Most antidepressants prescribed for chronic pain lack reliable evidence of efficacy or safety, scientists warn

Scientists warn that antidepressants used for chronic pain lack evidence of effectiveness

Scientists warn that antidepressants used for chronic pain lack evidence of effectiveness CREDIT University of Southampton

  • Largest ever investigation into antidepressants used for chronic pain shows insufficient evidence to determine how effective or harmful they may be
  • Study reviewed commonly prescribed medications including amitriptyline, duloxetine, fluoxetine, citalopram, paroxetine, and sertraline
  • One third of people globally are living with long-term pain with many prescribed antidepressants to relieve symptoms

Most antidepressants used for chronic pain are being prescribed with “insufficient” evidence of their effectiveness, scientists have warned.

A major investigation into medications used to manage long-term pain found that harms of many of the commonly recommended drugs have not been well studied.

The Cochrane review, led by scientists from several UK universities including Southampton and Newcastle, examined 176 trials consisting of nearly 30,000 patients involved in assessments which prescribed antidepressants for chronic pain.

Among the drugs studied were amitriptyline, fluoxetine, citalopram, paroxetine, sertraline, and duloxetine – with only the latter showing reliable evidence for pain relief. One third of people globally are living with chronic pain, World Health Organisation data shows, with many prescribed antidepressants for relieving symptoms.

Lead author Professor Tamar Pincus from the University of Southampton said: “This is a global public health concern. Chronic pain is a problem for millions who are prescribed antidepressants without sufficient scientific proof they help, nor an understanding of the long-term impact on health.

“Our review found no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for their safety for chronic pain at any point. Though we did find that duloxetine provided short-term pain relief for patients we studied, we remain concerned about its possible long-term harm due to the gaps in current evidence.”

Amitriptyline is one of the most commonly prescribed antidepressants for pain management worldwide. In the last 12 months, around ten million prescriptions were given to patients in England at the 10mg dose recommended for pain. By comparison, five million prescriptions were given at the higher doses recommended for depression.

For duloxetine, three and a half million prescriptions were dispensed in England, but the recommended doses do not currently differ between conditions.

The two-year Cochrane study was the largest ever assessment of antidepressants recommended by leading bodies including the UK’s National Institute for Health and Care Excellence (NICE) and the Food and Drug Administration (FDA) in the USA.

Statistician Gavin Stewart, review co-author from Newcastle University, said: “We are calling on governing health bodies NICE and the FDA to update their guidelines to reflect the new scientific evidence, and on funders to stop supporting small and flawed trials. Evidence synthesis is often complex and nuanced but the evidence underpinning the use of these treatments is not equivalent, so current treatment modalities are hard to justify.”

The review revealed that duloxetine was consistently the highest-rated medication and was equally as effective for fibromyalgia, musculoskeletal, and neuropathic pain conditions.

Other results showed:

  • Standard doses of duloxetine are as successful for reducing pain as higher quantities,
  • Milnacipran was also effective at reducing pain, but scientists are not as confident as duloxetine due to fewer studies with fewer people.

Prof Tamar Pincus added: “We simply cannot tell about other antidepressants because sufficiently good studies are not available – but it does not mean that people should stop taking prescribed medication without consulting their GP.”

Scientists responsible for the review, funded by the NIHR’s Health Technology Assessment programme, were from the universities of Southampton, Newcastle, Bristol, UCL, Bath, and Keele, alongside Oxford University Hospital.

The team assessed the trials using a statistical method that enables researchers to combine data from relevant studies to estimate the effects of different drugs, which have not been compared directly in individual trials.

University of Southampton researcher Dr Hollie Birkinshaw said: “Though previous investigations show that some antidepressants might relieve pain, there has never been a comprehensive study examining all medications across all chronic conditions – until now.

“The only reliable evidence is for duloxetine. Adopting a person-centred approach is critical to treatment, and when patients and clinicians decide together to try antidepressants they should start from the drug for which there is good evidence.”

Neuropathic pain: The underlying mechanism and a therapeutic target are revealed

Neuropathic pain — abnormal hypersensitivity to stimuli — is often poorly managed and associated with impaired quality of life. Estimates suggest that 3 percent to 17 percent of adults suffer from neuropathic pain, including a quarter of people with diabetes and a third of people with HIV.

In a paper published in the journal Neuron, researchers report that a mechanism involving the enzyme Tiam1 in dorsal horn excitatory neurons of the spinal cord both initiates and maintains neuropathic pain. Moreover, they show that targeting spinal Tiam1 with anti-sense oligonucleotides injected into the cerebrospinal fluid effectively alleviated neuropathic pain hypersensitivity.

