{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:44:21Z","timestamp":1760244261903,"version":"3.41.2"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T00:00:00Z","timestamp":1727136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pain Res."],"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p>Despite their dangerous side effects, opioid drugs remain a standard of care for moderate to severe pain with few alternatives. Strategies to maintain the analgesic effects of opioids while minimizing the associated risks are needed. Pre-clinical studies have shown using a dopamine 3 receptor (D3R) agonist as an adjuvant to morphine provides superior analgesia against painful stimuli compared to morphine alone. Our objective was to test if adjunct treatment with a D3R agonist can lead to a reduction in opioid use while maintaining effective analgesia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and methods<\/jats:title><jats:p>This study was set up as a double-blinded, placebo-controlled randomized trial. Enrollment included acute renal colic patients presenting to the emergency department, from which patients were randomized to either the \u201ccontrol\u201d or \u201cstudy arm\u201d. The control group received standard treatment of care (morphine, 0.1\u2005mg\/kg; i.v.) and an oral placebo pill. The experimental group received half-dosed morphine and oral pramipexole pill (0.25\u2005mg). Pain measurements including a numerical pain scale and visual analog scale were collected from enrollees at baseline and every subsequent 15\u2005min.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 19 patients completed the study, 10 in the experimental arm and 9 in the control arm. During the study period, effective analgesia (50% decrease from baseline) was achieved in 80% of patients in the experimental arm vs. 33.3% in the control arm.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our pilot clinical trial demonstrated that D3R recruitment can serve as an effective adjuvant to low-dose morphine for control of renal colic pain and potentially other acute pain conditions.\n<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical Trial Registration<\/jats:title><jats:p><jats:uri>ClinicalTrials.gov<\/jats:uri>, identifier, (NCT04160520).<\/jats:p><\/jats:sec>","DOI":"10.3389\/fpain.2024.1422298","type":"journal-article","created":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T05:10:35Z","timestamp":1727154635000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A novel opioid\/pramipexole combination treatment for the management of acute pain: a pilot study"],"prefix":"10.3389","volume":"5","author":[{"given":"Cara","family":"Girardi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Duronio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Patton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"O\u2019Brien","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Clemens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kori L.","family":"Brewer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1002\/pds.4366","article-title":"Opioid analgesic dose and the risk of misuse, overdose, and death: a narrative review","volume":"27","author":"Coyle","year":"2018","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15585\/mmwr.rr6501e1","article-title":"CDC guideline for prescribing opioids for chronic pain - United States, 2016","volume":"65","author":"Dowell","year":"2016","journal-title":"MMWR Recomm Rep"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15585\/mmwr.rr7103a1","article-title":"CDC clinical practice guideline for prescribing opioids for pain - United States, 2022","volume":"71","author":"Dowell","year":"2022","journal-title":"MMWR Recomm Rep"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2526","DOI":"10.1016\/j.pain.2014.09.012","article-title":"Synaptic upregulation and superadditive interaction of dopamine D2- and mu-opioid receptors after peripheral nerve injury","volume":"155","author":"Aira","year":"2014","journal-title":"Pain"},{"key":"B5","doi-asserted-by":"publisher","first-page":"7778","DOI":"10.1021\/acs.jmedchem.1c00611","article-title":"Novel dual-target mu-opioid receptor and dopamine D(3) receptor ligands as potential nonaddictive pharmacotherapeutics for pain management","volume":"64","author":"Bonifazi","year":"2021","journal-title":"J Med Chem"},{"key":"B6","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1016\/j.neuroscience.2019.03.034","article-title":"Dopamine