Pramipexole and Morphine for Renal Colic

Study Overview
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Brief Summary
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Opioid analgesics are among the most commonly prescribed class of medications in the US. While opioids may effectively control pain and other sensory disorders under acute conditions, the rates of misuse/abuse and accidental overdose have reached epidemic proportions. Clinicians are being challenged to find alternatives to opioid analgesics, or to reduce their use in treating pain whenever possible. Pre-clinical studies have shown that combining morphine (opioid drug) with pramipexole (dopamine 3 receptor agonist with some D2/D4 action) provides superior analgesia against painful stimuli than morphine alone. This analgesia is maintained even when the dose of morphine is lowered to a dose that is not effective on its own. A recent case report describes the use of this combination to restore pain control in a patient with restless legs syndrome, for which opioids alone have lost their effectiveness (Happe S, Clemens S and Brewer KL, In Review). This application proposes to establish a new therapeutic approach for treatment of a pain associated with renal colic (a common painful condition) using a novel combination of 2 existing, FDA-approved drugs. The immediate goal is to demonstrate that this drug combination can provide similar analgesia to opioid alone, and that analgesia is maintained when the opioid dose is reduced by 50%.

Detailed Description
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This is a double-blinded randomized controlled trial to take place in the Vidant Medical Center (VMC) Emergency Department (ED). A convenience sample of 96 participants will be drawn from patients presenting to the ED presentation with pain associated with suspected renal colic who do not experience pain relief after initial treatment with nonsteroidal anti-inflammatories. Written informed consent will be sought by a study team member after screening to ensure all inclusion criteria and no exclusion criteria are met. Once a patient has consented, they will be randomized into 1 of 2 study arms: Arm 1 (Control arm) = 0.1mg/kg of intravenous morphine + placebo pill, single dose Arm 2 (Study arm) = 0.05mg/kg intravenous morphine + 0.25mg pramipexole, single dose. Both arms include a maximum dose of 10mg/kg for the IV morphine. Pain scores will be obtained prior to administration of study drugs, and at 15-minute intervals (+/- 2 mins) after treatment for up to 2 hours, or discharge from the ED. Subjective response to each drug treatment will also be assessed every 15 minutes (+/- 2 mins) after treatment for up to 2 hours, or discharge from ED. Morphine will have a max dose of 10mg IV.

Official Title
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Adjuvant Treatment With Pramipexole to Reduce the Dose of Opioids Necessary for Analgesia in Acute Renal Colic

Conditions
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Renal Colic

Intervention / Treatment
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* Drug: Pramipexole
* Drug: Morphine
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 19 - 65 ED presentation with pain associated with suspected renal colic Patient reported failure to achieve pain relief with NSAID treatment in ED (additional pain treatment needed per treatment team) Exclusion Criteria: Age < 19 or ≥ 66 Allergy to any study medication Known pregnancy or breastfeeding Received opioid prior to enrollment Received IV Lidocaine during current ED visit Known chronic renal disease Currently taking any dopamine receptor agonist or antagonists (Do I need to list?) Unable to consent

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 66 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pramipexole and half-standard dose of morphine<br>0.25 mg oral tablet of pramipexole in combination with 0.05mg/kg of IV morphine | Drug: Pramipexole<br>* Establish proof of concept that low dose morphine in combination with pramipexole is non-inferior to standard dose morphine with respect to providing analgesia in patients presenting to the ED with pain associated with renal colic.<br>Drug: Morphine<br>* Establish proof of concept that low dose morphine in combination with pramipexole is non-inferior to standard dose morphine with respect to providing analgesia in patients presenting to the ED with pain associated with renal colic.<br>|
| Active Comparator: Standard dose of morphine and placebo<br>0.1mg/kg of IV morphine in combination with a placebo pill | Drug: Morphine<br>* Establish proof of concept that low dose morphine in combination with pramipexole is non-inferior to standard dose morphine with respect to providing analgesia in patients presenting to the ED with pain associated with renal colic.<br>Drug: Placebo oral tablet<br>* Establish proof of concept that low dose morphine in combination with pramipexole is non-inferior to standard dose morphine with respect to providing analgesia in patients presenting to the ED with pain associated with renal colic.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients who have an effective analgesic response (defined as at least a 50% improvement in pain scores) at 120 minutes post-randomization. | Pain scores used are the numerical rating scale (0 low to 10 high) or visual analogue scale (0 low to 100mm high). | 120 minutes | 
| Total dose of opioid received at 120 minutes in patients reporting a reduction in pain scores from baseline. | Dose of opioid measured in mg/kg | 120 minutes | 
| Proportion of patients who require rescue medications at 30 minutes post-randomization. |  | 30 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to reach effective pain reduction (defined as at least a 50% improvement in pain scores) within 120 minutes of treatment. | Pain scores used are the numerical rating scale (0 low to 10 high) or visual analogue scale (0 low to 100mm high). | 120 minutes | 
| Subjective effects of the drugs measured by scores on the drug effects questionnaire. | Drug effects questionnaire rates symptoms from 'not at all' at 0mm to 'extremely' at 100mm. | 120 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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morphine, Pramipexole, Renal Colic, Kidney Stone, opioids, analgesia, pain relief