respiratory, or addiction issues.

“The problem in the field is we’ve lacked the molecular understanding of the interplay between opioid peptides and their receptors,” said Dr. Roth, cosenior author and the Michael Hooker Distinguished Professor of Pharmacology. “We’ve needed this understanding in order to try to rationally design potent and safe peptide or peptide-inspired drugs.”

Using cryogenic electron microscopy (cryoEM) and a battery of biomechanistic experiments in cells, the Xu and Roth laboratories systematically solved the detailed structures of endogenous peptides bound to all four opioid receptors. These structures revealed details and insights into how specific naturally occurring opioid peptides selectively recognize and activate opioid receptors. The researchers also used exogenous peptides, or drug-like compounds, in some of their experiments to learn how they activate the receptors.

The cryoEM structures of agonist-bound receptors with their G protein effectors (called their “active state”) represent what these receptors look like when they are signaling in cells, giving a detailed view of peptide-receptor interactions. The Roth laboratory used the structures solved by the Xu laboratory to guide the design of mutant receptors and then tested these receptors in biochemical assays in cells to determine how they alter receptor signaling. Understanding these interactions might be useful in designing drugs that are selective for opioid receptor subtypes as well as to produce certain signaling outcomes that may be more beneficial than those of conventional opioids.

“This collaboration revealed conserved, or shared, mechanisms of activation and recognition of all four opioid receptors, as well as differences in peptide recognition that can be exploited for creating subtype-selective drugs,” said Mr. DiBerto, first author and PhD candidate in the Roth laboratory. “We provide more needed information to keep pushing the field forward, to answer basic science questions we hadn’t been able to answer before now.”

Drugs such as oxycontin, oxycodone, and morphine cause various effects inside cells and throughout the nervous system, including pain relief. But they have effects in the digestive and respiratory systems, too, and interact with cells to lead to addiction. Fentanyl, meanwhile, is another powerful pain reliever, but it binds to opioid receptors in such a way as to cause severe side effects, including the shutdown of the respiratory system.

The thrust behind such research led by Drs. Xu and Roth is to home in on the mechanistic reasons for pain relief potency without triggering the cellular mechanisms that lead to severe side effects and overdosing. “We are attempting to build a better kind of opioid,” Dr. Roth said. “We’re never going to get there without these kind of basic molecular insights, wherein we can see why pain is relieved and why side effects occur.”

Vitamin D Fails to Reduce Statin-Associated Muscle Pain

Some clinicians have recommended vitamin D supplements to ease the muscle aches of patients taking a statin, but a study from scientists at Northwestern University, Harvard University, and Stanford University and published in late 2022 in JAMA Cardiology showed that the vitamin appears to have no substantial impact.

Although nonrandomized studies have reported vitamin D to be an effective treatment for statin-associated muscle symptoms, the study, which is the first randomized clinical trial to look at the effect of vitamin D on statin-associated muscle symptoms, was large enough to rule out any important benefits.

In the randomized, double-blind trial, 2,083 participants ingested either 2,000 units of vitamin D supplements daily or a placebo. The study found that  participants in both categories were equally likely to develop muscle symptoms and discontinue statin therapy.

Over 4.8 years of follow-up, statin-related muscle pain was reported by 31% of the participants assigned vitamin D and 31% assigned a placebo.

“We had high hopes that vitamin D would be effective because in our clinic and across the country, statin-associated muscle symptoms were a major reason why so many patients stopped taking their statin medication,” said senior author Neil Stone, professor of medicine in cardiology and preventive medicine at Northwestern University Feinberg School of Medicine and a Northwestern Medicine cardiologist. “So, it was very disappointing that vitamin D failed a rigorous test. Nevertheless, it’s important to avoid using ineffective treatments and instead focus on research that can provide an answer.”

Statins and vitamin D supplements are two of the most commonly used medications in American adults: About 30 million to 35 million Americans are prescribed statins, and about half of the U.S. population aged 60 years and older take vitamin D.

“We took advantage of a large placebo-controlled, randomized trial to test whether vitamin D would reduce statin-associated muscle symptoms and help patients keep taking their statins,” said lead study author Mark Hlatky, a professor of health policy and cardiovascular medicine at Stanford. “The placebo control in the study was important because if people think vitamin D is supposed to reduce their muscle pains, they just might feel better while taking it, even if vitamin D has no specific effect.”

