Does co-treatment with ultra-low-dose naloxone and morphine provide better analgesia in renal colic patients?

Published:August 14, 2018DOI:



      This study attempted to evaluate the efficacy of ultra-low-dose intravenous (IV) naloxone combined with IV morphine, as compared to IV morphine alone, in terms of reducing pain and morphine-induced side effects in patients with renal colic.


      In this double-blind clinical trial, 150 patients aged 34 to 60 years old who presented to the emergency department (ED) with renal colic were randomly allocated to either an intervention group that received ultra-low-dose IV naloxone combined with IV morphine or to a control group that received morphine plus a placebo. The severity of pain, sedation, and nausea were assessed and recorded for all patients at entrance to the ED (T1), then at 20 (T2), 40 (T3), 60 (T4), 120 (T5), and 180 (T6) minutes after starting treatment. The Numeric Rating Scale (NRS) was used for the assessment of pain and nausea intensities, and the Ramsay Sedation Scale (RSS) was used to assess sedation.


      A GEE model revealed that patients in the naloxone group had non-significantly reduced pain scores compared to those in the morphine group (coefficient = −0.68; 95% CI: −1.24 to −0.11, Wald X2 (1) = 5.41, p = 0.02). The sedation outcome demonstrated no statistically significant differences at T1 to T4 among patients with renal colic compared to the ones who only received morphine. At T5 and T6, 1.5% vs. 20% and 1.5% vs. 16.9% of subjects from the naloxone group versus the morphine group obtained RSS scores equal to 3, respectively (p = 0.001 and p = 0.004, respectively).


      Compared to patients who only received IV morphine, co-treatment of ultra-low-dose naloxone with morphine could not provide better analgesia and sedation/agitation states in renal colic patients.


      IV (intravenous), NSAIDs (non-steroidal anti-inflammatory drugs), ED (emergency department), NRS (Numeric Rating Scale), KUB (kidney, ureter, bladder), CT (computed tomography), RR (respiratory rate), SBP (systolic blood pressure), DBP (diastolic blood pressure), RSS (Ramsay Sedation Scale), SD (standard deviation), GEE (generalized estimating equation), ITT (intention-to-treat)


