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Analgesic Effect of a Single Preoperative Dose of the Antibiotic Ceftriaxone in Humans

      Abstract

      Repeated injections of the antibiotic ceftriaxone cause analgesia in rodents by upregulating the glutamate transporter, GLT-1. No evidence is available in humans. We studied the effect of a single intravenous administration of ceftriaxone in patients undergoing decompressive surgery of the median or ulnar nerves. Forty-five patients were randomized to receive saline, ceftriaxone (2 g), or cefazolin (2 g), 1 hour before surgery. Cefazolin, which is structurally related to ceftriaxone, was used as a negative control. Pain thresholds were measured 10 minutes before drug injections and then 4 to 6 hours after surgery. Ceftriaxone caused analgesia in all patients, whereas cefazolin was inactive. We also performed animal studies to examine whether a single dose of ceftriaxone was sufficient to induce analgesia. A single intraperitoneal injection of ceftriaxone (200 mg/kg), but not cefazoline (200 mg/kg), caused analgesia in mouse models of inflammatory or postsurgical pain, and upregulated GLT-1 in the spinal cord. Ceftriaxone-induced analgesia was additive to that produced by blockade of mGlu5 receptors, which are activated by extrasynaptic glutamate. These data indicate that a single dose of ceftriaxone causes analgesia in humans and mice and suggest that ceftriaxone should be used for preoperative antimicrobial prophylaxis when a fast relief of pain is desired.

      Perspective

      The study reports for the first time that a single preoperative dose of ceftriaxone causes analgesia in humans. A single dose of ceftriaxone could also relieve inflammatory and postsurgical pain and upregulate GLT-1 expression in mice. Ceftriaxone should be preferred to other antibiotics for antimicrobial prophylaxis to reduce postoperative pain.

