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

Trial Summary

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.

What data supports the effectiveness of pro-dopaminergic drugs for chronic pain?

Research suggests that methylphenidate, a pro-dopaminergic drug, can enhance the pain-relieving effects of opioids, which are commonly used for chronic pain management. This combination has shown positive results in both animal and human studies, indicating potential benefits for patients with chronic pain. ^{1 2 3 4 5}

Is there safety data for pro-dopaminergic drugs like methylphenidate in humans?

Methylphenidate, a pro-dopaminergic drug, has been studied for safety in both children and adults with attention-deficit/hyperactivity disorder (ADHD). In these studies, it was generally well tolerated, meaning most people did not experience serious side effects. ^{6 7 8 9 10}

How does the drug Carbidopa-Levodopa, Methylphenidate, and Placebo differ from other treatments for chronic pain?

This drug combination is unique because it targets the dopaminergic system, which is typically associated with Parkinson's disease treatment, by using Carbidopa-Levodopa to enhance dopamine levels and Methylphenidate to increase dopamine activity, potentially offering a novel approach for managing chronic pain. ^{11 12 13 14 15}

What is the purpose of this trial?

Chronic pain is associated with plasticity in the brain limbic system composed mainly of the amygdala, hippocampus, ventral striatum, and cingulate cortex (ACC) /medial prefrontal cortex (mPFC). These brain areas, especially the ventral striatum, receive dopaminergic input from the ventral-tegmental area (VTA). Although there is a significant literature now showing that limbic brain tracks chronic pain intensity and predicts the risk of transition from sub-acute to chronic pain, the role of dopaminergic input to the limbic brain and the change thereof which occurs in chronic pain, is still not clear. Given the role of dopamine in motivational control and the loss of motivation associated with chronic pain understanding how dopaminergic transmission is altered in the limbic brain of chronic pain patients is critical to the understanding of the pathophysiology of chronic pain. Therefore, the overall aim of this project is to use brain imaging to study how dopaminergic transmission through the oral administration of pro-dopaminergic medications carbidopa/levodopa (CD/LD) and methylphenidate will modulate the brain signature of chronic pain. Chronic pain subjects will be scanned at baseline (no drug administration) and three times after treatment with the two drugs or placebo. The protocol will follow a randomized double-blind approach.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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 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]

References

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

Methylphenidate and Morphine Combination Therapy in a Rat Model of Chronic Pain. [2021]

2. France pubmed.ncbi.nlm.nih.gov

[The pharmacologic basis of pain treatment]. [2006]

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

Coanalgesics for chronic pain therapy: a narrative review. [2011]

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

Potentiation of opioid analgesia by psychostimulant drugs: a review. [2022]

5. Denmark pubmed.ncbi.nlm.nih.gov

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

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

Efficacy and tolerability of OROS methylphenidate in Korean children with attention-deficit/hyperactivity disorder. [2013]

7. United States 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. [2022]

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

Efficacy and safety of dexmethylphenidate extended-release capsules in children with attention-deficit/hyperactivity disorder. [2015]

9. New Zealand 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. [2021]

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

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

11. Austria pubmed.ncbi.nlm.nih.gov

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

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

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

13. Austria pubmed.ncbi.nlm.nih.gov

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

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

Treatment of Parkinson's disease should begin with a dopamine agonist. [2019]

15. England pubmed.ncbi.nlm.nih.gov

Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance. [2010]