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        • Hosseininejad S.M.
        • Zeydi A.E.
        Can intracutaneous sterile water injection be used as a possible treatment for acute renal colic pain in the emergency department? A short literature review.
        Urol Ann. 2015; 7: 130-132
        • Roughley M.J.
        • Belcher J.
        • Mallen C.D.
        • Roddy E.
        Gout and risk of chronic kidney disease and nephrolithiasis: meta-analysis of observational studies.
        Arthritis Res Ther. 2015; 17: 90
        • Sin B.
        • Cao J.
        • Yang D.
        • Ambert K.
        • Punnapuzha S.
        Intravenous lidocaine for intractable renal colic unresponsive to standard therapy.
        Am J Ther. 2018; ([Epub ahead of print], PMID: 29443696. 23 Jan 2018.
        • Kan W.-C.
        • Chou Y.-H.
        • Chiu S.-J.
        • Hsu Y.-W.
        • Lu H.-F.
        • Hsu W.
        • et al.
        Study of the association between ITPKC genetic polymorphisms and calcium nephrolithiasis.
        Biomed Res Int. 2014; 2014: 397826
        • Ziapor B.
        • Motamed H.
        • Verki M.M.
        • Norani H.
        Comparison of effect of morphine-chlorpheniramine combined versus morphine alone in alleviating acute renal colic pain: a randomized clinical trial.
        Jundishapur J Nat Pharm Prod. 2017; 12e15585
        • García-Perdomo H.
        • Echeverría-García F.
        • López H.
        • Fernández N.
        • Manzano-Nunez R.
        Pharmacologic interventions to treat renal colic pain in acute stone episodes: systematic review and meta-analysis.
        Prog Urol. 2017; 27: 654-665
        • Cervenakov I.
        • Fillo J.
        • Mardiak J.
        • Kopečnú M.
        • Šmirala J.
        • Labaš P.
        Speedy elimination of ureterolithiasis in the lower part of ureters with the alpha 1-blocker–Tamsulosin.
        Int Urol Nephrol. 2002; 34: 25-29
        • Firouzian A.
        • Alipour A.
        • Dezfouli H.R.
        • Kiasari A.Z.
        • Baradari A.G.
        • Zeydi A.E.
        • et al.
        Does lidocaine as an adjuvant to morphine improve pain relief in patients presenting to the ED with acute renal colic? A double-blind, randomized controlled trial.
        Am J Emerg Med. 2016; 34: 443-448
        • Morteza-Bagi H.R.
        • Amjadi M.
        • Mirzaii-Sousefidi R.
        The comparison of apotel plus low dose of morphine and full dose of morphine in pain relief in patients with acute renal colic.
        Addict Health. 2015; 7: 66
        • Karamese M.
        • Akdağ O.
        • Kara I.
        • Yıldıran G.U.
        • Tosun Z.
        The comparison of intrathecal morphine and IV morphine PCA on pain control, patient satisfaction, morphine consumption, and adverse effects in patients undergoing reduction mammoplasty.
        Eplasty. 2015; 15e15
        • Rebel A.
        • Sloan P.
        • Andrykowski M.
        Postoperative analgesia after radical prostatectomy with high-dose intrathecal morphine and intravenous naloxone: a retrospective review.
        J Opioid Manag. 2009; 5: 331-339
        • Kosiński S.
        • Siudut B.
        Pain treatment in the emergency department: what do patients think?.
        Anestezjol Intens Ter. 2011; 43: 234-238
        • Tsai R.-Y.
        • Jang F.-L.
        • Tai Y.-H.
        • Lin S.-L.
        • Shen C.-H.
        • Wong C.-S.
        Ultra-low-dose naloxone restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in PTX-treated rats.
        Neuropsychopharmacology. 2008; 33: 2772
        • Movafegh A.
        • Shoeibi G.
        • Ansari M.
        • Sadeghi M.
        • Azimaraghi O.
        • Aghajani Y.
        Naloxone infusion and post-hysterectomy morphine consumption: a double-blind, placebo-controlled study.
        Acta Anaesthesiol Scand. 2012; 56: 1241-1249
        • Hayl J.
        • Vincentel S.
        • Somogyil A.
        • Chapleol C.
        • Whitel J.
        Potentiation of buprenorphine antinociception with ultra-low dose naltrexone in healthy subjects.
        Eur J Pain. 2011; 15: 293-298
        • Maxwell L.G.
        • Kaufmann S.C.
        • Bitzer S.
        • Jackson Jr., E.V.
        • McGready J.
        • Kost-Byerly S.
        • et al.
        The effects of a small-dose naloxone infusion on opioid-induced side effects and analgesia in children and adolescents treated with intravenous patient-controlled analgesia: a double-blind, prospective, randomized, controlled study.
        Anesth Analg. 2005; 100: 953-958
        • Firouzian A.
        • Baradari A.G.
        • Alipour A.
        • Zeydi A.E.
        • Kiasari A.Z.
        • Emadi S.A.
        • et al.
        Ultra–low-dose naloxone as an adjuvant to patient controlled analgesia (PCA) with morphine for postoperative pain relief following lumber discectomy: a double-blind, randomized, placebo-controlled trial.
        J Neurosurg Anesthesiol. 2018; 30: 26-31
        • Yang C.-P.
        • Cherng C.-H.
        • Wu C.-T.
        • Huang H.-Y.
        • Tao P.-L.
        • Wong C.-S.
        Intrathecal ultra-low dose naloxone enhances the antinociceptive effect of morphine by enhancing the reuptake of excitatory amino acids from the synaptic cleft in the spinal cord of partial sciatic nerve–transected rats.
        Anesth Analg. 2011; 113: 1490-1500
        • Sartain J.B.