D1 and D3 receptor modulators restore morphine analgesia and prevent opioid preference in a model of neuropathic pain","volume":"406","author":"Rodgers","year":"2019","journal-title":"Neuroscience"},{"key":"B7","doi-asserted-by":"crossref","DOI":"10.23970\/AHRQEPCCER240","volume-title":"Treatments for Acute Pain: A Systematic Review. Comparative Effectiveness Review no. 240","author":"Chou","year":"2020"},{"key":"B8","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.sleep.2006.10.008","article-title":"First night efficacy of pramipexole in restless legs syndrome and periodic leg movements","volume":"8","author":"Manconi","year":"2007","journal-title":"Sleep Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.neuroscience.2016.05.017","article-title":"Modulation of pain, nociception, and analgesia by the brain reward center","volume":"338","author":"Mitsi","year":"2016","journal-title":"Neuroscience"},{"key":"B10","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1016\/j.sleep.2008.05.014","article-title":"A dose-ranging study of pramipexole for the symptomatic treatment of restless legs syndrome: polysomnographic evaluation of periodic leg movements and sleep disturbance","volume":"10","author":"Jama","year":"2009","journal-title":"Sleep Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1038\/s41572-021-00311-z","article-title":"Restless legs syndrome","volume":"7","author":"Manconi","year":"2021","journal-title":"Nat Rev Dis Primers"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1212\/01.wnl.0000231513.23919.a1","article-title":"Efficacy and safety of pramipexole in restless legs syndrome","volume":"67","author":"Winkelman","year":"2006","journal-title":"Neurology"},{"key":"B13","doi-asserted-by":"publisher","first-page":"2495","DOI":"10.1002\/art.21191","article-title":"A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications","volume":"52","author":"Holman","year":"2005","journal-title":"Arthritis Rheum"},{"key":"B14","doi-asserted-by":"publisher","first-page":"327","DOI":"10.2165\/11204570-000000000-00000","article-title":"Pramipexole extended release: in Parkinson\u2019s disease","volume":"24","author":"Chwieduk","year":"2010","journal-title":"CNS Drugs"},{"key":"B15","doi-asserted-by":"publisher","first-page":"612619","DOI":"10.4061\/2010\/612619","article-title":"Pramipexole extended release: a novel treatment option in Parkinson\u2019s disease","volume":"2010","author":"Eisenreich","year":"2010","journal-title":"Parkinsons Dis"},{"key":"B16","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.jns.2006.05.027","article-title":"A dopamine agonist, pramipexole, and cognitive functions in Parkinson\u2019s disease","volume":"248","author":"Relja","year":"2006","journal-title":"J Neurol Sci"},{"key":"B17","doi-asserted-by":"publisher","first-page":"172935","DOI":"10.1016\/j.pbb.2020.172935","article-title":"Dopamine D1 or D3 receptor modulators prevent morphine tolerance and reduce opioid withdrawal symptoms","volume":"194","author":"Rodgers","year":"2020","journal-title":"Pharmacol Biochem Behav"},{"key":"B18","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1212\/WNL.49.3.724","article-title":"Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson\u2019s disease. The pramipexole study group","volume":"49","author":"Shannon","year":"1997","journal-title":"Neurology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/S1353-8020(00)00031-6","article-title":"The long-term safety and efficacy of pramipexole in advanced Parkinson\u2019s disease","volume":"7","author":"Weiner","year":"2001","journal-title":"Parkinsonism Relat Disord"},{"key":"B20","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1007\/s00359-008-0368-5","article-title":"Unaltered D1, D2, D4, and D5 dopamine receptor mRNA expression and distribution in the spinal cord of the D3 receptor knockout mouse","volume":"194","author":"Zhu","year":"2008","journal-title":"J Comp Physiol A Neuroethol Sens Neural Behav Physiol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"11337","DOI":"10.1523\/JNEUROSCI.3698-04.2004","article-title":"Conversion of the modulatory actions of dopamine on spinal reflexes from depression to facilitation in D3 receptor knock-out mice","volume":"24","author":"Clemens","year":"2004","journal-title":"J Neurosci"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1716","DOI":"10.1038\/s41386-023-01590-8","article-title":"Effects of selective dopamine