Anti-depressants vs Anti-convulsants for Chronic Pain

(SPEC-AA Trial)

Overseen By Vafi Salmasi, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Stanford University

Must not be taking: SSRIs

Disqualifiers: Patient refusal, 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

Compensation: Varies

Number of Visits: 3

Duration: 6 months

450 Participants Needed

Trial Summary

What is the purpose of this trial?

Chronic pain is a major healthcare problem with an annual cost of above $600 billion. The quality of data available for treatments of chronic pain is not optimal. Generalizability of explanatory randomized controlled trial data is problematic as these trials exclude up to 90% of patients: leaving out real-world patients with serious medical and psychological comorbidities. Pragmatic trials embedded in patient care compare effectiveness of currently used treatments in real-world application leading to findings that generalize to broader range of patients. The changes in clinical practice and workflow necessary to integrate this type of research within patient care present pragmatic challenges. In this research, the overall objective is to overcome these challenges using an open-source learning health care system - CHOIR. CHOIR is currently used to track patients' clinical trajectory and treatment response across multiple academic sites resulting in over 25 publications characterizing chronic pain. Through the pilot studies, the investigators have already developed a point-of-care randomization for CHOIR that facilitates integration of research and patient care by allowing the physicians to randomize patients during clinic visits. The investigators have already demonstrated feasibility of the randomization and data collection platform in two ongoing pilot pragmatic clinical trials. The investigators are proposing to better integrate pragmatic research within clinical practice through conducting a randomized comparative effectiveness trial in 450 patients with chronic pain comparing effectiveness of anti-convulsants and anti-depressants (two most commonly used classes of medications for treatment of chronic pain). The investigators will also perform a qualitative interview with all physicians in our clinic to study the impact of integrating pragmatic research into clinical care. The investigators will use the data available in CHOIR as well as the real-world data generated from this clinical trial to build, validate and test a model to predict what clinical characteristics can predict response to either of these classes of medications. The proposed study is the first step to use flexible point-of-care randomization to compare effectiveness of different treatments in different subgroups of patients whenever equipoise exists. The prediction model will guide decision making process of clinicians choosing between these medications based on clinical characteristics of individual patients.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications. However, if you are on a large dose of a specific type of anti-depressant (SSRI), you might be excluded from the trial.

What evidence supports the effectiveness of the drugs Lyrica and Cymbalta for chronic pain?

Research shows that anticonvulsant drugs like Lyrica (pregabalin) and antidepressants like Cymbalta (duloxetine) can help manage chronic pain, especially neuropathic pain (pain from nerve damage). These drugs have been found effective in conditions like painful diabetic neuropathy and fibromyalgia, providing pain relief by affecting certain chemicals in the brain. ^{1 2 3 4 5}

Is it safe to use anticonvulsant and antidepressant medications for chronic pain?

Anticonvulsant drugs like gabapentin and pregabalin have been used for chronic pain since the 1960s, and while they are generally considered safe, some reviews have been withdrawn due to concerns about unpublished data. Antidepressants like duloxetine (Cymbalta) are also used for pain management, but specific safety data for chronic pain is not detailed in the provided research. ^{1 6 7 8 9}

How do antidepressant and anticonvulsant drugs differ from other drugs for chronic pain?

Antidepressant and anticonvulsant drugs for chronic pain are unique because they not only help relieve pain but also address related issues like sleep disturbances, depression, and anxiety. Unlike opioids, these drugs work by interacting with neurotransmitters and ion channels, offering a valuable alternative with different safety and side effect profiles. ^{2 4 7 8 10}

Eligibility Criteria

This trial is for adults over 18 with chronic pain lasting more than 3 months, who could be treated with anti-convulsants or anti-depressants. Patients must have a balanced chance of benefiting from either medication as judged by their doctor. Those with conditions that prevent the use of these drugs or who refuse to participate are excluded.

Inclusion Criteria

The treating pain provider is unsure about the best choice between anti-convulsants and anti-depressants for your condition.

I have been experiencing pain for over 3 months.

My doctor recommends anti-convulsants or anti-depressants for my pain.

Exclusion Criteria

I have chosen not to participate in certain treatments or procedures.