        • Barry J.J.
        • Richardson C.A.
        • Branagan H.C.
        Effect of combining naloxone and morphine for intravenous patient-controlled analgesia.
        Anesthesiology. 2003; 99: 148-151
        • Bijur P.E.
        • Schechter C.
        • Esses D.
        • Chang A.K.
        • Gallagher E.J.
        Intravenous bolus of ultra-low-dose naloxone added to morphine does not enhance analgesia in emergency department patients.
        J Pain. 2006; 7: 75-81
        • Ling W.
        • Hillhouse M.
        • Jenkins J.
        • Miotto K.
        • Torrington M.
        • Chapleo C.
        Comparisons of analgesic potency and side effects of buprenorphine and buprenorphine with ultra-low-dose naloxone.
        J Addict Med. 2012; 6: 118-123
        • Cepeda M.S.
        • Alvarez H.
        • Morales O.
        • Carr D.B.
        Addition of ultralow dose naloxone to postoperative morphine PCA: unchanged analgesia and opioid requirement but decreased incidence of opioid side effects.
        Pain. 2004; 107: 41-46
        • Sadeghi M.
        • Movafegh A.
        • Nouralishahi B.
        The effect of an intravenous bolus of ultra-low-dose naloxone on intraoperative sedation, post operative pain intensity and morphine consumption in cesarean section patients under spinal anesthesia.
        Res J Biol Sci. 2008; 10: 1223-1226
        • Movafegh A.
        • Nouralishahi B.
        • Sadeghi M.
        • Nabavian O.
        An ultra-low dose of naloxone added to lidocaine or lidocaine-fentanyl mixture prolongs axillary brachial plexus blockade.
        Anesth Analg. 2009; 109: 1679-1683
        • Xiao Y.
        • Wu L.
        • Zhou Q.
        • Xiong W.
        • Duan X.
        • Huang X.
        A randomized clinical trial of the effects of ultra-low-dose naloxone infusion on postoperative opioid requirements and recovery.
        Acta Anaesthesiol Scand. 2015; 59: 1194-1203
        • Birnbaum A.
        • Esses D.
        • Bijur P.E.
        • Holden L.
        • Gallagher E.J.
        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; 49 ([e2]): 445-453
        • Holdgate A.
        • Pollock T.
        Systematic review of the relative efficacy of non-steroidal anti-inflammatory drugs and opioids in the treatment of acute renal colic.
        BMJ. 2004; 328: 1401
        • Shokeir A.A.
        Renal colic: new concepts related to pathophysiology, diagnosis and treatment.
        Curr Opin Urol. 2002; 12: 263-269
        • Lee J.S.
        • Hobden E.
        • Stiell I.G.
        • Wells G.A.
        Clinically important change in the visual analog scale after adequate pain control.
        Acad Emerg Med. 2003; 10: 1128-1130
        • Shih M.T.
        • Juho Y.C.
        • Meng E.
        • Sun G.H.
        • Cha T.L.
        • Wu S.T.
        • et al.
        Pain severity in renal colic: a retrospective evaluation of initial visits in patients at a medical center.
        Int Surg J. 2016; 3: 480-483
        • Ramsay M.
        • Savege T.
        • Simpson B.
        • Goodwin R.
        Controlled sedation with alphaxalone-alphadolone.
        Br Med J. 1974; 2: 656
        • Yeaman F.
        • Meek R.
        • Egerton-Warburton D.
        • Rosengarten P.
        • Graudins A.
        Sub-dissociative-dose intranasal ketamine for moderate to severe pain in adult emergency department patients.
        Emerg Med Australas. 2014; 26: 237-242
        • Mégarbane B.
        • Declèves X.
        • Bloch V.
        • Bardin C.
        • Chast F.
        • Baud F.J.
        Case report: quantification of methadone-induced respiratory depression using toxicokinetic/toxicodynamic relationships.
        Crit Care. 2007; 11: R5
        • Burns L.H.
        Ultra-low-dose opioid antagonists enhance opioid analgesia while reducing tolerance, dependence and addictive properties.
        in: Recent developments in pain research Kerala. Research Signpost, India2005: 115-136
        • Wang H.-Y.
        • Frankfurt M.
        • Burns L.H.
        High-affinity naloxone binding to filamin A prevents mu opioid receptor–Gs coupling underlying opioid tolerance and dependence.
        PLoS One. 2008; 3e1554
        • Sloan P.
        • Hamann S.
        Ultra-low-dose opioid antagonists to enhance opioid analgesia.
        J Opioid Manag. 2006; 2: 295-304
        • Cepeda M.S.
        • Africano J.M.
        • Manrique A.M.
        • Fragoso W.
        • Carr D.B.
        The combination of low dose of naloxone and morphine in PCA does not decrease opioid requirements in the postoperative period.
        Pain. 2002; 96: 73-79
        • Powell K.J.
        • Abul-Husn N.S.
        • Jhamandas A.
        • Olmstead M.C.
        • Beninger R.J.
        • Jhamandas K.
        Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats.
        J Pharmacol Exp Ther. 2002; 300: 588-596
        • Connelly N.
        • Rahimi A.
        • Parker R.
        Nalmefene or naloxone for preventing intrathecal opioid mediated side effects in cesarean delivery patients.
        Int J Obstet Anesth. 1997; 6: 231-234
        • Dailey P.A.
        • Brookshire G.L.
        • Shnider S.M.
        • Abboud T.K.
        • Kotelko D.M.
        • Noueihid R.
        • et al.
        The effects of naloxone associated with the intrathecal use of morphine in labor.
        Anesth Analg. 1985; 64: 658-666