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      References

        • Aroori S.
        • Spence R.A.
        Carpal tunnel syndrome.
        Ulster Med J. 2008; 77: 6-17
        • Bar-Peled O.
        • Ben-Hur H.
        • Biegon A.
        • Groner Y.
        • Dewhurst S.
        • Furuta A.
        • Rothstein J.D.
        Distribution of glutamate transporter subtypes during human brain development.
        J Neurochem. 1997; 69: 2571-2580
        • Beam Jr., T.R.
        Ceftriaxone: a beta-lactamase-stable, broad-spectrum cephalosporin with an extended half-life.
        Pharmacotherapy. 1985; 5: 237-253
        • Cabañero D.
        • Campillo A.
        • Célérier E.
        • Romero A.
        • Puig M.M.
        Pronociceptive effects of remifentanil in a mouse model of postsurgical pain: effect of a second surgery.
        Anesthesiology. 2009; 111: 1334-1345
        • Campillo A.
        • González-Cuello A.
        • Cabañero D.
        • Garcia-Nogales P.
        • Romero A.
        • Milanés M.V.
        • Laorden M.L.
        • Puig M.M.
        Increased spinal dynorphin levels and phospho-extracellular signal-regulated kinases 1 and 2 and c-Fos immunoreactivity after surgery under remifentanil anesthesia in mice.
        Mol Pharmacol. 2010; 77: 185-194
        • Cavallaro V.
        • Catania V.
        • Bonaccorso R.
        • Mazzone S.
        • Speciale A.
        • Di Marco R.
        • Blandino G.
        • Caccamo F.
        Effect of a broad-spectrum cephalosporin on the oral and intestinal microflora in patients undergoing colorectal surgery.
        J Chemother. 1992; 4: 82-87
        • Célérier E.
        • González J.R.
        • Maldonado R.
        • Cabañero D.
        • Puig M.M.
        Opioid-induced hyperalgesia in a murine model of postoperative pain: role of nitric oxide generated from the inducible nitric oxide synthase.
        Anesthesiology. 2006; 104: 546-555
        • Chiechio S.
        • Copani A.
        • Zammataro M.
        • Battaglia G.
        • Gereau 4th, R.W.
        • Nicoletti F.
        Transcriptional regulation of type-2 metabotropic glutamate receptors: an epigenetic path to novel treatments for chronic pain.
        Trends Pharmacol Sci. 2010; 31: 153-160
        • Coderre T.J.
        • Fundytus M.E.
        • McKenna J.E.
        • Dalal S.
        • Melzack R.
        The formalin test: a validation of the weighted-scores method of behavioural pain rating.
        Pain. 1993; 54: 43-50
        • Cranford C.S.
        • Ho J.Y.
        • Kalainov D.M.
        • Hartigan B.J.
        Carpal tunnel syndrome.
        J Am Acad Orthop Surg. 2007; 15: 537-548
        • Esposito S.
        Is single-dose antibiotic prophylaxis sufficient for any surgical procedure?.
        J Chemother. 1999; 11: 556-564
        • Geroulanos S.
        • Marathias K.
        • Kriaras J.
        • Kadas B.
        Cephalosporins in surgical prophylaxis.
        J Chemother. 2001; 13 Spec No 1: 23-26
        • Gillespie W.J.
        • Walenkamp G.H.
        Antibiotic prophylaxis for surgery for proximal femoral and other closed long bone fractures.
        Cochrane Database Syst Rev. 2010; : CD000244
        • Guggenbichler J.P.
        • Kofler J.
        • Allerberger F.
        The influence of third-generation cephalosporins on the aerobic intestinal flora.
        Infection. 1985; 13: S137-S139
        • Gunduz O.
        • Oltulu C.
        • Ulugol A.
        Role of GLT-1 transporter activation in prevention of cannabinoid tolerance by the beta-lactam antibiotic, ceftriaxone, in mice.
        Pharmacol Biochem Behav. 2011; 99: 100-103
        • Hell K.
        Use of a long-acting cephalosporin (ceftriaxone) for antimicrobial prophylaxis in abdominal and biliary surgery.
        Eur Surg Res. 1989; 21: 6-13
        • Höjgård S.
        Antibiotic resistance - why is the problem so difficult to solve?.
        Infect Ecol Epidemiol. 2012; ([Epub ahead of print])https://doi.org/10.3402/iee.v2i0.18165
        • Hu H.J.
        • Alter B.J.
        • Carrasquillo Y.
        • Qiu C.S.
        • Gereau 4th, R.W.
        Metabotropic glutamate receptor 5 modulates nociceptive plasticity via extracellular signal-regulated kinase-Kv4.2 signaling in spinal cord dorsal horn neurons.
        J Neurosci. 2007; 27: 13181-13191
        • Hu Y.
        • Li W.
        • Lu L.
        • Cai J.
        • Xian X.
        • Zhang M.
        • Li Q.
        • Li L.
        An anti-nociceptive role for ceftriaxone in chronic neuropathic pain in rats.
        Pain. 2010; 148: 284-301
        • Kohr G.
        NMDA Receptor function: subunit composition versus spatial distribution.
        Cell Tissue Res. 2006; 326: 439-446
