Physical Therapy + Antidepressant for Chronic Lower Back Pain with Depression

(TNA-LBP Trial)

Not currently recruiting at 2 trial locations

Overseen By Bhagyasri Jain Dharmaraj, BPharm

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Ajay Wasan, MD, Msc

Must be taking: Opioids

Disqualifiers: Back surgery, Worker’s compensation, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 8

Duration: 4 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the effectiveness of physical therapy, antidepressants (such as Selective Serotonin Reuptake Inhibitors or Tricyclic Antidepressants), or a combination of both in treating chronic lower back pain associated with depression. Participants will be assigned to different groups to receive either an antidepressant, physical therapy, or both, to identify which treatment best improves pain, function, and mood. This trial suits individuals who have experienced lower back pain for more than six months and also suffer from depression or anxiety. As a Phase 2, Phase 3 trial, it evaluates the treatment's effectiveness in an initial group and represents the final step before FDA approval, offering participants a chance to contribute to significant advancements in treatment.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are taking opioids, you must have been on them for at least three months and cannot increase the dosage during the study. New pain or psychiatric treatments should not be started within two weeks of enrollment or during the study.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are on opioids, you must have been taking them for at least three months and cannot increase the dosage during the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that certain antidepressants can be safe and effective for treating long-term low back pain. Specifically, serotonin-noradrenaline reuptake inhibitors (SNRIs), a type of antidepressant, reduce pain and improve quality of life. One study found that SNRIs decreased disability from back pain over 3 to 13 weeks. Another study demonstrated that duloxetine, a common SNRI, improved quality of life for people with chronic low back pain.

Enhanced Fear Avoidance Rehabilitation (EFAR) has also been researched as a treatment. EFAR helps reduce fear and avoidance of movement, which can worsen pain. Studies suggest that EFAR improves outcomes for those with chronic low back pain by addressing the mental aspects of pain.

Both treatments have shown promise in studies and are generally well-tolerated. However, like any medical treatment, side effects may occur, and individual experiences can differ. It's important to discuss any concerns with healthcare providers when considering joining a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine physical therapy and antidepressants to tackle chronic lower back pain with depression in a comprehensive way. Unlike standard treatments that might focus solely on pain relief through opioids or antidepressants alone, this approach integrates Enhanced Fear Avoidance Rehabilitation (EFAR) to address both physical and psychological aspects of pain. This dual-action method aims not only to reduce pain but also to enhance mobility and improve mental well-being, offering a more holistic solution. By potentially reducing reliance on opioids and addressing the fear and avoidance behaviors associated with chronic pain, these treatments could provide a more sustainable and effective option for patients.

What evidence suggests that this trial's treatments could be effective for chronic lower back pain with depression?

Research has shown that certain antidepressants, particularly serotonin-noradrenaline reuptake inhibitors (SNRIs), can help reduce back pain. One study found that SNRIs reduced pain by an average of 5.30 points compared to a placebo. Antidepressants like duloxetine are often used to treat long-term pain conditions, including low back pain. In this trial, some participants will receive antidepressants as part of their treatment. Enhanced Fear Avoidance Rehabilitation (EFAR) helps people who avoid activities due to fear of pain by reducing their disability. Other participants in this trial will receive EFAR. Combining antidepressants with EFAR, as done in one of the trial arms, might provide more comprehensive benefits by addressing both the physical and mental aspects of chronic low back pain. Both treatments have shown promise, and using them together could potentially improve overall results. ^{4 6 7 8 9}

Who Is on the Research Team?

Ajay Wasan, MD, MSc

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

This trial is for adults aged 18-75 with chronic lower back pain lasting over 6 months, scoring above a 3/10 on the pain scale. Participants must be able to use mobile devices and have no major thought disorders or recent substance abuse (except certain cases). They should not be pregnant, involved in litigation claims, planning new psychiatric treatments, or have had recent back surgery.

Inclusion Criteria

Must meet the minimum criteria for cognitive function using the PROMIS 2-item cognitive screener (>3)

I have been on opioids, like oxycodone or tramadol, for pain for at least 3 months.

