Pramipexole and Morphine for Renal Colic

NCT04160520 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: ECarolinaUniversity
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

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%.

Conditions

Renal Colic

Keywords

morphine; Pramipexole; Renal Colic; Kidney Stone; opioids; analgesia; pain relief

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (2)

• Time to reach effective pain reduction (defined as at least a 50% improvement in pain scores) within 120 minutes of treatment.

  120 minutes

• Subjective effects of the drugs measured by scores on the drug effects questionnaire.

  120 minutes

Study Arms (2)

Pramipexole and half-standard dose of morphine

EXPERIMENTAL

0.25 mg oral tablet of pramipexole in combination with 0.05mg/kg of IV morphine

Drug: Pramipexole; Drug: Morphine

Standard dose of morphine and placebo

ACTIVE COMPARATOR

0.1mg/kg of IV morphine in combination with a placebo pill

Drug: Morphine; Drug: Placebo oral tablet

Interventions

Pramipexole DRUG

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.

Pramipexole and half-standard dose of morphine

Morphine DRUG

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.

Pramipexole and half-standard dose of morphine; Standard dose of morphine and placebo

Placebo oral tablet DRUG

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.

Standard dose of morphine and placebo

Eligibility Criteria

• Age: 19 Years - 66 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• East Carolina University: lead

Study Sites (1)

Vidant Medical Center ED

Greenville, North Carolina, 27834, United States

Location

Related Publications (13)

• Rodgers HM, Yow J, Evans E, Clemens S, Brewer KL. Dopamine D1 and D3 receptor modulators restore morphine analgesia and prevent opioid preference in a model of neuropathic pain. Neuroscience. 2019 May 15;406:376-388. doi: 10.1016/j.neuroscience.2019.03.034. Epub 2019 Mar 23.

  PMID: 30910641 BACKGROUND

• Afshar K, Jafari S, Marks AJ, Eftekhari A, MacNeily AE. Nonsteroidal anti-inflammatory drugs (NSAIDs) and non-opioids for acute renal colic. Cochrane Database Syst Rev. 2015 Jun 29;2015(6):CD006027. doi: 10.1002/14651858.CD006027.pub2.

  PMID: 26120804 BACKGROUND

• Pathan SA, Mitra B, Bhutta ZA, Qureshi I, Spencer E, Hameed AA, Nadeem S, Tahir R, Anjum S, Cameron PA. A comparative, epidemiological study of acute renal colic presentations to emergency departments in Doha, Qatar, and Melbourne, Australia. Int J Emerg Med. 2018 Jan 3;11(1):1. doi: 10.1186/s12245-017-0160-9.

  PMID: 29299773 BACKGROUND

• Patanwala AE, Keim SM, Erstad BL. Intravenous opioids for severe acute pain in the emergency department. Ann Pharmacother. 2010 Nov;44(11):1800-9. doi: 10.1345/aph.1P438. Epub 2010 Oct 26.

  PMID: 20978218 BACKGROUND

• Altun A, Yildirim K, Ozdemir E, Bagcivan I, Gursoy S, Durmus N. Attenuation of morphine antinociceptive tolerance by cannabinoid CB1 and CB2 receptor antagonists. J Physiol Sci. 2015 Sep;65(5):407-15. doi: 10.1007/s12576-015-0379-2. Epub 2015 Apr 18.

  PMID: 25894754 BACKGROUND

• Altun A, Ozdemir E, Yildirim K, Gursoy S, Durmus N, Bagcivan I. The effects of endocannabinoid receptor agonist anandamide and antagonist rimonabant on opioid analgesia and tolerance in rats. Gen Physiol Biophys. 2015 Oct;34(4):433-40. doi: 10.4149/gpb_2015017.

  PMID: 26374993 BACKGROUND

• Terner JM, Barrett AC, Lomas LM, Negus SS, Picker MJ. Influence of low doses of naltrexone on morphine antinociception and morphine tolerance in male and female rats of four strains. Pain. 2006 May;122(1-2):90-101. doi: 10.1016/j.pain.2006.01.019. Epub 2006 Mar 9.

  PMID: 16527399 BACKGROUND

• Dourish CT, Hawley D, Iversen SD. Enhancement of morphine analgesia and prevention of morphine tolerance in the rat by the cholecystokinin antagonist L-364,718. Eur J Pharmacol. 1988 Mar 15;147(3):469-72. doi: 10.1016/0014-2999(88)90183-5.

  PMID: 3378566 BACKGROUND

• Bijur PE, Schechter C, Esses D, Chang AK, Gallagher EJ. Intravenous bolus of ultra-low-dose naloxone added to morphine does not enhance analgesia in emergency department patients. J Pain. 2006 Feb;7(2):75-81. doi: 10.1016/j.jpain.2005.08.008.

  PMID: 16459272 BACKGROUND

• Birnbaum A, Esses D, Bijur PE, Holden L, Gallagher EJ. Randomized double-blind placebo-controlled trial of two intravenous morphine dosages (0.10 mg/kg and 0.15 mg/kg) in emergency department patients with moderate to severe acute pain. Ann Emerg Med. 2007 Apr;49(4):445-53, 453.e1-2. doi: 10.1016/j.annemergmed.2006.06.030. Epub 2006 Sep 15.

  PMID: 16978739 BACKGROUND

• Chang AK, Bijur PE, Baccelieri A, Gallagher EJ. Efficacy and safety profile of a single dose of hydromorphone compared with morphine in older adults with acute, severe pain: a prospective, randomized, double-blind clinical trial. Am J Geriatr Pharmacother. 2009 Feb;7(1):1-10. doi: 10.1016/j.amjopharm.2009.02.002.

  PMID: 19281935 BACKGROUND

• Ostelo RW, Deyo RA, Stratford P, Waddell G, Croft P, Von Korff M, Bouter LM, de Vet HC. Interpreting change scores for pain and functional status in low back pain: towards international consensus regarding minimal important change. Spine (Phila Pa 1976). 2008 Jan 1;33(1):90-4. doi: 10.1097/BRS.0b013e31815e3a10.

  PMID: 18165753 BACKGROUND

• Girardi C, Duronio J, Patton R, O'Brien K, Clemens S, Brewer KL. A novel opioid/pramipexole combination treatment for the management of acute pain: a pilot study. Front Pain Res (Lausanne). 2024 Sep 24;5:1422298. doi: 10.3389/fpain.2024.1422298. eCollection 2024.

  PMID: 39411383 DERIVED

MeSH Terms

Conditions

Renal Colic; Kidney Calculi; Agnosia

Interventions

Pramipexole; Morphine

Condition Hierarchy (Ancestors)

Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Nephrolithiasis; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urolithiasis; Urinary Calculi; Male Urogenital Diseases; Calculi; Pathological Conditions, Anatomical; Perceptual Disorders; Neurobehavioral Manifestations; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Benzothiazoles; Thiazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Study Officials

• Kori Brewer, PhD

  East Carolina University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Participant and study team (i.e. investigators responsible for collecting pain scores) will be blinded as to treatment arm for the duration of the study (2 hours after initiation or until ED discharge/hospital admission). Treatment team (physicians and nurses involved in ED care of the patient) will be unblinded to maintain participant safety and proper medication administration. While the treating physician may be aware of what drugs have been ordered, the need for rescue medications is based on patient pain score at the 30-minute point.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 5, 2019
• First Posted: November 13, 2019
• Study Start: October 28, 2019
• Primary Completion: January 24, 2023
• Study Completion: January 24, 2023
• Last Updated: March 8, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)