Diclofenac up2date – Teil 1: Die Pharmakologie und der Vergleich mit anderen Medikamenten

Zusammenfassung

Das Nicht-Opioid-Analgetikum Diclofenac wird weltweit zur Therapie muskuloskelettaler und perioperativer Schmerzen eingesetzt. Nicht zuletzt wegen der freien Verfügbarkeit niedrigdosierter Präparate als “over-the-counter“-Medikament müssen renale, gastrointestinale und kardiale unerwünschte Wirkungen berücksichtigt werden. Die Vielzahl der verfügbaren Applikationsformen (u.a. Tabletten, Zäpfchen, Tropfen, Gele, Pflaster) mit ihren jeweils spezifischen zugelassenen Indikationen, Dosierungsempfehlungen und Anwendungsbeschränkungen kann verwirrend sein und sowohl einen inadäquaten Einsatz als auch die Vorenthaltung eines potenten Analgetikums bedingen. Die vorliegende Übersichtsarbeit soll Anästhesisten, Schmerztherapeuten und Intensivmedizinern die wichtigsten Aspekte dieser weit verbreiteten Substanz für den Einsatz bei bestimmten Krankheitsbildern und Patientengruppen präsentieren.

Abstract

The non-opioid analgesic diclofenac is used worldwide for musculoskeletal and perioperative pain therapy. Despite its frequent use and easy access as an “over the counter” drug, gastrointestinal, cardiovascular, and renal adverse drug effects have to be considered. Availability of diverse formulations (e.g. tablets, suppository, gel-formulations) with different indications, dosage recommendations and contraindications may easily lead to confusion, thus accounting for inadequate use on the one hand or withholding of an effective analgesic. This review may provide physicians in perioperative medicine, intensive care and pain therapy with important and suitable information about the pharmacology and appropriate use of this drug.

Kernaussagen

• Diclofenac wird weltweit vertrieben und ist v. a. in der ambulanten Schmerztherapie sehr verbreitet.

• Die Substanz entfaltet ihre analgetischen, antiphlogistischen und antipyretischen Effekte über verschiedene Wirkmechanismen.

• Die Hauptwirkung liegt in der Blockade der Cyclooxygenasen 1 und 2.

• Diclofenac ist seit 2013 bei Patienten mit kardialen und zerebrovaskulären Erkrankungen kontraindiziert und sollte bei hohem kardiovaskulärem Risikoprofil zurückhaltend verwendet werden.

Schlüsselwörter:

Diclofenac - Nicht-Opioid-Analgetikum - Schmerztherapie

Keywords:

Diclofenac - drug - pain therapy - non-opioid analgesic

• Literatur

• 1 Office, U.S.P.a.T., Certificate Extending patent term under 35 USC 156 – Patent No. 3, 652, 762; 1973.
• 2 Novartis, Novartis History. http://www.novartis.de 2013
• 3 Wie Voltaren zu seinem Namen kam. http://www.gutkommuniziert.ch 2012
• 4 Fachinformationen, R.L., Fachinformationen Diclofenac. 2013
• 5 Novartis. Novartis Financial results. http://www.novartis.de 2013
• 6 McGettigan P, Henry D. Use of non-steroidal anti-inflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-, and high-income countries. PLoS Med 2013; 10
• 7 Poehner R. Eine Geschichte, die ans Herz ging. Weltwoche 2006; 38-38
• 8 PubChem, PubChem Database: Diclofenac. 2013
• 9 Chuasuwan B et al. Biowaiver monographs for immediate release solid oral dosage forms: diclofenac sodium and diclofenac potassium. J Pharm Sci 2009; 98: 1206-1219
• 10 Lissy M et al. Pharmacokinetic comparison of an oral diclofenac potassium liquid-filled soft gelatin capsule with a diclofenac potassium tablet. Expert OpinPharmacother 2010; 11: 701-708
• 11 Idkaidek NM et al. Determination of the population pharmacokinetic parameters of sustained-release and enteric-coated oral formulations, and the suppository formulation of diclofenac sodium by simultaneous data fitting using NONMEM. Biopharm Drug Dispos 1998; 19: 169-174
• 12 Su SF et al. In vitro and in vivo comparison of two diclofenac sodium sustained release oral formulations. Int J Pharm 2003; 260: 39-46
• 13 Hasan M et al. A two-way cross-over bioequivalence study comparing two products of diclofenac sodium suppositories in healthy human volunteers. Basic ClinPharmacol Toxicol 2004; 95: 263-265
• 14 Gleiter CH et al. Colonoscopy in the investigation of drug absorption in healthy volunteers. GastrointestEndosc 1985; 31: 71-73
• 15 Ärzteschaft, A.d.d. Packungsgröße nicht-steroidaler Antiphlogistika zur parenteralen Anwendung. Deutsches Ärzteblatt 1999; 96
• 16 Ärzteschaft, A.d.d., Anaphylaktische Schockreaktionen nach parenteraler Gabe von Diclofenac. DeutschesÄrzteblatt 1995; 92
• 17 Colak S et al. Anaphylaxis after intramuscular injection of diclofenac sodium. Am J Emerg Med 2014; 32: 1-2
• 18 Rainsford KD, Kean WF, Ehrlich GE. Review of the pharmaceutical properties and clinical effects of the topical NSAID formulation, diclofenac epolamine. Curr Med Res Opin 2008; 24: 2967-2992
• 19 Banning M. Topical diclofenac: clinical effectiveness and current uses in osteoarthritis of the knee and soft tissue injuries. Expert OpinPharmacother 2008; 9: 2921-2929
• 20 Sanna V, Peana AT, Moretti MD. Effect of vehicle on diclofenac sodium permeation from new topical formulations: in vitro and in vivo studies. Curr Drug Deliv 2009; 6: 93-100
• 21 Brunner M et al. A new topical formulation enhances relative diclofenac bioavailability in healthy male subjects. Br J ClinPharmacol 2011; 71: 852-859
• 22 Kienzler JL, Gold M, Nollevaux F. Systemic bioavailability of topical diclofenac sodium gel 1% versus oral diclofenac sodium in healthy volunteers. J ClinPharmacol 2010; 50: 50-61
• 23 Brunner M et al. Favourable dermal penetration of diclofenac after administration to the skin using a novel spray gel formulation. Br J ClinPharmacol 2005; 60: 573-577
• 24 Heyneman CA, Lawless-Liday C, Wall GC. Oral versus topical NSAIDs in rheumatic diseases: a comparison. Drugs 2000; 60: 555-574
• 25 Massey T et al. Topical NSAIDs for acute pain in adults. Cochrane Database Syst Rev CD 007402 2010;
• 26 Lin J et al. Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-analysis of randomised controlled trials. BMJ 2004; 329: 324-324
• 27 Derry S, Moore RA, Rabbie R. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev CD 007400 2012; 9
• 28 Simone JN, Whitacre MM. Effects of anti-inflammatory drugs following cataract extraction. CurrOpinOphthalmol 2001; 12: 63-67
• 29 Schalnus R. Topical nonsteroidal anti-inflammatory therapy in ophthalmology. Ophthalmologica 2003; 217: 89-98
• 30 Huang CW et al. Underlying mechanism of regulatory actions of diclofenac, a nonsteroidal anti-inflammatory agent, on neuronal potassium channels and firing: an experimental and theorethical study. J PhysiolPharmacol 2013; 64: 269-280