Must meet criteria for high negative affect at 1st study visit: at least 5 on the PHQ-4 (also called the PHQ-2 + GAD-2). Scores above this level are highly associated with having a co-morbid major depression or generalized anxiety disorder diagnosis

Exclusion Criteria

History of cardiac, nervous system, or respiratory disease that, in the investigator's judgment, precludes participation in the study because of a heightened potential for respiratory depression

I have had back surgery in the last 6 months.

I plan to start new psychiatric treatments within the first 4 months of the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive antidepressant medication, physical therapy, or a combination of both for 4 months

4 months

Check-in visits every 4 weeks (virtually or in-person)

Re-randomization and Continued Treatment

Non-responders are re-randomized to continue receiving either antidepressant medication or physical therapy for another 4 months

4 months

Check-in visits every 4 weeks (virtually or in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 months

What Are the Treatments Tested in This Trial?

Interventions

• Antidepressant
• Enhanced Fear Avoidance Rehabilitation

Trial Overview The study tests how an antidepressant alone, physical therapy alone, or their combination can help manage pain and improve function and mood in those with chronic low back pain. It aims to see which method is most effective for patients who also experience negative emotions like depression.

How Is the Trial Designed?

Group I: Enhanced Fear Avoidance Rehabilitation (EFAR) Experimental Treatment 1 Intervention

Subjects will be randomly assigned to receive 8 1-hour physical therapy sessions, pain education, and motivational messaging via Vivify app for 4 months, in addition to their current opioid prescription and weaning guidelines, if applicable. Trained physical/occupational therapists will determine the activities as part of the treatment. Non-responders determined at the end of 4 months will be re-randomized to continue receiving EFAR or AD for another 4 months.

Group II: EFAR -> AD Experimental Treatment 2 Interventions

Subjects will be randomly assigned to receive 8 1-hour physical therapy sessions, pain education, and motivational messaging via Vivify app for 4 months, in addition to their current opioid prescription and weaning guidelines, if applicable. Trained physical/occupational therapists will determine the activities as part of the treatment. Non-responders determined at the end of 4 months will be re-randomized to continue receiving EFAR or AD for another 4 months. Those re-randomized to receive AD for another 4 months will be under the care of a nurse practitioner and psychiatrist, in addition to their current opioid prescription and weaning guidelines, if applicable. Dosage change and side effects are mitigated by check-in visits (virtually or in-person) every 4 weeks.

Group III: Antidepressant (AD) + Enhanced Fear Avoidance Rehabilitation (EFAR) Experimental Treatment 2 Interventions

Subjects will receive a combination of antidepressant medication and physical therapy for 8 months, in addition to their current opioid prescription and weaning guidelines, if applicable. No re-randomization will be done in this treatment group.

Group IV: Antidepressant (AD) Experimental Treatment 1 Intervention

Subjects will be randomly assigned to receive the antidepressant medication for 4 months under the care of a nurse practitioner and psychiatrist, in addition to their current opioid prescription and weaning guidelines, if applicable. Dosage change and side effects are mitigated by check-in visits (virtually or in-person) every 4 weeks. Non-responders determined at the end of 4 months will be re-randomized to continue receiving AD or EFAR for another 4 months.

Group V: AD -> EFAR Experimental Treatment 2 Interventions

Subjects will be randomly assigned to receive the antidepressant medication for 4 months under the care of a nurse practitioner and psychiatrist, in addition to their current opioid prescription and weaning guidelines, if applicable. Dosage change and side effects are mitigated by check-in visits (virtually or in-person) every 4 weeks. Non-responders determined at the end of 4 months will be re-randomized to continue receiving AD or EFAR for another 4 months. Those re-randomized to receive EFAR for another 4 months will receive a combination of antidepressant medication and physical therapy, in addition to their current opioid prescription and weaning guidelines, if applicable.