“Thus, our study has uncovered a pathophysiological mechanism that initiates, transitions and sustains neuropathic pain, and we have identified a promising therapeutic target for treating neuropathic pain with long-lasting consequences,” said Lingyong Li, Ph.D., an associate professor at the University of Alabama at Birmingham Department of Anesthesiology and Perioperative Medicine. “Understanding the pathophysiological mechanisms underlying neuropathic pain is critical for developing new therapeutic strategies to treat chronic pain effectively.”

Li and Kimberley Tolias, Ph.D., a professor at Baylor College of Medicine in Houston, Texas, were co-leaders of the research.

It was known that one feature of neuropathic pain is maladaptive changes in neurons of the spinal dorsal horn — increases in the size and density of dendritic spines, the primary postsynaptic sites of excitatory synapses. However, the mechanisms driving this synaptic plasticity were unclear. Dendrites are tree-like appendages attached to the body of a neuron that receive communications from other neurons. The spinal dorsal horn is one of the three gray columns of the spinal cord.

In related work, Li and Tolias last year found that chronic pain in a mouse model leads to an activated Tiam1 in anterior cingulate cortex pyramidal neurons of the brain, resulting in an increased number of spines on the neural dendrites. 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 chronic pain-related depression in the mouse model.

The current neuropathic pain study by Li and Tolias used mouse models of neuropathic pain caused by nerve injury, chemotherapy or diabetes. The researchers showed that Tiam1 is activated in the spinal dorsal horn of mice subjected to neuropathic pain and that global knockout of Tiam1 in mice prevented the development of neuropathic pain. Global knockout causes no other apparent abnormalities in the mice.

The UAB and Baylor researchers found that Tiam1 expression in the spinal dorsal horn neurons — but not in the dorsal root ganglion neurons or excitatory forebrain neurons — was essential for the development of neuropathic pain. Furthermore, they found that neuropathic pain development depended on Tiam1 expression in excitatory neurons — not in inhibitory neurons.

After showing where Tiam1 acts in neuropathic pain, Li, Tolias and colleagues showed what Tiam1 does. Tiam1 is known to modulate the activity of other proteins that help build or unbuild the cytoskeletons of cells, and the building of cytoskeleton actin filaments is part of dendritic spine creation. The researchers found that Tiam1 is necessary during the development of neuropathic pain to increase the density of dendritic spines on wide dynamic range neurons from the spinal dorsal horn and to increase synaptic NMDA receptor activity of spinal dorsal horn neurons.

Tiam1 functions to activate the small GTPase Rac1 enzyme that promotes actin polymerization. The researchers showed that the development of Tiam1-mediated neuropathic pain was dependent on Tiam1-Rac1 signaling. They then used a small molecule inhibitor to block Rac1 activation at three different time points — right after peripheral nerve injury, four days after nerve injury when neuropathic pain hypersensitivity gradually develops, or three weeks after nerve injury when chronic neuropathic pain is fully established. They found that neuropathic pain was prevented or reversed at each time point. Thus, Tiam1-Rac1 signaling is essential for the initiation, transition and maintenance of neuropathic pain.

Since Tiam1 appeared to be a promising therapeutic target for treating neuropathic pain, Li and Tolias also tested whether they could reduce neuropathic pain by injecting antisense oligonucleotides, or ASOs — short, synthetic, single-stranded oligodeoxynucleotides designed to alter Tiam1 expression by modulating its mRNA processing or degradation — into the cerebrospinal fluid of the spine.

In a rat model, they found that injecting an ASO against Tiam1 decreased Tiam1 protein levels in the spinal dorsal horn by 50 percent and significantly reduced neuropathic pain hypersensitivity one week after injection, a reduction that lasted another two weeks.

Therefore, Tiam1 is an essential player in the pathogenesis of neuropathic pain that coordinates actin cytoskeletal dynamics, dendritic spine morphogenesis and synaptic receptor function in spinal dorsal horn excitatory neurons in response to nerve damage, Li and Tolias say.

The two researchers are corresponding authors of the study, “Tiam1 coordinates synaptic structural and functional plasticity underpinning the pathophysiology of neuropathic pain.”

Music therapy significantly reduces pain, stress, and anxiety in community hospitals

UH Cleveland Medical Center
IMAGE: UH CLEVELAND MEDICAL CENTER view more CREDIT: UNIVERSITY HOSPITALS

CLEVELAND – A new study from University Hospitals (UH) Connor Whole Health found patients with moderate-to-severe pain, stress, or anxiety treated at UH community hospitals reported clinically significant reductions in pain, stress, and anxiety in response to a single session of music therapy. Furthermore, the clinically significant effect on pain was not influenced by patients’ demographic or clinical characteristics, suggesting that music therapy can be effective for acute pain management across various inpatient adult populations. The findings from this study were recently published in the journal, Pain Reports, a leading journal focusing on advancing pain research.

