Pro-Dopaminergic Drugs for Chronic Pain

Overseen By Pain Lab

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Rochester

Must be taking: Pro-dopaminergic medications

Must not be taking: Methadone

Disqualifiers: Diabetes, Heart disease, Substance misuse, others

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

Compensation: Varies

Number of Visits: 5

Duration: 3 visits

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how certain drugs, such as carbidopa/levodopa (a pro-dopaminergic drug) and methylphenidate, affect brain activity in people with chronic pain. Researchers are exploring how these treatments might alter the brain's pain processing, focusing on areas influenced by dopamine, a chemical related to motivation and reward. Participants will receive either one of the study drugs or a placebo (a pill with no active ingredient) in a randomized, controlled setting. Individuals who have experienced chronic pain for over a year and find it significantly impacts their life might be suitable for this study. As a Phase 2 trial, this study measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important research on pain management.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are treated with methadone for opioid use disorder, you would be excluded from participating.

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

Research has shown that carbidopa/levodopa is usually well-tolerated by patients. One study found that even at higher doses, such as 800 mg, patients with Parkinson's disease experienced significant benefits. However, another study reported that 89% of participants experienced some side effects.

For methylphenidate, studies indicate it is safe for long-term use, with no increased risk of serious heart problems. A review found that methylphenidate can help manage pain in individuals with conditions like ADHD (attention deficit hyperactivity disorder).

Both carbidopa/levodopa and methylphenidate have been used safely for other conditions, suggesting they might also be safe for new uses, such as treating chronic pain. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they explore pro-dopaminergic drugs like Carbidopa-Levodopa and Methylphenidate for chronic pain, which offer a fresh approach compared to typical painkillers. Unlike conventional pain relief options, such as NSAIDs or opioids, Carbidopa-Levodopa targets dopamine pathways in the brain, potentially addressing pain at its neurological source. Methylphenidate, often used for ADHD, enhances dopamine and norepinephrine levels, which might offer pain relief with possibly fewer side effects than traditional analgesics. This focus on neurotransmitter modulation sets these treatments apart and could open new avenues for managing chronic pain effectively.

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

In this trial, participants will receive either methylphenidate, carbidopa/levodopa, or a placebo. Earlier studies have shown that methylphenidate eases chronic pain, with patients reporting significant relief within a month of starting treatment. Similarly, research on carbidopa/levodopa, a medication often used for Parkinson's disease, suggests it might also help with pain, as studies have found it can reduce pain severity over time. Both treatments affect dopamine, a brain chemical related to motivation and pleasure, which may be linked to chronic pain. ^{2 6 7 8 9}

Are You a Good Fit for This Trial?

Adults over 18, in stable health, who have experienced chronic pain for more than a year and rate their pain at least 40/100. Participants must speak English and represent the local demographic diversity. Excluded are those with certain implants, major psychiatric disorders or abnormal lab values, severe medical conditions, substance misuse or gambling addiction, specific allergic reactions to trial drugs, involvement in pain-related litigation or claims.

Inclusion Criteria

In generally stable health

I represent the gender and racial/ethnic diversity of my area.

Able to speak, read, and understand English

Exclusion Criteria

You are involved in a lawsuit related to your pain, have filed for disability, are receiving workman's compensation, or are seeking any of these because of your pain.

I have been experiencing pain for more than 4 weeks in the past year.

I struggle with tasks that require following movements with my eyes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

Baseline Assessment

Participants undergo baseline assessments including pain questionnaires and a baseline scan

1 visit

1 visit (in-person)

Treatment

Participants receive randomized treatments (placebo, LD/CD, or MP) and undergo scanning

3 visits

3 visits (in-person)

Follow-up

Participants are monitored for changes in brain activity and volume post-treatment

3 hours post-treatment

What Are the Treatments Tested in This Trial?

Interventions

• Carbidopa-Levodopa
• Methylphenidate
• Placebo

Trial Overview The study tests how brain dopamine affects chronic pain by using imaging to observe changes after taking pro-dopaminergic medications (carbidopa-levodopa and methylphenidate) versus placebo. It's randomized and double-blind: participants won't know if they're getting real meds or a dummy pill.

How Is the Trial Designed?

Group I: Methylphenidate Active Control 1 Intervention

0.5mg/kg

Group II: Carbidopa/levodopa, Active Control 1 Intervention

25mg/100mg

Group III: Placebo Placebo Group 1 Intervention

Oral Pill

Carbidopa-Levodopa is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Sinemet for:

• Parkinson's disease
• Postencephalitic parkinsonism
• Symptomatic parkinsonism following injury to the brain

Approved in European Union as Sinemet for:

• Parkinson's disease
• Postencephalitic parkinsonism
• Symptomatic parkinsonism following injury to the brain

Approved in Canada as Sinemet for:

• Parkinson's disease
• Postencephalitic parkinsonism
• Symptomatic parkinsonism following injury to the brain

Approved in Japan as Sinemet for:

• Parkinson's disease
• Postencephalitic parkinsonism
• Symptomatic parkinsonism following injury to the brain

Who Is Running the Clinical Trial?