        • Latremoliere A.
        • Woolf C.J.
        Central sensitization: a generator of pain hypersensitivity by central neural plasticity.
        J Pain. 2009; 10: 895-926
        • Lee S.G.
        • Su Z.Z.
        • Emdad L.
        • Gupta P.
        • Sarkar D.
        • Borjabad A.
        • Volsky D.J.
        • Fisher P.B.
        Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes.
        J Biol Chem. 2008; 283: 13116-13123
        • Lin Y.
        • Roman K.
        • Foust K.D.
        • Kaspar B.K.
        • Bailey M.T.
        • Stephens R.L.
        Glutamate transporter GLT-1 upregulation attenuates visceral nociception and hyperalgesia via spinal mechanisms not related to anti-inflammatory or probiotic effects.
        Pain Res Treat. 2011; 507029
        • Maragakis N.J.
        • Dietrich J.
        • Wong V.
        • Xue H.
        • Mayer-Proschel M.
        • Rao M.S.
        • Rothstein J.D.
        Glutamate transporter expression and function in human glial progenitors.
        Glia. 2004; 45: 133-143
        • Nicoletti F.
        • Bockaert J.
        • Collingridge G.L.
        • Conn P.J.
        • Ferraguti F.
        • Schoepp D.D.
        • Wroblewski J.T.
        • Pin J.P.
        Metabotropic glutamate receptors: from the workbench to the bedside.
        Neuropharmacology. 2011; 60: 1017-1041
        • Periti P.
        Ceftriaxone for surgical prophylaxis: clinical experience and pharmacoeconomics.
        J Chemother. 2000; 12: 2-4
        • Queen S.A.
        • Kesslak J.P.
        • Bridges R.J.
        Regional distribution of sodium-dependent excitatory amino acid transporters in rat spinal cord.
        J Spinal Cord Med. 2007; 30: 263-271
        • Rawls S.M.
        • Zielinski M.
        • Patel H.
        • Sacavage S.
        • Baron D.A.
        • Patel D.
        Beta-lactam antibiotic reduces morphine analgesic tolerance in rats through GLT-1 transporter activation.
        Drug Alcohol Depend. 2010; 107: 261-263
        • Rothstein J.D.
        • Patel S.
        • Regan M.R.
        • Haenggeli C.
        • Huang Y.H.
        • Bergles D.E.
        • Jin L.
        • Dykes Hoberg M.
        • Vidensky S.
        • Chung D.S.
        • Toan S.V.
        • Bruijn L.I.
        • Su Z.Z.
        • Gupta P.
        • Fisher P.B.
        Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression.
        Nature. 2005; 433: 73-77
        • Schmitt A.
        • Asan E.
        • Lesch K.P.
        • Kugler P.
        A splice variant of glutamate transporter GLT1/EAAT2 expressed in neurons: cloning and localization in rat nervous system.
        Neuroscience. 2002; 109: 45-61
        • Schroeder J.A.
        • Quick K.F.
        • Landry P.M.
        • Rawls S.M.
        Glutamate transporter activation enhances nicotine antinociception and attenuates nicotine analgesic tolerance.
        Neuroreport. 2011; 22: 970-973
        • Sullivan R.
        • Rauen T.
        • Fischer F.
        • Wiessner M.
        • Grewer C.
        • Bicho A.
        • Pow D.V.
        Cloning, transport properties, and differential localization of two splice variants of GLT-1 in the rat CNS: implications for CNS glutamate homeostasis.
        Glia. 2004; 45: 155-169
        • Teixeira Rodruguez A.
        • Roque F.
        • Falcão A.
        • Figueiras A.
        • Herdeiro M.T.
        Understanding physician antibiotic prescribing behaviour: a systematic review of qualitative studies.
        Int J Antimicrob Agents. 2013; 41: 203-212
        • Tjølsen A.
        • Berge O.G.
        • Hunskaar S.
        • Rosland J.H.
        • Hole K.
        The formalin test: an evaluation of the method.
        Pain. 1992; 51: 5-17
        • van Zundert B.
        • Yoshii A.
        • Constantine-Paton M.
        Receptor compartmentalization and trafficking at glutamate synapses: a developmental proposal.
        Trends Neurosci. 2004; 27: 428-437
        • Welling G.W.
        • Meijer-Severs G.J.
        • Helmus G.
        • van Santen E.
        • Tonk R.H.
        • de Vries-Hospers H.G.
        • van der Waaij D.
        The effect of ceftriaxone on the anaerobic bacterial flora and the bacterial enzymatic activity in the intestinal tract.
        Infection. 1991; 19: 313-316
        • Yang M.
        • Roman K.
        • Chen D.F.
        • Wang Z.G.
        • Lin Y.
        • Stephens Jr., R.L.
        GLT-1 overexpression attenuates bladder nociception and local/cross-organ sensitization of bladder nociception.
        Am J Physiol Renal Physiol. 2011; 300: F1353-1359
        • Zimmermann M.
        Ethical guidelines for investigations of experimental pain in conscious animals.
        Pain. 1983; 16: 109-110