Buprenorphine + CBT + TMS for Chronic Pain

(ACTION Trial)

Overseen By Rafael Mendoza

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Medical University of South Carolina

Must be taking: Opioids

Must not be taking: Anticonvulsants, Methadone, Naltrexone

Disqualifiers: Seizure disorder, Bipolar, Pregnancy, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 20 days

240 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are on certain medications like methadone, buprenorphine for opioid use disorder, naltrexone, or medications that prolong the QTc interval.

What data supports the effectiveness of the treatment Buprenorphine + CBT + TMS for Chronic Pain?

Research suggests that repetitive transcranial magnetic stimulation (rTMS), a part of the treatment, can help reduce cravings in individuals with opioid use disorder and may provide pain relief in chronic pain conditions. Additionally, rTMS has shown potential benefits for depressive symptoms and impulse control, which could be relevant for patients with chronic pain. ^{1 2 3 4 5}

Is the combination of Buprenorphine, CBT, and TMS generally safe for humans?

Buprenorphine has been studied for safety in various forms, such as transdermal systems and injections, and is generally well-tolerated with common side effects like irritability, anxiety, and nausea. Transcranial Magnetic Stimulation (TMS) is also considered safe, with mild side effects like headaches or scalp discomfort. Cognitive Behavioral Therapy (CBT) is a non-invasive psychological treatment and is generally safe with no known physical side effects. ^{6 7 8 9 10}

How is the treatment of Buprenorphine + CBT + TMS for chronic pain different from other treatments?

This treatment is unique because it combines buprenorphine, a medication often used for pain and opioid use disorder, with cognitive behavioral therapy (CBT) and transcranial magnetic stimulation (TMS), which are non-drug therapies that can help manage pain and improve mental health. This combination aims to address both the physical and psychological aspects of chronic pain, offering a more comprehensive approach than using medication alone. ^{8 11 12 13 14}

What is the purpose of this trial?

This study will sequentially evaluate three novel and scalable interventions for at-risk individuals on long term opioid therapy for chronic pain: (1) low-dose transdermal buprenorphine initiation without a period of opioid withdrawal; (2) a brief Cognitive Behavioral Intervention for pain (CBI); and (3) "accelerated" rTMS over the left dorsolateral prefrontal cortex, by examining standardized repeated measures of clinical outcomes at baseline, during treatment, and at 4-, 12-, 24- and 52-week follow-up.

Research Team

Kelly Barth

Principal Investigator

Medical University of South Carolina

Eligibility Criteria

This trial is for individuals on long-term opioid therapy for chronic pain who may be at risk. Participants should not currently be in opioid withdrawal and must commit to follow-up visits over a year.

Inclusion Criteria

Willing and able to complete written informed consent

English-speaking

Willing and able to use a mobile/cell phone

Exclusion Criteria

Known allergy to buprenorphine

Pregnancy

I have a known seizure disorder.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Sequential evaluation of low-dose transdermal buprenorphine, Cognitive Behavioral Intervention for pain, and accelerated rTMS

20 days

Multiple visits for treatment and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

52 weeks

Follow-up assessments at 4, 12, 24, and 52 weeks

Treatment Details

Interventions

• Buprenorphine
• Cognitive Behavioral Intervention
• Transcranial Magnetic Stimulation (TMS)

Trial Overview The study tests three interventions: a low-dose buprenorphine patch without prior opioid withdrawal, Cognitive Behavioral Intervention (CBI) for pain, and accelerated Transcranial Magnetic Stimulation (TMS) targeting the brain's prefrontal cortex.

Participant Groups

Group I: open label BUP Experimental Treatment 1 Intervention

Group II: Real vs Placebo BUP Active Control 2 Interventions

Group III: Real vs Sham TMS Active Control 2 Interventions

Buprenorphine is already approved in United States, European Union for the following indications:

Approved in United States as Buprenorphine for:

• Moderate to severe opioid addiction (dependence)

Approved in European Union as Buprenorphine for:

• Opioid dependence

Who Is Running the Clinical Trial?

Medical University of South Carolina

Lead Sponsor

Trials

994

Recruited

7,408,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Findings from Research

Repetitive transcranial magnetic stimulation (rTMS) is a safe and effective treatment for chronic pain, with 12 randomized controlled trials involving 350 patients showing significant pain relief, particularly with high-frequency stimulation on the motor cortex.

