{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T20:30:51Z","timestamp":1791664251109,"version":"4.3.4"},"reference-count":159,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,12,16]],"date-time":"2023-12-16T00:00:00Z","timestamp":1702684800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Chronic neuropathic pain (NP) is an increasingly prevalent disease and leading cause of disability which is challenging to treat. Several distinct classes of drugs are currently used for the treatment of chronic NP, but each drug targets only narrow components of the underlying pathophysiological mechanisms, bears limited efficacy, and comes with dose-limiting side effects. Multimodal therapies have been increasingly proposed as potential therapeutic approaches to target the multiple mechanisms underlying nociceptive transmission and modulation. However, while preclinical studies with combination therapies showed promise to improve efficacy over monotherapy, clinical trial data on their efficacy in specific populations are lacking and increased risk for adverse effects should be carefully considered. Drug-drug co-crystallization has emerged as an innovative pharmacological approach which can combine two or more different active pharmaceutical ingredients in a single crystal, optimizing pharmacokinetic and physicochemical characteristics of the native molecules, thus potentially capitalizing on the synergistic efficacy between classes of drugs while simplifying adherence and minimizing the risk of side effects by reducing the doses. In this work, we review the current pharmacological options for the treatment of chronic NP, focusing on combination therapies and their ongoing developing programs and highlighting the potential of co-crystals as novel approaches to chronic NP management.<\/jats:p>","DOI":"10.3390\/biom13121802","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T03:59:24Z","timestamp":1702871964000},"page":"1802","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Combination Drug Therapy for the Management of Chronic Neuropathic Pain"],"prefix":"10.3390","volume":"13","author":[{"given":"Serena","family":"Boccella","sequence":"first","affiliation":[{"name":"Research & Early Development (R&D), Domp\u00e9 Farmaceutici S.p.A, Via De Amicis, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidia","family":"De Filippis","sequence":"additional","affiliation":[{"name":"Research & Early Development (R&D), Domp\u00e9 Farmaceutici S.p.A, Via S. Lucia, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8868-8326","authenticated-orcid":false,"given":"Cristina","family":"Giorgio","sequence":"additional","affiliation":[{"name":"Research & Early Development (R&D), Domp\u00e9 Farmaceutici S.p.A, Via De Amicis, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5959-4443","authenticated-orcid":false,"given":"Laura","family":"Brandolini","sequence":"additional","affiliation":[{"name":"Research & Early Development (R&D), Domp\u00e9 Farmaceutici S.p.A, Via Campo di Pile, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan","family":"Jones","sequence":"additional","affiliation":[{"name":"Research & Early Development (R&D), Domp\u00e9 US, 181 2nd Avenue, STE 600, San Mateo, CA 94401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7990-7507","authenticated-orcid":false,"given":"Rubina","family":"Novelli","sequence":"additional","affiliation":[{"name":"Research & Early Development (R&D), Domp\u00e9 Farmaceutici S.p.A, Via S. Lucia, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9068-5952","authenticated-orcid":false,"given":"Ezio","family":"Amorizzo","sequence":"additional","affiliation":[{"name":"Pain Unit, San Paolo Hospital, 00053 Civitavecchia, Italy"},{"name":"Pain Clinic Roma, 00191 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo Luigi Giuseppe","family":"Leoni","sequence":"additional","affiliation":[{"name":"Azienda USL di Piacenza, 29121 Piacenza, Italy"},{"name":"Department of Medical and Surgical Sciences and Translational Medicine, Sapienza University, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"Terranova","sequence":"additional","affiliation":[{"name":"Pain Unit, ASST Gaetano Pini, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabatino","family":"Maione","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livio","family":"Luongo","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Leone","sequence":"additional","affiliation":[{"name":"Research & Early Development (R&D), Domp\u00e9 Farmaceutici S.p.A, Via S. Lucia, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0617-0233","authenticated-orcid":false,"given":"Marcello","family":"Allegretti","sequence":"additional","affiliation":[{"name":"Research & Early Development (R&D), Domp\u00e9 Farmaceutici S.p.A, Via Campo di Pile, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico Maria","family":"Minnella","sequence":"additional","affiliation":[{"name":"Research & Early Development (R&D), Domp\u00e9 Farmaceutici S.p.A, Via S. 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Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1016\/S0140-6736(12)61729-2","article-title":"Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990\u20132010: A systematic analysis for the Global Burden of Disease Study 2010","volume":"380","author":"Vos","year":"2012","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1097\/j.pain.0000000000001365","article-title":"The IASP classification of chronic pain for ICD-11: Chronic neuropathic pain","volume":"160","author":"Scholz","year":"2019","journal-title":"Pain"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.pain.2013.11.013","article-title":"Neuropathic pain in the general population: A systematic review of epidemiological studies","volume":"155","author":"Austin","year":"2014","journal-title":"Pain"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.jpain.2003.12.004","article-title":"Clinical characteristics and economic costs of patients with painful neuropathic disorders","volume":"5","author":"Berger","year":"2004","journal-title":"J. Pain"},{"key":"ref_6","first-page":"CD007076","article-title":"Pregabalin for neuropathic pain in adults","volume":"1","author":"Derry","year":"2019","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1474-4422(14)70251-0","article-title":"Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis","volume":"14","author":"Finnerup","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1517\/14728214.2014.915025","article-title":"Emerging drugs for neuropathic pain","volume":"19","author":"Gilron","year":"2014","journal-title":"Expert. Opin. Emerg. Drugs"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Sultan, A., Gaskell, H., Derry, S., and Moore, R.A. (2008). Duloxetine for painful diabetic neuropathy and fibromyalgia pain: Systematic review of randomised trials. BMC Neurol., 8.","DOI":"10.1186\/1471-2377-8-29"},{"key":"ref_10","unstructured":"IASP (2023, November 01). International Association for the Study of Pain (IASP) Taxonomy. Available online: https:\/\/www.iasp-pain.org\/resources\/terminology\/?navItemNumber=576."