• 31 Gwanyanya A, Macianskiene R, Mubagwa K. Insights into the effects of diclofenac and other non-steroidal anti-inflammatory agents on ion channels. J Pharm Pharmacol 2012; 64: 1359-1375
• 32 Voilley N. Acid-sensing ion channels (ASICs): new targets for the analgesic effects of non-steroid anti-inflammatory drugs (NSAIDs). Curr Drug Targets Inflamm Allergy 2004; 3: 71-79
• 33 Gan TJ. Diclofenac: an update on its mechanism of action and safety profile. Curr Med Res Opin 2010; 26: 1715-1731
• 34 Kojo H et al. Evaluation of human peroxisome proliferator-activated receptor (PPAR) subtype selectivity of a variety of anti-inflammatory drugs based on a novel assay for PPAR delta(beta). J PharmacolSci 2003; 93: 347-355
• 35 Dastidar SG et al. The anti-bacterial action of diclofenac shown by inhibition of DNA synthesis. Int J Antimicrob Agents 2000; 14: 249-251
• 36 Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 2004; 56: 387-437
• 37 Masferrer JL, Seibert K. Regulation of prostaglandin synthesis by glucocorticoids. Receptor 1994; 4: 25-30
• 38 Zha XM. Acid-sensing ion channels: trafficking and synaptic function. Mol Brain 2013; 6: 1-1
• 39 Tenenbaum A, Motro M, Fisman EZ. Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons. CardiovascDiabetol 2005; 4: 14-14
• 40 Vaish V, Tanwar L, Sanyal SN. The role of NF-kappaB and PPARgamma in experimentally induced colorectal cancer and chemoprevention by cyclooxygenase-2 inhibitors. TumourBiol 2010; 31: 427-436
• 41 Vellani V et al. Effects of NSAIDs and paracetamol (acetaminophen) on protein kinase C epsilon translocation and on substance P synthesis and release in cultured sensory neurons. J Pain Res 2013; 6: 111-120
• 42 Fachinformationen, R.L., Ketamin. 2014
• 43 Dong XD, Svensson P, Cairns BE. The analgesic action of topical diclofenac may be mediated through peripheral NMDA receptor antagonism. Pain 2009; 147: 36-45
• 44 Ortiz MI, Granados-Soto V, Castaneda-Hernandez G. The NO-cGMP-K+ channel pathway participates in the antinociceptive effect of diclofenac, but not of indomethacin. PharmacolBiochemBehav 2003; 76: 187-195
• 45 Deutschland B. Belastung von Abwasser und Klärschlämmen mit Arzneimittelwirkstoffen. Antworten der Bundesregierung. Drucksache 16/5383. 2007
• 46 Tixier C et al. Occurrence and fate of carbamazepine, clofibric acid, diclofenac, ibuprofen, ketoprofen, and naproxen in surface waters. Environ SciTechnol 2003; 37: 1061-1068
• 47 Langenhoff A et al. Microbial removal of the pharmaceutical compounds Ibuprofen and diclofenac from wastewater. Biomed Res Int 2013; 2013: 325806-325806
• 48 Memmert U et al. Diclofenac: New data on chronic toxicity and bioconcentration in fish. Environ ToxicolChem 2013; 32: 442-452
• 49 Scheytt T et al. Transport of pharmaceutically active compounds in saturated laboratory columns. Ground Water 2004; 42: 767-773
• 50 Heberer T, Feldmann D. Contribution of effluents from hospitals and private households to the total loads of diclofenac and carbamazepine in municipal sewage effluents--modeling versus measurements. J Hazard Mater 2005; 122: 211-218
• 51 Prakash V et al. The population decline of Gyps vultures in India and Nepal has slowed since veterinary use of diclofenac was banned. PLoSOne 2012; 7
• 52 Regenthal LU. Vergiftungen und Arzneimittelüberdosierungen. 2007; 10: 130-737
• 53 Smolinske SC et al. Toxic effects of nonsteroidal anti-inflammatory drugs in overdose. An overview of recent evidence on clinical effects and dose-response relationships. Drug Saf 1990; 5: 252-274
• 54 Kulling PE et al. Renal impairment after acute diclofenac, naproxen, and sulindac overdoses. J ToxicolClinToxicol 1995; 33: 173-177
• 55 Pschenitza M et al. Application of a heterogeneous immunoassay for the quality control testing of release-active forms of diclofenac. IntImmunopharmacol 2014; 21: 225-230
• 56 Mukherjee B et al. HPLC detection of plasma concentrations of diclofenac in human volunteers administered with povidone-ethylcellulose-based experimental transdermal matrix-type patches. Methods Find ExpClinPharmacol 2006; 28: 301-306
• 57 Maurer HH, Tauvel FX, Kraemer T. Screening procedure for detection of non-steroidal anti-inflammatory drugs and their metabolites in urine as part of a systematic toxicological analysis procedure for acidic drugs and poisons by gas chromatography-mass spectrometry after extractive methylation. J Anal Toxicol 2001; 25: 237-244
