Molecular machines could treat fungal infections

Rice scientists show that light-activated nanoscale drills can kill pathogenic fungi

Peer-Reviewed Publication

RICE UNIVERSITY

 

IMAGE: JAMES TOUR IS THE T. T. AND W. F. CHAO PROFESSOR OF CHEMISTRY AND A PROFESSOR OF MATERIALS SCIENCE AND NANOENGINEERING. (PHOTO BY JEFF FITLOW/RICE UNIVERSITY) view more 

CREDIT: PHOTO BY JEFF FITLOW/RICE UNIVERSITY

HOUSTON – (Feb.1, 2023) – That stubborn athlete’s foot infection an estimated 70% of people get at some point in their life could become much easier to get rid of thanks to nanoscale drills activated by visible light.

Proven effective against antibiotic-resistant infectious bacteria and cancer cells, the molecular machines developed by Rice University chemist James Tour and collaborators are just as good at combating infectious fungi, according to a new study published in Advanced Science.

Based on the work of Nobel laureate Bernard Feringa, the Tour group’s molecular machines are nanoscale compounds whose paddlelike chain of atoms moves in a single direction when exposed to visible light. This causes a drilling motion that allows the machines to bore into the surface of cells, killing them.

“Dr. Tour posed the question of whether they can also kill fungi, which had never been explored before,” said lead co-author Ana Santos, a Rice alumna who is currently a Marie Curie Global Postdoctoral Fellow at Fundación Instituto de Investigación Sanitaria Islas Baleares in Spain. “Our study is the first to show that, indeed, these molecules can also be effective against fungi."

Fungal infections pose a particular threat to patients with a weakened immune system, such as cancer patients and transplant recipients. The cost of treating bacterial infections in the U.S. alone is estimated at more than $7 billion per year.

COVID-19 has made matters worse. Immunosuppressants were widely used early in the pandemic to reduce the risk of long-term organ damage caused by an overactive immune system in response to the virus, a tactic that allowed fungal infections to proliferate. 

“In the aftermath of that first wave of the pandemic, doctors started seeing an increase in cases of mucormycosis, or ‘black fungus,’ a normally rare fungal infection which causes a pneumonia-like illness, as a result of the overuse of immunosuppressant drugs,” Santos said. “We want to develop a way to combat fungal infections that does not tax a weakened immune system further, and we hope these molecular machines might be a way to do so.”

Santos said overuse of antifungals in agriculture is also contributing to resistance in humans.

“This is an emergent phenomenon that we are just starting to understand,” she said. “Antifungals are used in agriculture to combat damage to crops caused by fungal infestation. However, most of the antifungal drugs that are used in agriculture are also used in humans. Therefore, overuse of antifungals can lead to resistance not just in the fungi that cause plant illnesses but also in other fungi, including those that can be harmful to humans.”

In contrast to most antifungals, development of resistance to the visible-light activated nanoscale drills was not detected. Spinning at 2-3 million times per second, their rotors cause fungal cells to disintegrate by disrupting their metabolism.

“There are only a few classes of antifungals in clinical use,” Santos said. “These conventional antifungals typically employ one of a few different mechanisms of action, including inhibiting the synthesis of the fungal cell wall, targeting the fungal cell membrane or inhibiting the production of ergosterol, which is an essential component for normal fungal cell membrane structure.

“Our molecules differ from conventional antifungals in that they specifically target what we call the powerhouses of the cell, that is, the mitochondria,” she continued. Mitochondria are responsible for producing adenosine triphosphate, or ATP, which drives cellular metabolism.

"By targeting the mitochondria, our molecules disrupt the cell's metabolism, resulting in an overall energy imbalance that leads to an uncontrolled flow of water and ions such as calcium into the cell, eventually causing the cell to explode," Santos explained.

Tour is the T. T. and W. F. Chao Professor of Chemistry and a professor of materials science and nanoengineering. Rice graduate student Jacob L. Beckham is a lead co-author on the study along with Santos.