University of Rochester

Lead Sponsor

Trials

883

Recruited

555,000+

Published Research Related to This Trial

In a post hoc analysis of a phase III study involving 336 children and adolescents with ADHD, lisdexamfetamine demonstrated significantly greater improvement in ADHD symptoms compared to osmotic-release oral system methylphenidate (OROS-MPH), with a mean change in ADHD-RS-IV total score of -24.3 for lisdexamfetamine versus -18.7 for OROS-MPH.

While lisdexamfetamine was more effective, it also had a higher incidence of treatment-emergent adverse events, such as decreased appetite and insomnia, compared to OROS-MPH, indicating that both medications have safety profiles typical of stimulant treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A post hoc comparison of the effects of lisdexamfetamine dimesylate and osmotic-release oral system methylphenidate on symptoms of attention-deficit hyperactivity disorder in children and adolescents. Soutullo, C., Banaschewski, T., Lecendreux, M., et al.[2021]

Dopamine receptors D(2) and D(3) can form heteromers, which enhance the effectiveness of certain medications like pramipexole and ropinirole, making them more potent at these receptor complexes compared to their individual forms.

When D(2) receptors are paired with an excess of D(3) receptors, some partial agonists can lose their effectiveness and act as antagonists, suggesting that the balance of these receptors could play a significant role in treating neuropsychiatric diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance. Maggio, R., Millan, MJ.[2010]

The study evaluated the effects of various dopamine D-2 antagonists and agonists on behavior in rats, revealing that D-2 agonists like quinpirole and (-)-NPA can reduce locomotor activity and induce circling behavior, indicating their efficacy in modulating dopamine activity.

YM 09151-2, a D-2 antagonist, effectively inhibited the effects of d-amphetamine, suggesting its potential as a therapeutic agent in conditions where dopamine modulation is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dopamine D-2 agonists with high and low efficacies: differentiation by behavioural techniques. Arnt, J., Hyttel, J.[2019]

In a four-week trial involving 119 Korean children with ADHD, Concerta (OROS methylphenidate) was found to be well tolerated and effective in improving attention, behavior, and cognitive function as reported by parents, teachers, and investigators.

The study demonstrated significant improvements in cognitive performance through various tests, supporting the use of Concerta as a beneficial once-daily treatment option for children with ADHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and tolerability of OROS methylphenidate in Korean children with attention-deficit/hyperactivity disorder. Lee, SI., Hong, SD., Kim, SY., et al.[2013]

In a 7-week study involving 226 adults with ADHD, OROS methylphenidate significantly improved ADHD symptoms compared to placebo, as shown by lower scores on the Adult ADHD Investigator Symptom Report Scale.

The treatment was well tolerated, with no serious adverse events reported, and a higher percentage of participants on OROS methylphenidate were classified as responders compared to those on placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, double-blind, parallel group, dose-escalation study. Adler, LA., Zimmerman, B., Starr, HL., et al.[2022]

Dexmethylphenidate extended release (d-MPH-ER) significantly improved ADHD symptoms in children and adolescents compared to placebo, with 67.3% of patients showing substantial improvement on the Clinical Global Impressions scale.

While d-MPH-ER was effective, it was associated with a higher rate of reported adverse events (49.1% vs. 25.5% for placebo), indicating the need for careful monitoring of side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of dexmethylphenidate extended-release capsules in children with attention-deficit/hyperactivity disorder. Greenhill, LL., Muniz, R., Ball, RR., et al.[2015]

Dopamine agonists, such as pramipexole and ropinirole, can effectively manage Parkinson's disease symptoms for over 3 years when used early, potentially delaying the side effects associated with long-term levodopa therapy.

These agonists primarily stimulate the D2 dopamine receptor, which is likely responsible for their therapeutic effects, although their impact on other dopamine receptor subtypes remains unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Parkinson's disease should begin with a dopamine agonist. Montastruc, JL., Rascol, O., Senard, JM.[2019]

Dopamine agonists (DAGs) are effective in reducing the required dose of levodopa (LD) for Parkinson's disease patients, helping to minimize side effects associated with LD.

Newer DAGs like cabergoline, ropinirole, and pramipexole show promise in delaying motor fluctuations and improving treatment outcomes in the early stages of Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second generation of dopamine agonists: pros and cons. Rabey, JM.[2018]

Most new treatments for Parkinson's disease target the dopaminergic system, focusing on enhancing dopamine function through amino acid precursors like levodopa and dopamine receptor agonists.

Recent developments in dopamine agonists, such as pramipexole, ropinirole, and cabergoline, aim to improve treatment options alongside existing medications like bromocriptine and pergolide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New strategies with dopaminergic drugs: modified formulations of levodopa and novel agonists. Goetz, CG.[2013]

Dexmethylphenidate, a chirally pure form of methylphenidate, has been shown to effectively manage ADHD in children at half the dose of traditional Ritalin, based on clinical trials involving 684 children.