D3 receptor partial agonist\/antagonists on oxycodone self-administration and antinociception in monkeys","volume":"48","author":"Woodlief","year":"2023","journal-title":"Neuropsychopharmacology"},{"key":"B23","doi-asserted-by":"publisher","first-page":"2309","DOI":"10.1038\/s41386-022-01379-1","article-title":"A highly D(3)R-selective and efficacious partial agonist (S)-ABS01-113 compared to its D(3)R-selective antagonist enantiomer (R)-ABS01-113 as potential treatments for opioid use disorder","volume":"47","author":"Galaj","year":"2022","journal-title":"Neuropsychopharmacology"},{"key":"B24","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1016\/j.eururo.2017.11.001","article-title":"A systematic review and meta-analysis comparing the efficacy of nonsteroidal anti-inflammatory drugs, opioids, and paracetamol in the treatment of acute renal colic","volume":"73","author":"Pathan","year":"2018","journal-title":"Eur Urol"},{"year":"","key":"B25","article-title":"Highlights of Prescribing Information"},{"key":"B26","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1097\/00000542-200507000-00023","article-title":"Sex- and age-related differences in morphine requirements for postoperative pain relief","volume":"103","author":"Aubrun","year":"2005","journal-title":"Anesthesiology"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.amjopharm.2009.02.002","article-title":"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","volume":"7","author":"Chang","year":"2009","journal-title":"Am J Geriatr Pharmacother"},{"key":"B28","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1097\/BRS.0b013e31815e3a10","article-title":"Interpreting change scores for pain and functional status in low back pain: towards international consensus regarding minimal important change","volume":"33","author":"Ostelo","year":"2008","journal-title":"Spine"},{"key":"B29","doi-asserted-by":"publisher","first-page":"10304","DOI":"10.1021\/acs.jmedchem.3c00417","article-title":"Pharmacological and physicochemical properties optimization for dual-target dopamine D(3) (D(3)R) and mu-opioid (MOR) receptor ligands as potentially safer analgesics","volume":"66","author":"Bonifazi","year":"2023","journal-title":"J Med Chem"},{"key":"B30","doi-asserted-by":"publisher","first-page":"137419","DOI":"10.1016\/j.neulet.2023.137419","article-title":"The FDA-approved compound, pramipexole and the clinical-stage investigational drug, dexpramipexole, reverse chronic allodynia from sciatic nerve damage in mice, and alter IL-1beta and IL-10 expression from immune cell culture","volume":"814","author":"Sanchez","year":"2023","journal-title":"Neurosci Lett"},{"key":"B31","doi-asserted-by":"crossref","DOI":"10.23970\/AHRQEPCERTA218","volume-title":"The Effectiveness and Risks of Long- Term Opioid Treatment of Chronic Pain. Evidence Report\/Technology Assessment no. 218. AHRQ Publication no 14-E005-EF","author":"Chou","year":"2014"},{"key":"B32","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1007\/s11606-016-3810-3","article-title":"Association between initial opioid prescribing patterns and subsequent long-term use among opioid-naive patients: a statewide retrospective cohort study","volume":"32","author":"Deyo","year":"2017","journal-title":"J Gen Intern Med"},{"key":"B33","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.jpain.2017.10.001","article-title":"Association of prescription drug monitoring program use with opioid prescribing and health outcomes: a comparison of program users and nonusers","volume":"19","author":"Deyo","year":"2018","journal-title":"J Pain"},{"key":"B34","doi-asserted-by":"crossref","DOI":"10.23970\/AHRQEPCCER229","volume-title":"Opioid Treatments for Chronic Pain. Comparative Effectiveness Review, No. 229","author":"Chou","year":"2020"},{"volume-title":"Acute Treatments for Episodic Migraine. Comparative Effectiveness Review no. 239","year":"2020","author":"VanderPluym","key":"B35"},{"volume-title":"Noninvasive Nonpharmacological Treatment for Chronic Pain: A Systematic Review Update. Comparative Effectiveness Review no. 227","year":"2020","author":"Skelly","key":"B36"},{"key":"B37","doi-asserted-by":"publisher","first-page":"5661","DOI":"10.1523\/JNEUROSCI.2469-15.2016","article-title":"Dopamine D1-like receptors regulate constitutive, mu-opioid receptor-mediated repression of use-dependent synaptic plasticity in dorsal horn neurons: more harm than good?","volume":"36","author":"Aira","year":"2016","journal-title":"J