The European Union’s Horizon 2020 program (843116), the National Science Foundation Graduate Research Fellowship Program, the Discovery Institute, the Robert A. Welch Foundation (C-2017-20190330) and the DEVCOM Army Research Laboratory (W911NF-19-2-0269, W911NF-18-2-0234) supported the research.

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Schematic representation of the mechanisms by which light-activated molecular machines kill fungi. Molecular machines bind to fungal mitochondria, decreasing adenosine triphosphate (ATP) production and impairing the function of energy-dependent transporters that control the movement of ions, such as calcium. This leads to the influx of water, which causes the organelles to swell and eventually the cells to burst.

CREDIT

Image courtesy of Tour Group/Rice University

Ultrastructural changes induced by light-activated molecular machines in the fungus Candida albicans, detected by transmission electron microscopy, compared to a solvent control (1% dimethyl sulfoxide).

CREDIT

Image courtesy of Matthew Meyer, Electron Microscopy Facilities/Rice University

Peer-reviewed paper:

“Visible-light-activated molecular machines kill fungi by necrosis following mitochondrial dysfunction and calcium overload” | Advanced Science | DOI: 10.1002/advs.202205781

https://doi.org/10.1002/advs.202205781

Authors: Ana Santos, Jacob Beckham, Dongdong Liu, Gang Li, Alexis van Venrooy, Antonio Oliver, George Tegos and James Tour

Image downloads:

https://news-network.rice.edu/news/files/2023/01/Tour_fitlow_LG.jpg
CAPTION: James Tour is the T. T. and W. F. Chao Professor of Chemistry and a professor of materials science and nanoengineering. (Photo by Jeff Fitlow/Rice University)

https://news-network.rice.edu/news/files/2023/01/Schematic-MOA-Antifungal_LG.jpg
CAPTION: Schematic representation of the mechanisms by which light-activated molecular machines kill fungi. Molecular machines bind to fungal mitochondria, decreasing adenosine triphosphate (ATP) production and impairing the function of energy-dependent transporters that control the movement of ions, such as calcium. This leads to the influx of water, which causes the organelles to swell and eventually the cells to burst. (Image courtesy of Tour Group/Rice University)

https://news-network.rice.edu/news/files/2023/01/Electron-microscopy-photo_LG.jpg
CAPTION: Ultrastructural changes induced by light-activated molecular machines in the fungus Candida albicans, detected by transmission electron microscopy, compared to a solvent control (1% dimethyl sulfoxide). (Image courtesy of Matthew Meyer, Electron Microscopy Facilities/Rice University)

Related stories:

New weapon targets antibiotic resistance:
https://news.rice.edu/news/2022/new-weapon-targets-antibiotic-resistance

Bacteria-killing drills get an upgrade:
https://news.rice.edu/news/2022/bacteria-killing-drills-get-upgrade

Chemists build a better cancer-killing drill:
https://news2.rice.edu/2019/05/28/chemists-build-a-better-cancer-killing-drill-2/

Deadly ‘superbugs’ destroyed by molecular drills:
https://news2.rice.edu/2019/12/12/deadly-superbugs-destroyed-by-molecular-drills/

Motorized molecules drill through cells:
https://news2.rice.edu/2017/08/30/motorized-molecules-drill-through-cells-2/

Links:

Tour Group: https://www.jmtour.com/
Rice Department of Chemistry: https://chemistry.rice.edu/
Wiess School of Natural Sciences: https://naturalsciences.rice.edu/

Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation’s top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences and Social Sciences and is home to the Baker Institute for Public Policy. With 4,240 undergraduates and 3,972 graduate students, Rice’s undergraduate student-to-faculty ratio is just under 6-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice is ranked No. 1 for lots of race/class interaction and No. 1 for quality of life by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger’s Personal Finance.