The drug works by inhibiting the reuptake of norepinephrine and dopamine, and has been found to be well tolerated, with ongoing research to further understand its therapeutic action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexmethylphenidate--Novartis/Celgene. Focalin, D-MPH, D-methylphenidate hydrochloride, D-methylphenidate, dexmethylphenidate, dexmethylphenidate hydrochloride. [2018]

In a rat model of chronic pain, combining low-dose methylphenidate (MPH) with low-dose morphine (MOR) significantly enhanced and prolonged the analgesic effect of morphine compared to using either drug alone, suggesting a potential for improved pain management.

The combination therapy did not increase locomotor activity or reward behavior in the rats, indicating that low-dose MPH may help reduce the required dose of morphine without increasing the risk of misuse or addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methylphenidate and Morphine Combination Therapy in a Rat Model of Chronic Pain. You, Z., Ding, W., Doheny, JT., et al.[2021]

Chronic pain treatment involves a range of analgesics, with minor analgesics like paracetamol for moderate pain and opioids for severe pain, highlighting the importance of tailoring pain management to the severity of the condition.

The use of coanalgesic drugs, such as psychotropic medications and corticosteroids, can enhance pain relief and address associated symptoms, but the long-term use of opioids raises concerns about tolerance, dependence, and toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The pharmacologic basis of pain treatment]. Tillement, JP., Albengres, E.[2006]

Chronic pain is often not effectively managed, prompting the exploration of existing medications, known as coanalgesics, which include antidepressants, anticonvulsants, and topical agents, for their pain-relieving properties.

This review aims to provide an evidence-based overview of these coanalgesics and their applications in treating neuropathic and musculoskeletal pain, along with guidelines for their clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Coanalgesics for chronic pain therapy: a narrative review. Bair, MJ., Sanderson, TR.[2011]

Research shows that combining opioids with psychostimulants like amphetamine or methylphenidate can significantly enhance pain relief, as demonstrated in both animal and human studies.

Psychostimulants not only boost the analgesic effects of opioids but also improve cognitive function and reduce drowsiness, allowing for higher opioid doses and potentially better pain management, although further research is needed to optimize these combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potentiation of opioid analgesia by psychostimulant drugs: a review. Dalal, S., Melzack, R.[2022]

In Denmark, 19% of adults experience chronic pain, with most being treated by general practitioners rather than specialists.

For conditions like fibromyalgia and low back pain, tricyclic antidepressants and gabapentinoids are the primary recommended treatments, while regular use of non-steroidal anti-inflammatory drugs and paracetamol is not advised.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological treatment of chronic non-cancer pain]. Handberg, G.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7768530/

Chronic Pain Treatment Strategies in Parkinson's Disease At the end of 12 weeks, the study demonstrated an improvement in average pain severity over the preceding seven days in those patches receiving ...

2. annclinlabsci.org annclinlabsci.org/content/19/6/415.full.pdf

Long-Term Efficacy of Controlled-Release Carbidopa/ ... Total levodopa dosage was not significantly changed over the year. These data suggest that, in long-term use, CR4 remains more efficacious than SS alone for ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/2586769/

Long-term clinical efficacy of Sinemet CR in patients with ... After both 3 and 36 or 39 months of Sinemet CR therapy, 5 patients showed increased daily "on" time compared with baseline. All 8 required fewer daily doses ...

4. thelancet.com thelancet.com/journals/laneur/article/PIIS1474-4422(24)00052-8/abstract

Safety and efficacy of continuous subcutaneous levodopa ... Hierarchical testing ended after the fourth secondary endpoint. Adverse events were reported by 287 (89%) of 322 participants during open-label ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT01951105

Effect of L-dopa In Subacute Back Pain Population This study aims to determine if early treatment with Carbidopa/Levodopa and Naproxen in individuals with sub-acute back pain (SBP) is associated with changes in ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3533055/

Carbidopa/levodopa dose elevation and safety concerns in ... The data suggest that PD patients have the potential for enhanced clinical benefits when eclipsing the 800 mg carbidopa/levodopa threshold.

7. jamanetwork.com jamanetwork.com/journals/jamaneurology/fullarticle/2808496

IPX203 vs Immediate-Release Carbidopa-Levodopa for ... The results of this study suggest that IPX203 vs immediate-release carbidopa-levodopa may be useful in patients with Parkinson disease and motor fluctuations.

8. sciencedirect.com sciencedirect.com/science/article/pii/S1353802020308221

A 12-month, dose-level blinded safety and efficacy study of ... At 12 months, 73.0% of patients on 84 mg achieved an ON state within 60 min. Total daily OFF time was reduced by 0.55 h (month 1) and 0.88 h (month 12) for the ...

9. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/1782612/

Long-term evaluation of Sinemet CR in parkinsonian ... The safety and efficacy of Sinemet CR, a controlled-release formulation of carbidopa/levodopa, were investigated in a three year, open-label trial.