In this retrospective study conducted between January 2017 and July 2020, researchers from UH Connor Whole Health examined the first music therapy interventions provided to 1,056 adults receiving inpatient medical care who reported pre-session pain, anxiety, and/or stress scores greater than or equal to 4 on the 0 to 10 numeric rating scale. Unlike prior studies of music therapy, which have primarily been conducted at academic medical centers, this is the first and largest investigation of the real-world effectiveness of music therapy within community medical centers. This study builds upon a history of seminal music therapy studies funded by the Kulas Foundation, the country’s leading foundation for funding scientific research in music therapy, that have investigated the efficacy of music therapy in palliative caresurgery, and sickle cell disease as well as the clinical effectiveness of music therapy within an academic cancer center.

“The music therapists at UH Connor Whole Health offer non-pharmacological frontline treatment throughout our medical system while addressing issues of stress, pain, and anxiety. Greater Cleveland residents may receive these services during hospitalizations at UH as a clinical service line offering direct evidence-based community benefit,” said Seneca Block, The Lauren Rich Fine Endowed Director of Expressive Therapies at UH Connor Whole Health. UH Connor Whole Health manages the largest health system-based music therapy program in the US with 11 board-certified music therapists who collaborate with providers across the system to help patients and their families manage the physical and emotional toll of an illness or hospitalization. Additionally, UH Connor Whole Health provides a diverse offering of integrative health and medicine modalities, including acupuncture, chiropractic, and integrative medicine consults, that are centered on patients’ entire well-being.

In “Effectiveness of Music Therapy within Community Hospitals: An EMMPIRE Retrospective Study,” researchers examined the real-world effectiveness of music therapy at eight UH community medical centers and explored variables associated with pain reduction of greater than or equal to 2 units on a 0 to 10 unit numeric rating scale.

Music therapists provided interventions including live music listening, music-assisted relaxation and imagery, and active music making to address patients’ needs including pain management, coping, stress reduction, and anxiety reduction. As part of clinical care, the music therapists assessed patients’ self-reported pain, stress, and anxiety on a 0 to 10 scale at the beginning and end of each session and documented their sessions in the electronic health record.

“What makes this research novel is our ability to streamline data collection from music therapy clinical practice to the electronic health record. We can then use these data to understand the real-world impact of music therapy throughout multiple medical centers and how best to tailor music therapy interventions to meet patients’ needs,” said Sam Rodgers-Melnick, a music therapist, first author of the study, and a co-investigator on the EMMPIRE project (Effectiveness of Medical Music Therapy Practice: Integrative Research using the Electronic Health Record). The present EMMPIRE study was funded by a 3-year grant from the Kulas Foundation to UH Hospitals.org/ConnorWholeHealth with Jeffery A. Dusek PhD, Director of Research, UH Connor Whole Health, Block and Rodgers-Melnick as prime investigators. Said Dusek, “Routine collection of patient-reported outcomes from clinical practice (also called practice-based research) is becoming increasingly common as a patient-centered quality of care measure.”

Prior research has demonstrated that reductions of at least 1.3 units on the numeric rating scale for pain are clinically significant for patients with non-cancer pain, meaning that the symptom reduction represents a meaningful difference for patients with moderate-to-severe symptoms. Reductions of at least 2 units in stress and anxiety are also considered clinically significant. In this study, patients reported clinically significant mean reductions in pain (2.04 units), anxiety (2.80 units), and stress (3.48 units) in response to music therapy, with all changes exceeding clinically significant thresholds. Additionally, of the patients reporting a pain score greater than or equal to 4, 14% fell asleep during music therapy sessions, an important observation given the sleep challenges patients with moderate-to-severe pain face during hospitalization.

Additionally, after adjusting for demographic, clinical, and operational characteristics, patients receiving a music therapy session in which pain management was a goal were 4.32 times more likely to report pain reduction greater than or equal to 2 units than patients receiving a music therapy session in which pain management was not a session goal. Said Rodgers-Melnick, “this finding raises important questions regarding how music therapists tailor their interventions to address pain when that is the goal of the session, and we will be examining these specific features of music therapy interventions in future research.

Income rank is linked to the experience of physical pain, irrespective of whether in a rich or poor country; this study suggests

New study suggests that comparing one’s earnings relative to peers may induce negative emotions that lead to physical pain
A new study suggests that comparing one’s earnings to peers may induce negative emotions that lead to physical pain.

A new study of worldwide polling data suggests that a person’s income rank relative to their peers is linked to their experience of physical pain. A lower income rank is linked to a higher likelihood of experiencing pain. It is the first time such a relationship has been shown.