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JOURNAL

Advanced Science

DOI

10.1002/advs.202205781 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Cells

ARTICLE TITLE

Visible-light-activated molecular machines kill fungi by necrosis following mitochondrial dysfunction and calcium overload

ARTICLE PUBLICATION DATE

30-Jan-2023

COI STATEMENT

Rice University owns intellectual property on the use of electromagnetic (light) activation of MMs for the killing of cells. This intellectual property has been licensed to a company in which J.M.T. is a stockholder, although he is not an officer or director of that company. Conflicts of interest are mitigated through regular disclosure to the Rice University Office of Sponsored Projects and Research Compliance. The remaining authors declare no conflict of interest.

Babies remember faces despite face masks, UC Davis study suggests

Babies can form memories of masked faces

Peer-Reviewed Publication

UNIVERSITY OF CALIFORNIA - DAVIS

Babies learn from looking at human faces, leading many parents and childhood experts to worry about possible developmental harm from widespread face-masking during the pandemic.

A new study by researchers at the University of California, Davis, allays those concerns, finding that 6- to 9-month-old babies can form memories of masked faces and recognize those faces when unmasked.

Michaela DeBolt, a doctoral candidate in cognitive psychology, and Lisa Oakes, a professor in the Department of Psychology and at the Center for Mind and Brain, used eye tracking to study how masks influence infants’ facial recognition. 

In the study, 58 babies, each seated on a parent’s lap or in a highchair, were shown pairs of masked and unmasked women’s faces on a computer screen, while cameras recorded where they looked. Because babies linger longer over unfamiliar images, the researchers could derive which faces they recognized, DeBolt said.

The findings appear in a paper published in the January/February special issue of the journal Infancy, which focused on the impact of COVID-19 on infant development.

The testing took place at Oakes’ Infant Cognition Lab at the Center for Mind and Brain in Davis, California, from late December 2021 to late March 2022, during a statewide mask mandate and the arrival of the coronavirus omicron variant.

“When babies learned a masked face, and then they saw that face again unmasked, they recognized it,” DeBolt said.

However, when the order was reversed, babies did not show strong recognition of masked faces that they first saw unmasked. DeBolt said that was similar to her own experience of not instantly recognizing a friend who was wearing a face mask.

Learning faces is central to how babies learn to talk, perceive emotions, develop relationships with their caregivers and explore their environment, Oakes said. “So people were very worried about face masks and the effect they would have on how infants are learning about human faces.”

Oakes, an expert on cognitive development in infancy, said the study highlighted a remarkable ability of babies to adapt. “I think that it should be very reassuring to parents in general,” she said. “Babies all over the world develop and thrive.

“There are so many variations in babies’ everyday lived experience,” she added. “As long as they are well cared for and fed and they get love and attention, they thrive. We can get into a mode where we think the way we do things is the best way to do things and that anything different is going to be a problem. And that’s clearly not the case.”

JOURNAL

Infancy

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

People

ARTICLE TITLE

The impact of face masks on infants' learning of faces: An eye tracking study

Urinary tract infections impair the sex life, sleep and exercise of over half of women who experience them, and are associated with reduced quality of life, in U.S. survey

Peer-Reviewed Publication

PLOS

 

IMAGE: THE GRAPH SHOWS THE ACTIVITIES REPORTED BY SURVEY PARTICIPANTS AS THOSE MOST AFFECTED BY THEIR RECENT UNCOMPLICATED URINARY TRACT INFECTION. view more 

CREDIT: GSK, CC-BY 4.0 (HTTPS://CREATIVECOMMONS.ORG/LICENSES/BY/4.0/)

Article URL:  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0277728

Article Title: Activity impairment, health-related quality of life, productivity, and self-reported resource use and associated costs of uncomplicated urinary tract infection among women in the United States

Author Countries: USA

Funding: This study, including study design, data collection, analysis, and interpretation, and medical writing and submission support for the manuscript, was funded by GSK (study 212518). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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JOURNAL