I cannot take anti-convulsants or anti-depressants as advised by my doctor.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive either anti-convulsant or anti-depressant medication for chronic pain management

6 months

3 visits (in-person) at 1, 3, and 6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Observation

Data collection from patients who do not enter the randomization arms

6 months

Treatment Details

Interventions

• Anti-convulsant medications
• Anti-depressant medications

Trial Overview The study compares the effectiveness of two common chronic pain treatments: anti-convulsant and anti-depressant medications. It involves randomly assigning patients to one treatment group during clinic visits using an open-source system called CHOIR, which tracks patient outcomes.

Participant Groups

Group I: Anti-depressant medication Experimental Treatment 1 Intervention

The participants will be randomized to receiving an anti-depressant medication. Then using a patient centered approach, the participant and their treating pain provider will choose one medication within the class. Participants will continue the medications for at least 6 months provided that they can tolerate the side effects, consider the treatment effective, and are willing to continue the treatment. We are studying two classes of medications and specific names of medications do not apply.

Group II: Anti-convulsant medication Experimental Treatment 1 Intervention

The participants will be randomized to receiving an anti-convulsant medication. Then using a patient centered approach, the participant and their treating pain provider will choose one medication within the class. Participants will continue the medications for at least 6 months provided that they can tolerate the side effects, consider the treatment effective, and are willing to continue the treatment. We are studying two classes of medications and specific names of medications do not apply.

Anti-convulsant medications is already approved in European Union, United States for the following indications:

Approved in European Union as Lyrica for:

• Diabetic peripheral neuropathy
• Post-herpetic neuralgia
• Epilepsy

Approved in United States as Lyrica for:

• Diabetic nerve pain
• Post-herpetic neuralgia
• Partial seizures

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Findings from Research

In a study using a chronic pain model with male rats, both zonisamide and pregabalin showed significant efficacy in alleviating neuropathic pain, suggesting they could be effective alternatives to traditional pain medications.

The results indicate that anticonvulsants targeting N-type calcium channels or a combination of voltage-gated sodium and T-type calcium channels provide better pain relief compared to those that only inhibit T-type calcium channels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the Effects of Zonisamide, Ethosuximide and Pregabalin in the Chronic Constriction Injury Induced Neuropathic Pain in Rats. Goyal, S., Singla, S., Kumar, D., et al.[2020]

Newer generation anticonvulsants like gabapentin, tricyclic antidepressants (TCAs), and opioids are preferred therapies for treating neuropathic pain, but some patients may still experience pain despite these treatments.

For patients who do not respond to or cannot tolerate these first-line therapies, medications like venlafaxine or duloxetine may provide relief, although there are no direct comparisons between non-tricyclic options for neuropathic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nontricyclic antidepressants for neuropathic pain #187. Hawley, P.[2022]

Anticonvulsant drugs, particularly gabapentin, have shown significant efficacy in treating neuropathic pain conditions like painful diabetic neuropathy and postherpetic neuralgia, as evidenced by various clinical trials.

The emergence of newer anticonvulsants, such as pregabalin, suggests a promising future for their use in managing neuropathic pain, although further research is needed to fully understand their mechanisms and optimize treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of anticonvulsants drugs for neuropathic painful conditions. Hussain, AM., Afshan, G.[2009]

Tricyclic antidepressants and certain novel antidepressants are effective for treating neuropathic pain, with their analgesic effects being independent of their antidepressant properties, particularly favoring those with noradrenergic activity.

Both first and second-generation antiepileptic drugs are effective for neuropathic pain, with second-generation drugs like gabapentin and pregabalin being safer for elderly patients, while tricyclic antidepressants are the most cost-effective option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antidepressants and antiepileptic drugs for chronic non-cancer pain. Maizels, M., McCarberg, B.[2005]

Gabapentin is effective in providing pain relief for about one-third of adults with chronic neuropathic pain, with a number needed to treat (NNT) of 5.8 for moderate benefit and 6.8 for substantial benefit, based on a review of 29 studies involving 3571 participants.