Neurosci"},{"key":"B38","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.brainres.2009.11.009","article-title":"Dopamine D1, D2 and mu-opioid receptors are co-expressed with adenylyl cyclase 5 and phosphodiesterase 7B mRNAs in striatal rat cells","volume":"1310","author":"de Gortari","year":"2010","journal-title":"Brain Res"},{"key":"B39","doi-asserted-by":"publisher","first-page":"62","DOI":"10.3389\/fncir.2014.00062","article-title":"Dopamine D3 receptor dysfunction prevents anti-nociceptive effects of morphine in the spinal cord","volume":"8","author":"Brewer","year":"2014","journal-title":"Front Neural Circuits"},{"key":"B40","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.expneurol.2012.09.002","article-title":"Increased excitability of spinal pain reflexes and altered frequency-dependent modulation in the dopamine D3-receptor knockout mouse","volume":"238","author":"Keeler","year":"2012","journal-title":"Exp Neurol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"2250","DOI":"10.1152\/jn.00366.2011","article-title":"Opposing modulatory effects of D1- and D2-like receptor activation on a spinal central pattern generator","volume":"107","author":"Clemens","year":"2012","journal-title":"J Neurophysiol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.neulet.2018.11.043","article-title":"Dopaminergic modulation of pain signals in the medial prefrontal cortex: challenges and perspectives","volume":"702","author":"Huang","year":"2019","journal-title":"Neurosci Lett"},{"key":"B43","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/j.ejphar.2018.07.038","article-title":"Dopaminergic and serotonergic mechanisms in the modulation of pain: in vivo studies in human brain","volume":"834","author":"Martikainen","year":"2018","journal-title":"Eur J Pharmacol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1186\/s10194-022-01469-x","article-title":"Dopamine receptor D2 regulates GLUA1-containing AMPA receptor trafficking and central sensitization through the PI3K signaling pathway in a male rat model of chronic migraine","volume":"23","author":"Zhang","year":"2022","journal-title":"J Headache Pain"},{"key":"B45","doi-asserted-by":"publisher","first-page":"108976","DOI":"10.1016\/j.neuropharm.2022.108976","article-title":"Pramipexole treatment attenuates mechanical hypersensitivity in male rats experiencing chronic inflammatory pain","volume":"208","author":"Edwards","year":"2022","journal-title":"Neuropharmacology"},{"key":"B46","doi-asserted-by":"publisher","first-page":"377","DOI":"10.3897\/folmed.63.e55136","article-title":"Pramipexole and tolcapone alleviate thermal and mechanical nociception in naive rats","volume":"63","author":"Mihaylova","year":"2021","journal-title":"Folia Med (Plovdiv)"},{"key":"B47","doi-asserted-by":"publisher","first-page":"S476","DOI":"10.1002\/mds.21610","article-title":"Augmentation as a treatment complication of restless legs syndrome: concept and management","volume":"22","author":"Garcia-Borreguero","year":"2007","journal-title":"Mov Disord"},{"key":"B48","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1212\/WNL.52.5.938","article-title":"Restless legs syndrome improved by pramipexole: a double-blind randomized trial","volume":"52","author":"Montplaisir","year":"1999","journal-title":"Neurology"},{"key":"B49","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1093\/sleep\/26.7.819","article-title":"Pramipexole in the management of restless legs syndrome: an extended study","volume":"26","author":"Silber","year":"2003","journal-title":"Sleep"},{"key":"B50","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/nrneurol.2015.122","article-title":"Restless legs syndrome-current therapies and management of augmentation","volume":"11","author":"Trenkwalder","year":"2015","journal-title":"Nat Rev Neurol"}],"container-title":["Frontiers in Pain Research"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpain.2024.1422298\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T13:05:06Z","timestamp":1728997506000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpain.2024.1422298\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,24]]},"references-count":50,"alternative-id":["10.3389\/fpain.2024.1422298"],"URL":"https:\/\/doi.org\/10.3389\/fpain.2024.1422298","relation":{},"ISSN":["2673-561X"],"issn-type":[{"type":"electronic","value":"2673-561X"}],"subject":[],"published":{"date-parts":[[2024,9,24]]},"article-number":"1422298"}}