PLoS ONE

DOI

10.1371/journal.pone.0277728 

ARTICLE TITLE

Activity impairment, health-related quality of life, productivity, and self-reported resource use and associated costs of uncomplicated urinary tract infection among women in the United States

ARTICLE PUBLICATION DATE

1-Feb-2023

COI STATEMENT

Jeffrey Thompson is a former employee and Jonathon Wright a current employee of Cerner Enviza, which received funding from GSK to conduct this study. Alen Marijam, Fanny Mitrani-Gold, and Ashish Joshi are employees and shareholders of GSK. Some of the material in this manuscript has been presented previously at the Infectious Disease Week (IDWeek) 2021 Virtual Congress: Thompson et al, “A Survey Study of Healthcare Resource Use and, Direct and Indirect Costs, Among Females with an Uncomplicated Urinary Tract Infection in the United States”; and Thompson et al, “Activity Impairment and Health-Related Quality of Life Associated with an Uncomplicated Urinary Tract Infection Among US Females”. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Vitamin D supplementation is associated with a reduced risk of suicide attempts in a large cohort of U.S. veterans, especially in Black veterans and those with pre-existing low vitamin D

Peer-Reviewed Publication

PLOS

 

IMAGE: VITAMIN D SUPPLEMENTATION IS ASSOCIATED WITH A REDUCED RISK OF SUICIDE ATTEMPTS IN A LARGE COHORT OF U.S. VETERANS. view more 

CREDIT: MICHELE BLACKWELL, UNSPLASH, CC0 (HTTPS://CREATIVECOMMONS.ORG/PUBLICDOMAIN/ZERO/1.0/)

Article URL:  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0279166

Article Title: The association between vitamin D serum levels, supplementation, and suicide attempts and intentional self-harm

Author Countries: USA

Funding: This study was supported, in part, with resources from the Department of Veterans Affairs Center of Excellence for Suicide Prevention. Support for VA/CMS data was provided by the Department of Veterans Affairs, VA Health Services Research and Development Service, VA Information Resource Center (Project Numbers SDR 02-237 and 98-004), awarded to authors JG and JL. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.

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JOURNAL

PLoS ONE

DOI

10.1371/journal.pone.0279166 

ARTICLE TITLE

The association between vitamin D serum levels, supplementation, and suicide attempts and intentional self-harm

ARTICLE PUBLICATION DATE

1-Feb-2023

Chronic pain-induced depression: Underlying mechanism revealed in mice, showing how ketamine acts as antidepressant in chronic pain

Chronic pain often leads to depression, which increases suffering and is clinically difficult to treat. Understanding the underlying mechanism identifies a potential therapeutic target for treatment

Peer-Reviewed Publication

UNIVERSITY OF ALABAMA AT BIRMINGHAM

 

IMAGE: LINGYONG LI view more 

CREDIT: UAB

BIRMINGHAM, Ala. – Chronic pain often leads to depression, which increases suffering and is clinically difficult to treat. Now, for the first time, researchers have uncovered the underlying mechanism that drives those depressive systems, according to a study published in The Journal of Clinical Investigation.

The mechanism acts to cause hypersensitivity in a part of the brain called the anterior cingulate cortex, or ACC, and knowledge of this mechanism identifies a potential therapeutic target for the treatment of chronic pain-induced depression, say Lingyong Li, Ph.D., and Kimberley Tolias, Ph.D., co-leaders of the research.

“Chronic pain is a major, unmet health issue that impacts the quality of life,” said Li, an associate professor at the University of Alabama at Birmingham Department of Anesthesiology and Perioperative Medicine. “Unfortunately, patients suffering from chronic pain have limited effective treatment options.”

The research focused on a protein called Tiam1, which modulates the activity of other proteins that help build or unbuild the cytoskeletons of cells. Specifically, the research teams of Li and Tolias, a professor at Baylor College of Medicine, Houston, Texas, found that chronic pain in a mouse model leads to an activated Tiam1 in ACC pyramidal neurons, resulting in an increased number of spines on the neural dendrites. Dendrites are tree-like appendages attached to the body of a neuron that receive communications from other neurons.