Antidepressant is already approved in European Union, United States, Canada, United Kingdom for the following indications:

Approved in European Union as Antidepressants for:

• Depression
• Anxiety disorders
• Neuropathic pain
• Chronic back pain
• Fibromyalgia

Approved in United States as Antidepressants for:

• Major depressive disorder
• Generalized anxiety disorder
• Neuropathic pain
• Chronic low back pain
• Fibromyalgia

Approved in Canada as Antidepressants for:

• Depression
• Anxiety disorders
• Neuropathic pain
• Chronic pain syndromes

Approved in United Kingdom as Antidepressants for:

• Depression
• Anxiety disorders
• Neuropathic pain
• Chronic back pain
• Fibromyalgia

Who Is Running the Clinical Trial?

Ajay Wasan, MD, Msc

Lead Sponsor

Trials

3

Recruited

370+

Mayo Clinic

Collaborator

Trials

3,427

Recruited

3,221,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Collaborator

Trials

508

Recruited

1,090,000+

Brigham and Women's Hospital

Collaborator

Trials

1,694

Recruited

14,790,000+

Mass General Brigham

Collaborator

Trials

2

Recruited

830+

Massachusetts General Hospital

Collaborator

Trials

3,066

Recruited

13,430,000+

Published Research Related to This Trial

In a 12-week study involving 30 older adults, duloxetine combined with Depression and Pain Care Management (DPCM) led to a 46.7% remission rate in major depressive disorder (MDD) and a 93.3% significant pain response in chronic low back pain (CLBP).

The average time to achieve depression remission was about 7.6 weeks, while pain response was quicker at 2.8 weeks, indicating that this treatment approach effectively addresses both conditions in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duloxetine and care management treatment of older adults with comorbid major depressive disorder and chronic low back pain: results of an open-label pilot study. Karp, JF., Weiner, DK., Dew, MA., et al.[2022]

A review of six studies on the use of antidepressants for chronic low back pain found no consistent evidence that they are more effective than placebos in reducing pain or disability.

While one study suggested that amitriptyline might be superior in reducing analgesic medication use, overall, the findings indicate that more rigorous randomized controlled trials are necessary to clarify the role of antidepressants in treating low back pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Do antidepressant medications relieve chronic low back pain? Turner, JA., Denny, MC.[2022]

In a post hoc meta-analysis of 851 patients with chronic low back pain (CLBP), duloxetine significantly reduced pain scores compared to placebo, indicating its efficacy as an analgesic (p<0.001).

The majority of duloxetine's pain relief (91.1%) was attributed to its direct analgesic effects rather than its ability to alleviate depressive symptoms, suggesting that it primarily works through pain modulation mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of direct analgesic effect of duloxetine for chronic low back pain: post hoc path analysis of double-blind, placebo-controlled studies. Enomoto, H., Fujikoshi, S., Funai, J., et al.[2022]

Tricyclic antidepressants (TCAs) are effective for chronic pain relief but come with significant side effects, while newer antidepressants like venlafaxine and duloxetine show promise with fewer adverse effects and similar efficacy for both mood and pain symptoms.

Bupropion has been found effective for neuropathic pain, but more randomized controlled trials are needed to better understand the effectiveness of newer antidepressants like mirtazapine and reboxetine in treating chronic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The effectiveness of antidepressants in the treatment of chronic non-cancer pain--a review]. Miller, A., Rabe-Jabłońska, J.[2022]

Tricyclic antidepressants (TCAs) have been the primary choice for treating chronic pain conditions, such as neuropathic pain, for over 40 years, demonstrating their efficacy alongside traditional analgesics.

Newer antidepressants, including tetracyclics, SNRIs, and atypical antidepressants, show promise in treating chronic pain with potentially fewer side effects, but more research is needed to determine their effectiveness compared to TCAs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuronal and immunological basis of action of antidepressants in chronic pain - clinical and experimental studies. Mika, J., Zychowska, M., Makuch, W., et al.[2022]

A systematic review of 19 randomized controlled trials involving 2903 patients found that tricyclic antidepressants are the most effective for relieving chronic back pain, with a ranking probability of 84.4%.