While low-frequency rTMS showed no benefit, high-frequency rTMS produced short-term pain relief and a long-lasting analgesic effect, although the optimal stimulation parameters and target sites still need further investigation due to variability in study results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Noninvasive Transcranial Magnetic Stimulation (TMS) in Chronic Refractory Pain: A Systematic Review. Hamid, P., Malik, BH., Hussain, ML.[2020]

In a case study of a 62-year-old male with drug-resistant neuropathic pain due to spinal cord injury, 10 Hz repetitive transcranial magnetic stimulation (rTMS) resulted in significant pain reduction, with a 30% decrease in sternum pain and a 29% decrease in left foot pain after 6 weeks of treatment.

rTMS was safe and did not interfere with the patient's intrathecal baclofen pump, and it also led to substantial improvements in anxiety and depression scores, indicating its potential as an effective treatment for neuropathic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case report: The feasibility of rTMS with intrathecal baclofen pump for the treatment of unresolved neuropathic pain following spinal cord injury. Foglia, SD., Rehsi, RS., Turco, CV., et al.[2022]

Repetitive transcranial magnetic stimulation (rTMS) shows promise as a novel intervention for opioid use disorder (OUD), with a case report indicating a significant reduction in cravings for heroin and cocaine by approximately 60% to 82% after 7 sessions targeting the left dorsolateral prefrontal cortex.

This case highlights the potential of rTMS to augment medication-assisted treatment (MAT) for individuals with OUD, especially for those who continue to experience cravings despite comprehensive treatment, suggesting a need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case report illustrating the effects of repetitive transcranial magnetic stimulation on cue-induced craving in an individual with opioid and cocaine use disorder. Mahoney, JJ., Marshalek, PJ., Rezai, AR., et al.[2021]

In a pilot trial involving 22 participants with opioid use disorder undergoing methadone maintenance therapy, repetitive transcranial magnetic stimulation (rTMS) did not significantly reduce cravings or heroin use compared to a sham treatment.

However, rTMS was associated with significant improvements in depressive symptoms, impulse control, and attention, suggesting potential benefits for mental health aspects in individuals with opioid use disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Add-on repetitive transcranial magnetic stimulation in patients with opioid use disorder undergoing methadone maintenance therapy. Tsai, TY., Wang, TY., Liu, YC., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) has been shown to provide significant pain relief in chronic pain conditions, particularly with high-frequency stimulation over the primary motor cortex, achieving over 30% pain reduction compared to control treatments.

Despite the promising results, most studies did not utilize repetitive rTMS sessions, indicating a need for further research to explore the long-term effects and optimal treatment protocols for various chronic pain syndromes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation in chronic pain: a review of the literature. Galhardoni, R., Correia, GS., Araujo, H., et al.[2022]

In a study of 1,465 patients with moderate to severe pain, transdermal buprenorphine led to an average reduction of 25.1 points on the visual analog scale (VAS) over a median treatment period of 3.7 months, with 88.4% of patients experiencing at least a 10% decrease in pain.

The treatment was well-received, with 82.5% of patients rating it as 'Good' or 'Very Good', and while 50.2% experienced adverse events, only 4.0% were considered serious, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High dose transdermal buprenorphine for moderate to severe pain in spanish pain centres--a retrospective multicenter safety and efficacy study. Barutell, C., Camba, A., González-Escalada, JR., et al.[2013]

In a pilot study involving 26 participants with opioid use disorder, initiating buprenorphine extended-release injection (BUP-XR) after a single 4 mg dose of transmucosal buprenorphine (BUP-TM) was found to be safe and well tolerated, with no serious adverse events reported.

Participants showed significant improvement in withdrawal symptoms, with Clinical Opiate Withdrawal Scale (COWS) scores decreasing from an average of 14.6 to 4.2 within 24 hours after receiving BUP-XR, indicating effective management of cravings and withdrawal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label, rapid initiation pilot study for extended-release buprenorphine subcutaneous injection. Hassman, H., Strafford, S., Shinde, SN., et al.[2023]

A case report of a 56-year-old male on buprenorphine treatment for opioid use disorder showed that adding tramadol significantly improved his pain management without causing side effects or withdrawal symptoms.

The combination of buprenorphine and tramadol provided an additive analgesic effect, suggesting that tramadol may be a viable option for pain relief in patients undergoing buprenorphine treatment, warranting further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The problem of pain: Additive analgesic effect of tramadol and buprenorphine in a patient with opioid use disorder. Montalvo, C., Genovese, N., Renner, J.[2020]

In a study involving 280 patients with moderate to severe musculoskeletal pain, the buprenorphine transdermal system (BTDS) demonstrated noninferior effectiveness compared to sustained-release tramadol, with both treatments significantly reducing pain levels over an 8-week period.