This higher spine density increased the number of connections, and the strength of those connections, between neurons, a change known as synaptic plasticity. Those increases caused hypersensitivity and were associated with depression in the mouse model. Reversing the number and strength of connections in the model, by using an antagonist of Tiam1, relieved the mice of depression and diminished hypersensitivity of the neurons.

The ACC was already known as a critical hub for comorbid depressive symptoms in the brain. To investigate the mechanism for those symptoms, the team led by Li and Tolias first showed that Tiam1 in the ACC was activated in two mouse models of chronic pain with depressive or anxiety-like behaviors, as compared to controls.

To show that Tiam1 in the ACC modulates chronic pain-induced depressive-like behaviors, the researchers used molecular scissors to delete Tiam1 from the forebrain excitatory neurons of the mice. These mice were viable, and fertile, and displayed no gross alterations, and they still showed hypersensitivity to chronic pain. Strikingly, however, these Tiam1 conditional knockout mice did not display depressive- or anxiety-like behaviors in five different tests that gauge depression or anxiety.

When researchers specifically deleted Tiam1 from ACC neurons, they found the same results as the broader forebrain deletion. Thus, Tiam1 expressed in ACC neurons appears to specifically mediate chronic pain-induced depressive-like behaviors.

Other studies have established that an underlying cause of stress-induced depression and anxiety disorders is alterations in synaptic connections in brain regions involved in mood regulation, including the prefrontal cortex, the hippocampus and the amygdala. Li and Tolias found similar changes in dendritic neurons in the ACC for chronic pain-induced depressive-like behavior — they saw a significant increase in dendritic spine density and signs of increased cytoskeleton building. This was accompanied by increased NMDA receptor proteins and increased amplitudes of NMDA currents in the ACC neurons, both associated with hyperactivity.

These maladaptive changes were not seen in the Tiam1-knockout mice.

Researchers further showed that inhibiting Tiam1 signaling with a known inhibitor alleviated the chronic pain-induced depressive-like behaviors, without reducing the chronic pain hypersensitivity itself. The inhibition also normalized dendritic spine density, cytoskeleton building, NMDA receptor protein levels and NMDA current amplitudes.

Ketamine is a drug known to produce rapid and sustained antidepressant-like effects in chronic pain-induced depression, without decreasing sensory hypersensitivity. However, its mechanism is not fully understood. Li, Tolias and colleagues showed that ketamine’s sustained antidepressant-like effects in chronic pain are mediated, at least in part, by ketamine’s blocking the Tiam1-dependent, maladaptive synaptic plasticity in the mouse ACC neurons.

“Our work demonstrates the critical role Tiam1 plays in the pathophysiology of chronic pain-induced mood dysregulation and the sustained antidepressant-like effects of ketamine, revealing it as a potential therapeutic target for the treatment of comorbid mood disorders in chronic pain,” Li said.

Co-first authors of the study, “TIAM1-mediated synaptic plasticity underlies comorbid depression-like and ketamine antidepressant-like actions in chronic pain,” are Qin Ru and Yungang Lu, Baylor College of Medicine.

Co-authors with Li, Tolias, Ru and Lu are Ali Bin Saifullah, Francisco A. Blanco and Changqun Yao, Baylor College of Medicine; Juan P. Cata, MD Anderson Cancer Center, Houston, Texas; and De-Pei Li, University of Missouri School of Medicine, Columbia, Missouri.

Support came from United States Department of Defense grants W81XWH-20-10790 and W81XWH-21-10742, the Mission Connect/TIRR Foundation, and National Institutes of Health grant NS062829.

At UAB, Anesthesiology and Perioperative Medicine is a department in the Marnix E. Heersink School of Medicine.