While gabapentin is effective, it is associated with a high incidence of adverse events (66% of users), including dizziness (21%) and somnolence (16%), although serious adverse events were not more common than with placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Moore, RA., Wiffen, PJ., Derry, S., et al.[2022]

Gabapentin and pregabalin are the only antiepileptic drugs with reasonably good evidence supporting their efficacy in treating certain types of neuropathic pain, such as painful diabetic neuropathy and postherpetic neuralgia, with a notable reduction in pain intensity for some patients.

Despite the potential benefits of gabapentin and pregabalin, the overall response rate for achieving significant pain relief (at least 50% reduction) is low, and treatment is associated with a high risk of adverse events, highlighting the need for careful patient selection and management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiepileptic drugs for neuropathic pain and fibromyalgia - an overview of Cochrane reviews. Wiffen, PJ., Derry, S., Moore, RA., et al.[2023]

A systematic review of 23 trials involving 1,074 patients found that anticonvulsants like carbamazepine and gabapentin can be effective for chronic neuropathic pain, particularly in conditions like trigeminal neuralgia and diabetic neuropathy, with numbers-needed-to-treat (NNT) values indicating moderate effectiveness.

However, the review also highlighted that there is limited evidence supporting the use of anticonvulsants for acute pain management, and they should be considered only after other treatment options have been explored for chronic pain syndromes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticonvulsant drugs for acute and chronic pain. Wiffen, P., Collins, S., McQuay, H., et al.[2022]

A systematic review of 23 trials involving 1074 patients found that anticonvulsants like carbamazepine and gabapentin are effective for chronic neuropathic pain, particularly in conditions like trigeminal neuralgia and diabetic neuropathy, with numbers-needed-to-treat (NNT) values indicating moderate effectiveness.

However, the review concluded that there is insufficient evidence to support the use of anticonvulsants for acute pain management, and they should only be considered after other treatments have been tried for chronic pain syndromes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

WITHDRAWN. Anticonvulsant drugs for acute and chronic pain. Wiffen, PJ., Collins, S., McQuay, HJ., et al.[2022]

Gabapentin has been shown to be effective in managing chronic neuropathic pain, with a number needed to treat (NNT) of 4.3, meaning that about 4 patients need to be treated for one to experience significant pain relief.

In contrast, gabapentin did not demonstrate any benefit for acute pain management, indicating its effectiveness is primarily in chronic conditions like diabetic neuropathy and post-herpetic neuralgia, where the NNTs were even lower at 2.9 and 3.9, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

WITHDRAWN: Gabapentin for acute and chronic pain. Wiffen, PJ., McQuay, HJ., Edwards, J., et al.[2023]

Antidepressants and anticonvulsants are effective treatments for neuropathic pain and chronic headache, providing alternatives to opioids for managing chronic pain conditions.

In addition to pain relief, antidepressants help alleviate associated issues like sleep disturbances, depression, and anxiety, which are common in patients suffering from chronic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antidepressant and anticonvulsant medication for chronic pain. Sullivan, MD., Robinson, JP.[2006]

References

1. India pubmed.ncbi.nlm.nih.gov

Comparison of the Effects of Zonisamide, Ethosuximide and Pregabalin in the Chronic Constriction Injury Induced Neuropathic Pain in Rats. [2020]

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

Nontricyclic antidepressants for neuropathic pain #187. [2022]

3. Pakistan pubmed.ncbi.nlm.nih.gov

Use of anticonvulsants drugs for neuropathic painful conditions. [2009]

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

Antidepressants and antiepileptic drugs for chronic non-cancer pain. [2005]

5. England pubmed.ncbi.nlm.nih.gov

Gabapentin for chronic neuropathic pain and fibromyalgia in adults. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Antiepileptic drugs for neuropathic pain and fibromyalgia - an overview of Cochrane reviews. [2023]

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

Anticonvulsant drugs for acute and chronic pain. [2022]

8. England pubmed.ncbi.nlm.nih.gov

WITHDRAWN. Anticonvulsant drugs for acute and chronic pain. [2022]

9. England pubmed.ncbi.nlm.nih.gov

WITHDRAWN: Gabapentin for acute and chronic pain. [2023]

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

Antidepressant and anticonvulsant medication for chronic pain. [2006]