The 2,083 patients were among the larger cohort of participants in the VITamin D and OmegA-3 TriaL (VITAL), which randomized nearly 26,000 participants to double-blind vitamin D supplementation to determine whether it would prevent cardiovascular disease and cancer. This provided researchers a unique opportunity to test whether vitamin D reduces muscle symptoms among participants who initiated statins during the follow-up period of the larger VITAL trial. The mean age of the study participants was 67 years, and 51% were women.

“Randomized clinical trials are important because many very good ideas don’t work as well as we had hoped when they are put to the test,” Dr. Hlatky said. “Statistical associations do not prove a cause-and-effect relationship. Low levels of vitamin D are associated with many medical problems, but it turns out that giving people vitamin D does not generally fix those problems.”

Dr. Stone noted that sometimes the secret for understanding patients who have difficulty with statins is analyzing other medications they are taking, determining whether they have associated metabolic or inflammatory conditions, counseling them on their ability to hydrate adequately, and importantly, discussing “pill anxiety.”

“For those who have difficulties with statins, a systematic appraisal by a physician with experience in dealing with these matters is still very important,” he added.

Understanding Pain Disparities in the U.S.

Racial and ethnic disparities in pain prevalence in the United States are far larger than previously realized, according to the results of a study cowritten by a University at Buffalo (UB) medical sociologist. The research represents the first portrait of U.S. pain prevalence across six major racial and ethnic groups, as defined by the U.S. Census Bureau. While earlier studies of pain disparities have focused on black, white, and Hispanic groups, the current study also includes Native Americans (American Indians/Alaska Natives), Asian Americans, and the fast-growing “multiracial” category. The study also uses six measures of increasing severity of pain to test whether the findings are sensitive to a specific definition of pain.

The findings, based on data provided by nearly 274,000 participants and published in the journal Pain, indicate that Native Americans and multiracial Americans have by far the highest pain prevalence, while Asian Americans have the lowest pain prevalence, regardless of which specific pain measure is being assessed.

For example, compared with Asian Americans, Native Americans are over four times as likely to experience severe pain, and multiracial Americans are over three times as likely. Meanwhile, those who self-identify as white, black, or Hispanic have intermediate levels of severe pain. Similar racial/ethnic patterns are observed across other pain measures, as well.

The findings on pain prevalence among Native Americans, multiracial Americans, and Asian Americans substantially expand the limited previous research documenting pain levels for these groups.

“This research identifies the groups that have the highest unmet need for pain prevention and management,” said Hanna Grol-Prokopczyk, PhD, associate professor of sociology in the UB College of Arts and Sciences and coauthor of the study, which was led by Anna Zajacova, PhD, professor of sociology at Western University in Canada.

“We also want to learn from the groups that are doing well in terms of pain in order to understand why they’re doing well. We want to identify protective factors like good health practices, medical care, and social support and conduct further research to determine why these groups are not experiencing chronic pain as much as other groups.”

The CDC National Health Interview Survey (NHIS), which the researchers used for their analysis, estimates that more than 50 million people reported pain on most days or every day. That equates to slightly more than one out of every five American adults, with a cost to the economy greater than heart disease, cancer, and diabetes combined.

“There is growing literature showing that pain reflects both physical and mental health,” said Dr. Grol-Prokopczyk. “A mix of factors might be at play, some having to do with health behaviors, physical fitness, and quality of medical care, but some having to do with social stress, financial stress, and other things that are negatively impacting people’s psychological well-being.”

Yet, most research on pain prevalence has focused on comparisons between black and white people. More limited research attention has been given to Hispanic people, despite being the country’s largest nonwhite group, representing about 21% of the population. Even less research on pain prevalence has been devoted to Asian American and Native American adults, while pain among multiracial Americans, a population expected to double by 2050 to more than 20 million people, has never been systematically studied.

The current study uses NHIS data from 2010—the first survey wave to include global pain questions—to 2018, the most recent year data were available at the time the paper was being written. A different group of participants was surveyed each year.

Because of its large sample size, the study was able to include a representative sample of more racial and ethnic groups than previous research, which relied on smaller samples.

“Our results can be useful for both clinicians and public health researchers, now that we realize that Native Americans and multiracial adults, groups neglected in previous research, have extremely high rates of pain,” said Dr. Grol-Prokopczyk. “We recommend further research in this area to help better understand the factors driving pain prevalence.”

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