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JOURNAL

Journal of Clinical Investigation

DOI

10.1172/JCI158545 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Animals

ARTICLE TITLE

TIAM1-mediated synaptic plasticity underlies comorbid depression-like and ketamine antidepressant-like actions in chronic pain

Most antidepressants ineffective for common pain conditions

Overview adds to mounting evidence challenging the use of medicines for pain

Peer-Reviewed Publication

BMJ

Some antidepressant drugs are effective for some pain conditions, but most are either ineffective or the evidence is inconclusive, despite being used for a range of pain conditions, finds an overview of the latest evidence published by The BMJ today.

Researchers call for a more nuanced approach when prescribing antidepressants for pain.

The use of antidepressants doubled in OECD countries from 2000 to 2015 and their off-label (unapproved) use to treat common pain conditions such as fibromyalgia, persistent headaches, and osteoarthritis is thought to be part of this increase.

To explore this further, a team of researchers led by Giovanni Ferreira at the University of Sydney carried out an overview of the effectiveness, safety, and tolerability of antidepressants for pain according to condition.

They searched databases for systematic reviews comparing any antidepressant with placebo for any pain condition in adults and found 26 eligible evidence reviews published between 2012 and 2022 involving 156 separate trials and over 25,000 participants.

These reviews reported on the effectiveness of eight classes of antidepressant covering 22 pain conditions (42 distinct antidepressant versus placebo comparisons). Almost half (45%) of the trials in these reviews had ties to industry.

Using data from each review, the researchers estimated relative risks of pain or average differences in pain between groups on a 0-100 point scale, taking account of dose, treatment duration, and number of trials and participants.

They also assessed safety and tolerability (withdrawals due to adverse events), certainty of evidence, and risk of bias. Findings were then classified from each comparison as effective, not effective, or inconclusive. 

No review provided high certainty evidence on the effectiveness of antidepressants for pain for any condition. 

Nine reviews provided evidence that some antidepressants were effective compared with placebo for nine conditions in 11 distinct comparisons. 

For example, moderate certainty evidence suggested that serotonin-norepinephrine reuptake inhibitors (SNRIs) were effective for back pain (average 5.3 points lower on the pain scale than placebo), postoperative pain, fibromyalgia, and neuropathic pain.

Low certainty evidence suggested that SNRIs were effective for pain linked to breast cancer treatment, depression, knee osteoarthritis, and pain related to other underlying conditions.

Low certainty evidence also suggested that selective serotonin reuptake inhibitors (SSRIs) were effective for people with depression and pain related to other conditions; and that tricyclic antidepressants (TCAs) were effective for irritable bowel syndrome, neuropathic pain, and chronic tension-type headache. 

For the other 31 comparisons, antidepressants were either not effective (five comparisons) or the evidence was inconclusive (26 comparisons).

Most safety and tolerability data were imprecise, indicating that the safety of antidepressants for several conditions is still uncertain.

This was a well designed review based on a thorough literature search and the researchers took steps to minimise the impact of issues such as differences in study design and quality, imprecision, and publication bias.

But they acknowledge that most comparisons had a limited number of trials, and results may not apply to antidepressants prescribed for symptoms linked to pain conditions, such as fatigue or sleep disturbance. Caution is also needed in interpreting these findings because 45% of the trials forming the evidence for this review had ties to industry, they add.

In conclusion, they say: “Some antidepressants were efficacious for some pain conditions; however, efficacy appears to depend on the condition and class of antidepressant. The findings suggest that a more nuanced approach is needed when prescribing antidepressants for pain.”

These findings suggest that for most adults living with chronic pain, antidepressant treatment will be disappointing, say researchers in a linked editorial.

They acknowledge that clinicians continue to prescribe medicines for which the evidence is poor because they see that some people respond to them, albeit modestly, but say other less potentially harmful options, such as exercise and support with mobility and social isolation, can help people to live well with pain. 

For people with pain, compassionate and consistent relationships with clinicians remain the foundations of successful care, they write. 

Studies must also involve people living with pain to ensure, among many other things, that pain research is meaningful to those living with pain and helps them and their clinicians make better shared decisions about treatments, they conclude.