• 58 Thomas D et al. Days lost due to disability of diclofenac-induced adverse drug reactions. Pharm Pract (Granada) 2012; 10: 40-44
• 59 Kim KK. Nicolau syndrome in patient following diclofenac administration: a case report. Ann Dermatol 2011; 23: 501-503
• 60 Shetty SR et al. Stevens-Johnson syndrome: a case report. J Oral Sci 2010; 52: 343-346
• 61 Jurgensen JS, Seltsam A, Jorres A. Fatal acute diclofenac-induced immune hemolytic anemia. Ann Hematol 2001; 80: 440-442
• 62 Schabitz WR et al. Hypoxic brain damage after intramuscular self-injection of diclofenac for acute back pain. Eur J Anaesthesiol 2001; 18: 763-765
• 63 Shrivastava MP et al. Adverse drug reactions related to the use of non-steroidal anti-inflammatory drugs: results of spontaneous reporting from central India. J Indian Med Assoc 2013; 111: 106-106
• 64 Castellsague J et al. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project). Drug Saf 2012; 35: 1127-1146
• 65 Collaboration NT et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013; 382: 769-779
• 66 AWMF. S3-Leitlinie Behandlung akuter perioperativer und posttraumatischer Schmerzen, AWMF-Register Nr. 041/001. 2009
• 67 Bertsche T, Mikus G. [Adverse drug reactions and drug interactions in analgesic therapy]. TherUmsch 2011; 68: 19-26
• 68 Cascorbi I. Drug interactions – principles, examples and clinical consequences. DtschArzteblInt 2012; 109
• 69 Ramiro S et al. Combination therapy for pain management in inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis). Cochrane Database Syst Rev CD 008886 2011;
• 70 Penning-van Beest F et al. Main comedications associated with major bleeding during anticoagulant therapy with coumarins. Eur J ClinPharmacol 2005; 61: 439-444
• 71 Visser LE et al. Allelic variants of cytochrome P450 2C9 modify the interaction between nonsteroidal anti-inflammatory drugs and coumarin anticoagulants. ClinPharmacolTher 2005; 77: 479-485
• 72 Adarsh E et al. Effect of pre-operative rectal diclofenac suppository on post-operative analgesic requirement in cleft palate repair: A randomised clinical trial. Indian J Anaesth 2012; 56: 265-269
• 73 Thaweekul Y et al. Effect of intramuscular diclofenac after explore laparotomy for gynecologic surgery: a randomized double-blinded placebo controlled trial. J Med Assoc Thai 2011; 94 (Suppl. 07)
• 74 Anwari JS, Anjum S, Al-Khunain S. Placebo controlled comparison of the opioid sparing effect of meloxicam and diclofenac after abdominal hysterectomy. Saudi Med J 2008; 29: 379-383
• 75 Ng A et al. Does the opioid-sparing effect of rectal diclofenac following total abdominal hysterectomy benefit the patient?. Br J Anaesth 2002; 88: 714-716
• 76 Juhlin T et al. Acute administration of diclofenac, but possibly not long term low dose aspirin, causes detrimental renal effects in heart failure patients treated with ACE-inhibitors. Eur J Heart Fail 2004; 6: 909-916
• 77 Izhar M et al. Effects of COX inhibition on blood pressure and kidney function in ACE inhibitor-treated blacks and hispanics. Hypertension 2004; 43: 573-577
• 78 Lapi F et al. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study. BMJ 2013; 346
• 79 Knauf H et al. The influence of cardiovascular and antiinflammatory drugs on thiazide-induced hemodynamic and saluretic effects. Eur J ClinPharmacol 2006; 62: 885-892
• 80 Fournier JP et al. Non-steroidal anti-inflammatory drugs (NSAIDs) and hypertension treatment intensification: a population-based cohort study. Eur J ClinPharmacol 2012; 68: 1533-1540
• 81 Goswami SK et al. Potential pharmacodynamic drug-drug interaction between concomitantly administered lisinopril and diclofenac sodium: a call for appropriate management in hypertensive osteoarthritic patients. Drug Metabol Drug Interact 2011; 26: 127-137
• 82 Lafrance JP, Miller DR. Dispensed selective and nonselective nonsteroidal anti-inflammatory drugs and the risk of moderate to severe hyperkalemia: a nested case-control study. Am J Kidney Dis 2012; 60: 82-89
• 83 Grandjean EM, Aubry JM. Lithium: updated human knowledge using an evidence-based approach: part III: clinical safety. CNS Drugs 2009; 23: 397-418