Serotonin-noradrenaline reuptake inhibitors (SNRIs) also significantly reduced pain and disability scores compared to placebo, but they were associated with a higher risk of adverse events and withdrawal due to side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Efficacy and Safety of Antidepressants for Patients with Chronic Back Pain: A Network Meta-Analysis. Ma, T., Qi, H., Mao, Y., et al.[2023]

A clinical trial involving 146 adults with chronic low back pain found that low-dose amitriptyline (25 mg/d) did not significantly reduce pain compared to an active comparator (benztropine mesylate) at 3 or 6 months, suggesting limited efficacy for pain management.

While there was no significant difference in overall disability at 6 months, the amitriptyline group showed a statistically significant improvement in disability at 3 months, indicating a potential short-term benefit, with minimal adverse events reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Low-Dose Amitriptyline for Chronic Low Back Pain: A Randomized Clinical Trial. Urquhart, DM., Wluka, AE., van Tulder, M., et al.[2019]

In a study of 622 adult outpatients treated with duloxetine for depression, patients experienced a significant improvement in pain symptoms earlier than mood symptoms, with a mean time to 50% pain response of 6.3 days compared to 7.6 days for mood response.

This finding suggests that duloxetine may provide quicker relief from physical pain associated with depression, which could be important for treatment strategies focusing on both emotional and physical symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does pain improve earlier than mood in depressed patients with painful physical symptoms treated with duloxetine? Hegerl, U., Mergl, R., Quail, D., et al.[2015]

Duloxetine demonstrated a significant analgesic effect in patients with chronic low back pain (CLBP), showing greater improvements in pain scores compared to placebo in two out of three placebo-controlled trials.

The review highlighted the variability in findings from other antidepressant studies, suggesting that while duloxetine is effective, the overall evidence for the analgesic effects of antidepressants in CLBP remains inconclusive and requires further well-designed studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antidepressants in the treatment for chronic low back pain: questioning the validity of meta-analyses. Williamson, OD., Sagman, D., Bruins, RH., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8489297/

Efficacy and safety of antidepressants for the treatment of back ... Moderate certainty evidence showed that serotonin-noradrenaline reuptake inhibitors (SNRIs) reduced back pain (mean difference −5.30, 95% ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7905649/

Efficacy, acceptability, and safety of antidepressants for low ... Treatment of LBP with antidepressants is associated with small reductions in pain intensity and increased odds of stopping treatment for any ...

3. accp1.onlinelibrary.wiley.com accp1.onlinelibrary.wiley.com/doi/10.1002/jcph.2365

Comparative Efficacy and Safety of Antidepressants for ... The results of pairwise comparison analyses found the use of serotonin–noradrenaline reuptake inhibitors (SNRIs) significantly reduced pain ...

4. bmj.com bmj.com/content/380/bmj-2022-072415

Efficacy, safety, and tolerability of antidepressants for pain ... Moderate certainty evidence supported the efficacy of SNRIs, mostly duloxetine at median doses of 60-120 mg for back pain, postoperative pain, ...

5. mayoclinic.org mayoclinic.org/diseases-conditions/back-pain/in-depth/pain-medications/art-20045647

Antidepressants: Another weapon against chronic pain Antidepressants are a staple in the treatment of many chronic pain conditions, including arthritis, nerve damage, headache and low back pain.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11487954/

Efficacy of antidepressants in the treatment of chronic ... Aim: This study reassesses the efficacy and safety of antidepressants in treating nonspecific chronic low back pain (NCLBP).

7. bmj.com bmj.com/content/372/bmj.m4825

Efficacy and safety of antidepressants for the treatment ... Moderate certainty evidence showed that SNRIs reduced disability from back pain at 3-13 weeks (−3.55, −5.22 to −1.88) and disability due to ...

8. neurology.org neurology.org/doi/10.1212/WNL.0000000000206345

Efficacy and Safety of Duloxetine in Chronic Low Back Pain The total SF-36 score also showed a significant improvement in quality of life with duloxetine (MD: 3.63, 95% CI: [1.74 to 5.52], P= 0.0002).

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6248203/

Efficacy of Low-Dose Amitriptyline for Chronic Low Back Pain This trial suggests that amitriptyline may be an effective treatment for chronic low back pain. There were no significant improvements in outcomes at 6 months, ...