 

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JOURNAL

The BMJ

DOI

10.1136/bmj-2022-072415 

METHOD OF RESEARCH

Systematic review

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Efficacy, safety, and tolerability of antidepressants for pain in adults: overview of systematic review

ARTICLE PUBLICATION DATE

1-Feb-2023

Antidepressants use for chronic pain on the rise, but are they effective?

More thoughtful approach to prescribing for pain needed

Peer-Reviewed Publication

UNIVERSITY OF SYDNEY

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.

One in five people experience chronic pain in Australia and globally, and treatment of chronic pain is often suboptimal, with commonly used medicines having limited or unknown benefits. The use of antidepressants to help manage a person’s pain is on the rise, even when they do not have a mood disorder like depression.

An international team of researchers has found that some classes of antidepressants were effective in treating certain pain conditions in adults, but others were either 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.

The researchers say the results show that clinicians need to consider all the evidence before deciding to prescribe antidepressants for chronic pain management. 

“This review, for the first time, brings together all the existing evidence about the effectiveness of antidepressants to treat chronic pain in one comprehensive document,” said lead author Dr Giovanni Ferreira from The Institute for Musculoskeletal Health and Sydney Musculoskeletal Health at the University of Sydney.

The review examined 26 systematic reviews from 2012 to 2022 involving over 25,000 participants. This included data from 8 antidepressant classes and 22 pain conditions including back pain, fibromyalgia, headaches, postoperative pain, and irritable bowel syndrome.

Serotonin-norepinephrine reuptake inhibitors (SNRI) antidepressants such as duloxetine were found to be effective for the largest number of pain conditions, such as back pain, knee osteoarthritis, postoperative pain, fibromyalgia, and neuropathic pain (nerve pain).

By 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.

Dr Ferreira 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.”

Co-author Dr 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,” Dr Ferreira said.

Professor Christopher Maher, Co-Director of Sydney Musculoskeletal Health at the University of Sydney, said, “This review distilled the evidence from over 150 clinical trials into an accessible summary that clinicians can use to help them make better decisions for their patients with chronic pain.”

The current status of antidepressants in Australia and globally

Most antidepressant prescriptions for pain are ‘off-label’, which is when antidepressants have not been approved to be prescribed for pain.

Many antidepressants are thought to help with pain by acting on chemicals in the brain that can assist with pain relief, such as serotonin. However, it is unknown exactly why some antidepressants improve pain. In Australia, the only antidepressant approved for treating pain is duloxetine, which is approved for diabetic neuropathic pain (nerve pain caused by diabetes).

Amitriptyline is approved in the United Kingdom for some pain conditions, such as neuropathic pain (nerve pain), tension-type headaches and migraines, but it is not approved for treating any pain conditions in Australia.

The use of antidepressants has doubled in OECD countries from 2000 to 2015, and the use of ‘off-label’ prescriptions of antidepressants for pain is considered a contributing factor to this increase. Data from Canada, the United States, the United Kingdom and Taiwan, suggest that among older people, chronic pain was the most common condition leading to an antidepressant prescription, even more so than depression.

Currently, no data from Australia shows how many antidepressant prescriptions are for pain.

-ENDS-

 

Note:  Antidepressants are prescription-only medicines. Do not use antidepressants unless advised by a doctor. It is very important not to abruptly cease treatment with antidepressant medicines. This can lead to withdrawal effects which can be distressing and sometimes present as serious health issues. These withdrawal effects include dizziness, nausea, anxiety, agitation, tremor, sweating, confusion, and sleep disturbance.

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JOURNAL

The BMJ

DOI

10.1136/bmj-2022-072415 

METHOD OF RESEARCH

Systematic review

SUBJECT OF RESEARCH

Not applicable

ARTICLE TITLE

Efficacy, safety, and tolerability of antidepressants for pain: an overview of systematic reviews

ARTICLE PUBLICATION DATE

1-Feb-2023