• 84 Colebatch AN et al. Safety of nonsteroidalantiinflammatory drugs and/or paracetamol in people receiving methotrexate for inflammatory arthritis: a Cochrane systematic review. J RheumatolSuppl 2012; 90: 62-73
• 85 Iqbal Z et al. Pharmacokinetic interaction of ciprofloxacin with diclofenac: a single-dose, two-period crossover study in healthy adult volunteers. Clin Drug Investig 2009; 29: 275-281
• 86 Kovarik JM et al. Cyclosporine and nonsteroidalantiinflammatory drugs: exploring potential drug interactions and their implications for the treatment of rheumatoid arthritis. J ClinPharmacol 1997; 37: 336-343
• 87 Mueller EA et al. Pharmacokinetics of cyclosporine and multiple-dose diclofenac during coadministration. J ClinPharmacol 1993; 33: 936-943
• 88 Schwabe, Arzneimittelverordnungsreport 2013. Monographie 2013;
• 89 Joshi A, Parara E, Macfarlane TV. A double-blind randomised controlled clinical trial of the effect of preoperative ibuprofen, diclofenac, paracetamol with codeine and placebo tablets for relief of postoperative pain after removal of impacted third molars. Br J Oral MaxillofacSurg 2004; 42: 299-306
• 90 Collins SL et al. Single dose oral ibuprofen and diclofenac for postoperative pain. Cochrane Database Syst Rev CD 001548 2000;
• 91 Argoff CE. Topical analgesics in the management of acute and chronic pain. Mayo ClinProc 2013; 88: 195-205
• 92 Schjerning Olsen AM et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation 2011; 123: 2226-2235
• 93 Olsen AM et al. Cause-specific cardiovascular risk associated with nonsteroidal anti-inflammatory drugs among myocardial infarction patients--a nationwide study. PLoS One 2013; 8
• 94 Trelle S et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011; 342
• 95 Nezvalova-Henriksen K, Spigset O, Nordeng H. Effects of ibuprofen, diclofenac, naproxen, and piroxicam on the course of pregnancy and pregnancy outcome: a prospective cohort study. BJOG 2013; 120: 948-959
• 96 Olsen AM, Gislason GH, Fosbol EL. Time-perspective in cardiovascular risk of NSAID use after first-time myocardial infarction. CurrOpinCardiol 2013; 28: 683-688
• 97 Colombo G et al. Diclofenac dispersible provides superior analgesia with faster onset of action compared to naproxen granular in patients with acute, painful, minor sports injuries. J Sports Med Phys Fitness 1997; 37: 228-233
• 98 Akbulut N et al. Comparison of the effect of Naproxen, Etodolac and Diclofenac on postoperative sequelsfollowing third molar surgery: a randomised, double-blind, crossover study. Med Oral Patol Oral Cir Bucal 2014; 19: 149-156
• 99 Moore RA et al. Single dose oral analgesics for acute postoperative pain in adults. Cochrane Database Syst Rev CD 008659 2011;
• 100 EMEA, Questions and answers on the review of piroxicam Online webpage. 2007
• 101 Altungul AC, Sapmaz E, Kale A. Comparison of diclofenac sodium with indomethacin suppositories for mediolateral episiotomies. ClinExpObstetGynecol 2012; 39: 112-114
• 102 Yildizhan R et al. Comparison of the efficacy of diclofenac and indomethacin suppositories in treating perineal pain after episiotomy or laceration: a prospective, randomized, double-blind clinical trial. Arch GynecolObstet 2009; 280: 735-738
• 103 Rezaei Z et al. A comparative study on relieving post-episiotomy pain with diclofenac and indomethacin suppositories or placebo. J ObstetGynaecol 2014; 34: 293-296
• 104 Akhavanakbari G et al. The effects of indomethacin, diclofenac, and acetaminophen suppository on pain and opioids consumption after cesarean section. PerspectClin Res 2013; 4: 136-141
• 105 Crowley B et al. Controlled-release indomethacin and sustained-release diclofenac sodium in the treatment of rheumatoid arthritis: a comparative controlled clinical trial. Curr Med Res Opin 1990; 12: 143-150
• 106 agency, E.m., New safety advice for diclofenac - CMDh endorses PRAC recommendation. Online webpage. 2013
• 107 Krum H et al. Blood pressure and cardiovascular outcomes in patients taking nonsteroidalantiinflammatory drugs. CardiovascTher 2012; 30: 342-50
• 108 Fischbach W et al. [Pain treatment with traditional NSAR and coxibs: an interdisciplinary assessment]. Dtsch Med Wochenschr 2013; 138: 91-96
• 109 Harirforoosh S, Asghar W, Jamali F. Adverse effects of nonsteroidalantiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm PharmSci 2013; 16: 821-847