The study found the link to persist to the same degree, irrespective of whether the person lives in a rich or poor country.

Income rank is the position of an individual’s absolute income amount in a list ordered from lowest to highest.  The higher the position in the list, the higher the income rank.

The study, authored by Dr Lucía Macchia, Lecturer in Psychology at City, University of London, also suggests that people in poor countries fare no better than those living in rich countries when it comes to the effect of the absolute amount of personal income they earn on the likelihood of them experiencing pain. This was an unexpected finding and requires further investigation. The prediction was that those in poorer countries would be more strongly affected, assuming that an increase in absolute income would allow them to obtain more resources to support their well-being that is more readily available in rich countries.

Overall, the study findings suggest that an overriding factor affecting a person’s pain levels based on their personal income could be negative emotions related to their appraisal of their income ranking compared to their peers. It relates to their perception of their own levels of deprivation relative to their peers (in keeping with Relative Deprivation Theory) or their standing in a society and a feeling of a lack of social mobility (Social Comparison theory).

In the study, analyses were made of data from the annual World Gallup Poll (GWP), across the years 2009-18, and consisting of responses from approximately 1.3 million adult survey respondents from across 146 countries.  Respondents were asked what their total monthly household income was before taxes, which was divided by the number of people in their household to derive the respondent’s personal income amount.  Respondents were also asked whether they experienced physical pain the day before being surveyed, to which they could respond ‘yes’ or ‘no’. In the analyses, linear regression models were created from these data and further ancillary information.

This study refers to pain as the feeling that people experience when their body hurts regardless of the presence of physical damage.

Physical pain is one of the main reasons people visit the accident and emergency room in the UK. Approximately nine million people live with chronic pain in the UK and musculoskeletal pain alone accounts for 30 per cent of the country’s medical consultations.

Physical pain has been increasing dramatically in the last decades, becoming a priority for global public health. Pain affects leisure and productivity at work, increases health care costs, and represents a major challenge for healthcare systems. Pain plays a key role in suicide and in drug and alcohol misuse. In light of these circumstances, understanding the context of pain is crucial to addressing its consequences.

Study author, Dr Lucía Macchia, said:

“This is the first study that shows that income rank and pain are linked around the world. It suggests that psychological factors related to the well-known phenomenon of social comparison may influence people’s physical pain.”

Rice U. students engineer socks for on-the-go neuropathy treatment

insole


Top view of a smart insole containing transcutaneous electrical nerve stimulation (TENS) fabric electrodes and a circuit board to control the electrical signals. CREDIT Photo by Jeff Fitlow/Rice University

Need a little spring — or buzz — in your step? A wearable electrical stimulation and vibration therapy system designed by Rice University engineering students might be just what the doctor ordered for people experiencing foot pain and balance loss due to diabetic neuropathy.

Rice engineering students in the StimuSock team — Abby Dowse, Yannie Guo, Andrei Mitrofan, Sarah Park and Kelly Xu — designed a sock with a smart insole that can deliver both transcutaneous electrical nerve stimulation (TENS) and vibration therapy that block pain signals to the brain and provide haptic feedback to help with balance issues, respectively.

According to the Centers for Disease Control and Prevention’s 2022 estimates, over 37 million people in the U.S. suffer from diabetes. About half of them will develop some form of diabetic neuropathy, a type of nerve damage that occurs most often in the legs and feet.

The StimuSock team sought to combine the best aspects of existing therapies into a single, user-centered design.

“Existing products or devices used to treat the symptoms of diabetic neuropathy are either pharmaceuticals or large at-home vibration devices users stand on,” Dowse said. “But none of them can both treat pain and improve balance, which our device aims to do by combining the TENS and the vibrational therapy in one wearable, portable, user-controllable and easy-to-use device.”

A lot of the team’s effort went into making the device as low-profile as possible.

“The intent is for the patient to be able to wear the device for the whole day,” Guo said. “Even when everything’s off and they don’t want the electrostimulation or haptics effect, they can still wear their device. … You don’t want it to look like you’re wearing an ankle monitor.”

Patients use a smartphone app to control the type, intensity and duration of the desired therapeutic stimulus. The system also allows users to target a specific area of the foot.

“We have three regions: one in the front of the insole, one in the middle and one at the back,” Park said. “Our aim is to allow patients to be able to control both the amplitude of the vibration and the location where it’s delivered. Some patients might only want vibration at the front of their feet and some only at the back.”

Mitrofan said the team anticipates the device’s final form will have sufficient battery life to provide the recommended maximum of four 30-minute sessions of TENS therapy per day and operate on standby the rest of the day.