Physical Therapy + Antidepressant for Chronic Lower Back Pain with Depression

(TNA-LBP Trial)

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

330 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will examine how the use of antidepressant, physical therapy, and combination of both affects pain, function, and depression outcomes in chronic low back pain patients.

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.

What data supports the idea that Physical Therapy + Antidepressant for Chronic Lower Back Pain with Depression is an effective treatment?

The available research shows that using antidepressants, like duloxetine, along with physical therapy can help improve both pain and mood in people with chronic lower back pain and depression. One study found that tricyclic antidepressants were particularly effective in reducing pain. Another study showed that serotonin-noradrenaline reuptake inhibitors (SNRIs) significantly reduced pain and disability compared to a placebo. This suggests that combining physical therapy with these antidepressants can be an effective way to manage both pain and depression in patients. ^{1 2 3 4 5}

What data supports the effectiveness of the drug for chronic lower back pain with depression?

Research shows that certain antidepressants, like tricyclic antidepressants and serotonin-noradrenaline reuptake inhibitors (SNRIs), can help reduce pain and improve mood in people with chronic back pain. Duloxetine, an SNRI, has been found to improve both pain and depression symptoms, which can enhance overall quality of life. ^{1 2 3 4 5}

What safety data exists for using antidepressants and physical therapy to treat chronic lower back pain with depression?

The safety of antidepressants, including TCAs, SSRIs, and SNRIs, for chronic pain has been studied, with newer antidepressants showing fewer side effects. TCAs are effective but have more adverse effects. SNRIs like duloxetine are effective for both pain and depression. A network meta-analysis found TCAs and SNRIs effective for chronic back pain, with SNRIs reducing pain and disability scores. However, more research is needed to fully understand the safety and efficacy of these treatments. ^{1 2 3 6 7}

Is the combination of physical therapy and antidepressants safe for treating chronic lower back pain with depression?

Antidepressants, including tricyclic antidepressants (TCAs) and serotonin-noradrenaline reuptake inhibitors (SNRIs) like duloxetine, have been used for chronic pain and are generally considered safe, though TCAs may have more side effects. Newer antidepressants tend to have fewer side effects while maintaining effectiveness for mood disorders. ^{1 2 3 6 7}

Is the drug Antidepressant a promising treatment for chronic lower back pain with depression?

Yes, antidepressants, including drugs like duloxetine and tricyclic antidepressants, show promise in treating chronic lower back pain with depression. They have been found to reduce pain and improve mood, making them a valuable option for managing these conditions together. ^{1 3 5 8 9}

How is the treatment of physical therapy combined with antidepressants unique for chronic lower back pain with depression?

This treatment is unique because it combines physical therapy with antidepressants, which are typically used for depression, to address both chronic lower back pain and depression simultaneously. Antidepressants like duloxetine and amitriptyline have been shown to help with pain relief and mood improvement, making them a dual-purpose option for patients with both conditions. ^{1 5 8 9 10}

Research Team

Ajay Wasan, MD, MSc

Principal Investigator

University of Pittsburgh

Eligibility Criteria

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

I am between 18 and 75 years old.

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.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Antidepressants in the treatment for chronic low back pain: questioning the validity of meta-analyses. [2018]

2. England 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. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Comparative Efficacy and Safety of Antidepressants for Patients with Chronic Back Pain: A Network Meta-Analysis. [2023]

4. Germany pubmed.ncbi.nlm.nih.gov

Does pain improve earlier than mood in depressed patients with painful physical symptoms treated with duloxetine? [2015]

5. United States pubmed.ncbi.nlm.nih.gov

Do antidepressant medications relieve chronic low back pain? [2022]

6. Poland pubmed.ncbi.nlm.nih.gov

[The effectiveness of antidepressants in the treatment of chronic non-cancer pain--a review]. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Neuronal and immunological basis of action of antidepressants in chronic pain - clinical and experimental studies. [2022]

8. New Zealand 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. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Efficacy of Low-Dose Amitriptyline for Chronic Low Back Pain: A Randomized Clinical Trial. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

The treatment of depression in chronic low back pain: review and recommendations. [2022]