• 110 Cannon CP et al. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet 2006; 368: 1771-1781
• 111 Jarupongprapa S, Ussavasodhi P, Katchamart W. Comparison of gastrointestinal adverse effects between cyclooxygenase-2 inhibitors and non-selective, non-steroidal anti-inflammatory drugs plus proton pump inhibitors: a systematic review and meta-analysis. J Gastroenterol 2013; 48: 830-838
• 112 Patricio JP et al. Relative cardiovascular and gastrointestinal safety of non-selective non-steroidal anti-inflammatory drugs versus cyclo-oxygenase-2 inhibitors: implications for clinical practice. Clin Drug Investig 2013; 33: 167-183
• 113 Chan FK et al. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet 2010; 376: 173-179
• 114 Sostres C, Gargallo CJ, Lanas A. Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage. Arthritis Res Ther 2013; 16 (Suppl. 03)
• 115 Laine L et al. Lower gastrointestinal events in a double-blind trial of the cyclo-oxygenase-2 selective inhibitor etoricoxib and the traditional nonsteroidal anti-inflammatory drug diclofenac. Gastroenterology 2008; 135: 1517-1525
• 116 Kyriakidis AV et al. Parecoxib sodium in the treatment of postoperative pain after Lichtenstein tension-free mesh inguinal hernia repair. Hernia 2011; 15: 59-64
• 117 Chou R et al. Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review. Rockville (MD): 2011
• 118 Peterson K et al. Drug Class Review: NonsteroidalAntiinflammatory Drugs (NSAIDs): Final Update 4 Report. Portland (OR): 2010
• 119 Wetzel L et al. Intravenous nonopioid analgesic drugs in chronic low back pain patients on chronic opioid treatment: a crossover, randomised, double-blinded, placebo-controlled study. Eur J Anaesthesiol 2014; 31: 35-40
• 120 Pierre SC et al. Inhibition of cyclooxygenases by dipyrone. Br J Pharmacol 2007; 151: 494-503
• 121 Schug SA, Manopas A. Update on the role of non-opioids for postoperative pain treatment. Best Pract Res ClinAnaesthesiol 2007; 21: 15-30
• 122 Edwards J et al. Single dose dipyrone for acute postoperative pain. Cochrane Database Syst Rev CD 003227 2010;
• 123 Saray A et al. Diclofenac and metamizol in postoperative analgesia in plastic surgery. ActaChirPlast 2001; 43: 71-76
• 124 Babej-Dolle R et al. Parenteral dipyrone versus diclofenac and placebo in patients with acute lumbago or sciatic pain: randomized observer-blind multicenter study. Int J ClinPharmacolTher 1994; 32: 204-209
• 125 Oborilova A et al. Symptomatic intravenous antipyretic therapy: efficacy of metamizol, diclofenac, and propacetamol. J Pain Symptom Manage 2002; 24: 608-615
• 126 Fendrich Z. [Metamizol--a new effective analgesic with a long history. Overview of its pharmacology and clinical use]. CasLekCesk 2000; 139: 440-444
• 127 Fachinformationen, R.L., Novlagin Injektionslösung.
• 128 Ibanez L et al. Agranulocytosis associated with dipyrone (metamizol). Eur J ClinPharmacol 2005; 60: 821-829
• 129 Kramer MS, Lane DA, Hutchinson TA. The International Agranulocytosis and Aplastic Anemia Study (IAAAS). J ClinEpidemiol 1988; 41: 613-616
• 130 Medizinprodukte, B.f.A.u.,Metamizol (Novalgin, Berlosin, Novaminsulfon, etc.): BfArM weist auf richtige Indikationsstellung und Beachtung von Vorsichtsmaßnahmen und Warnhinweisen hin. 2009
• 131 Graham GG et al. The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology 2013; 21: 201-232
• 132 Squibb BM. Wichtige Informationen über das Risiko einer versehentlichen Überdosierung von PERFALGAN® 10mg/ml Infusionslösung (Paracetamol i. v.). 2012;
• 133 Darvish H et al. Analgesic Efficacy of Diclofenac and Paracetamol vs. Meperidine in Cesarean Section. Anesth Pain Med 2014; 4
• 134 Szelenyi I. Flupirtine, a re-discovered drug, revisited. Inflamm Res 2013; 62: 251-258
• 135 Raffa RB, Pergolizzi Jr. KV. The evolving understanding of the analgesic mechanism of action of flupirtine. J ClinPharmTher 2012; 37: 4-6
• 136 Deutschland, H.u.V.f.A.i. Einschränkung der therapeutischen Zielgruppe und Begrenzung der Behandlungsdauer für Flupirtin-haltige Arzneimittel nach Bewertung des Lebertoxizitätsrisikos. 2013
• 137 Yadav G et al. Evaluating the role of flupirtine for postcraniotomy pain and compare it with diclofenac sodium: a prospective, randomized, double blind, placebo-controlled study. J NeurosurgAnesthesiol 2014; 26: 32-361