The safety profiles of BTDS and tramadol were comparable, indicating that BTDS is a viable alternative for patients whose pain is not adequately managed by nonsteroidal anti-inflammatory drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and Safety of Transdermal Buprenorphine Versus Sustained-release Tramadol in Patients With Moderate to Severe Musculoskeletal Pain: An 8-Week, Randomized, Double-Blind, Double-Dummy, Multicenter, Active-controlled, Noninferiority Study. Leng, X., Li, Z., Lv, H., et al.[2015]

A post hoc analysis of 354 patients using the buprenorphine transdermal system (BTDS) for chronic pain showed that those who also used immediate-release (IR) opioids experienced significant improvements in pain intensity and interference without an increase in adverse events.

The study supports the safe and effective use of IR opioids as supplemental analgesia alongside BTDS, as patients reported similar pain relief and maintained treatment persistence over 6 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of immediate-release opioids as supplemental analgesia during management of moderate-to-severe chronic pain with buprenorphine transdermal system. Silverman, S., Raffa, RB., Cataldo, MJ., et al.[2020]

Buprenorphine shows promise for treating chronic pain in children due to its long duration of action and metabolism that is largely independent of renal function, making it potentially safer for those with kidney issues.

However, there is a significant lack of pediatric-specific pharmacokinetic and pharmacodynamic data, and the risk of respiratory depression remains uncertain, highlighting the need for further research before widespread use in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine TTS for children--a review of the drug's clinical pharmacology. Michel, E., Anderson, BJ., Zernikow, B.[2022]

In a randomized study comparing transdermal buprenorphine to sustained-release morphine for cancer pain management, patients using buprenorphine reported significantly better outcomes in physical pain, mental health, and vitality.

The transdermal buprenorphine group not only experienced improved pain control but also enhanced quality of life, suggesting it may be a more effective option for chronic cancer pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine in long-term control of chronic pain in cancer patients. Pace, MC., Passavanti, MB., Grella, E., et al.[2022]

In a 12-week clinical trial involving opioid-naive patients with moderate to severe chronic low back pain, the buprenorphine transdermal delivery system (BTDS) significantly improved patients' ability to perform daily activities, such as sleeping and lifting, compared to a placebo.

The analysis showed that BTDS users had odds ratios for performing 10 specific activities that ranged from 1.9 to 2.4, indicating a notable enhancement in their functional capabilities related to pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The impact of buprenorphine transdermal delivery system on activities of daily living among patients with chronic low back pain: an application of the international classification of functioning, disability and health. Miller, K., Yarlas, A., Wen, W., et al.[2014]

A survey of 3,255 patients indicated that transdermal buprenorphine is effective for managing chronic pain, with 81% of respondents reporting good or very good pain relief, especially beneficial for those with stable cancer and non-cancer pain.

Adverse effects were generally mild and similar to other opioids, with only 4% experiencing local erythema and 1% pruritus, suggesting that the buprenorphine patch may be a safer alternative for patients who have had side effects from oral pain medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine TDS: use in daily practice, benefits for patients. Radbruch, L.[2022]

References

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

Noninvasive Transcranial Magnetic Stimulation (TMS) in Chronic Refractory Pain: A Systematic Review. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Case report: The feasibility of rTMS with intrathecal baclofen pump for the treatment of unresolved neuropathic pain following spinal cord injury. [2022]

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

A case report illustrating the effects of repetitive transcranial magnetic stimulation on cue-induced craving in an individual with opioid and cocaine use disorder. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Add-on repetitive transcranial magnetic stimulation in patients with opioid use disorder undergoing methadone maintenance therapy. [2021]

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

Repetitive transcranial magnetic stimulation in chronic pain: a review of the literature. [2022]

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

High dose transdermal buprenorphine for moderate to severe pain in spanish pain centres--a retrospective multicenter safety and efficacy study. [2013]

7. England pubmed.ncbi.nlm.nih.gov

Open-label, rapid initiation pilot study for extended-release buprenorphine subcutaneous injection. [2023]

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

The problem of pain: Additive analgesic effect of tramadol and buprenorphine in a patient with opioid use disorder. [2020]

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

Effectiveness and Safety of Transdermal Buprenorphine Versus Sustained-release Tramadol in Patients With Moderate to Severe Musculoskeletal Pain: An 8-Week, Randomized, Double-Blind, Double-Dummy, Multicenter, Active-controlled, Noninferiority Study. [2015]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Use of immediate-release opioids as supplemental analgesia during management of moderate-to-severe chronic pain with buprenorphine transdermal system. [2020]

11. France pubmed.ncbi.nlm.nih.gov

Buprenorphine TTS for children--a review of the drug's clinical pharmacology. [2022]

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

Buprenorphine in long-term control of chronic pain in cancer patients. [2022]

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

The impact of buprenorphine transdermal delivery system on activities of daily living among patients with chronic low back pain: an application of the international classification of functioning, disability and health. [2014]

14. England pubmed.ncbi.nlm.nih.gov

Buprenorphine TDS: use in daily practice, benefits for patients. [2022]