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1097\/j.pain.0000000000001384","article-title":"Chronic pain as a symptom or a disease: The IASP Classification of Chronic Pain for the International Classification of Diseases (ICD-11)","volume":"160","author":"Treede","year":"2019","journal-title":"Pain"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2098","DOI":"10.1016\/S0140-6736(21)00392-5","article-title":"Nociplastic pain: Towards an understanding of prevalent pain conditions","volume":"397","author":"Fitzcharles","year":"2021","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1212\/01.wnl.0000282763.29778.59","article-title":"Neuropathic pain: Redefinition and a grading system for clinical and research purposes","volume":"70","author":"Treede","year":"2008","journal-title":"Neurology"},{"key":"ref_14","first-page":"83","article-title":"Polyneuropathies","volume":"115","author":"Sommer","year":"2018","journal-title":"Dtsch. Arztebl. Int."},{"key":"ref_15","first-page":"191","article-title":"Guillain-Barre syndrome","volume":"87","author":"Walling","year":"2013","journal-title":"Am. Fam. Physician"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Patil, A., Goldust, M., and Wollina, U. (2022). Herpes zoster: A Review of Clinical Manifestations and Management. Viruses, 14.","DOI":"10.3390\/v14020192"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.4103\/0028-3886.359257","article-title":"Neuropathic Pain in Parkinson\u2019s Disease","volume":"70","author":"Bandala","year":"2022","journal-title":"Neurol. India"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/S1474-4422(16)30358-1","article-title":"Pain in amyotrophic lateral sclerosis","volume":"16","author":"Chio","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8685954","DOI":"10.1155\/2019\/8685954","article-title":"Therapeutic Approaches for Peripheral and Central Neuropathic Pain","volume":"2019","author":"Szok","year":"2019","journal-title":"Behav. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.neuroscience.2016.06.057","article-title":"Antidepressants and gabapentinoids in neuropathic pain: Mechanistic insights","volume":"338","author":"Kremer","year":"2016","journal-title":"Neuroscience"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.pain.2007.08.033","article-title":"Pharmacologic management of neuropathic pain: Evidence-based recommendations","volume":"132","author":"Dworkin","year":"2007","journal-title":"Pain"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/j.1742-7843.2005.pto_96696601.x","article-title":"Antidepressants in the treatment of neuropathic pain","volume":"96","author":"Sindrup","year":"2005","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e00205","DOI":"10.1002\/prp2.205","article-title":"Mechanisms of the gabapentinoids and alpha 2 delta-1 calcium channel subunit in neuropathic pain","volume":"4","author":"Patel","year":"2016","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1097\/j.pain.0000000000001040","article-title":"Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain","volume":"158","author":"Bannister","year":"2017","journal-title":"Pain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S0304-3959(01)00316-5","article-title":"Gabapentin inhibits the substance P-facilitated K+)-evoked release of [3H]glutamate from rat caudial trigeminal nucleus slices","volume":"93","author":"Maneuf","year":"2001","journal-title":"Pain"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1097\/01.BRS.0000048464.57011.00","article-title":"Gabapentin effect on neuropathic pain compared among patients with spinal cord injury and different durations of symptoms","volume":"28","author":"Ahn","year":"2003","journal-title":"Spine"},{"key":"ref_27","first-page":"41","article-title":"Human experimental pain models in drug development: Translational pain research","volume":"8","author":"Curatolo","year":"2007","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_28","first-page":"CD007938","article-title":"Gabapentin for chronic neuropathic pain and fibromyalgia in adults","volume":"4","author":"Moore","year":"2011","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Deng, Y., Luo, L., Hu, Y., Fang, K., and Liu, J. (2016). Clinical practice guidelines for the management of neuropathic pain: A systematic review. BMC Anesthesiol., 16.","DOI":"10.1186\/s12871-015-0150-5"},{"key":"ref_30","first-page":"395","article-title":"Tramadol, Pharmacology, Side Effects, and Serotonin Syndrome: A Review","volume":"18","author":"Beakley","year":"2015","journal-title":"Pain Physician"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1007\/s00210-015-1167-5","article-title":"What is the main mechanism of tramadol?","volume":"388","author":"Minami","year":"2015","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1097\/AJP.0000000000000011","article-title":"Trends and regional variation in opioid overdose mortality among Veterans Health Administration patients, fiscal year 2001 to 2009","volume":"30","author":"Bohnert","year":"2014","journal-title":"Clin. J. Pain"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/dar.12089","article-title":"Correlations between prescription opioid analgesic dispensing levels and related mortality and morbidity in Ontario, Canada, 2005\u20132011","volume":"33","author":"Fischer","year":"2014","journal-title":"Drug Alcohol Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/nrn1431","article-title":"State-dependent opioid control of pain","volume":"5","author":"Fields","year":"2004","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_35","first-page":"S3","article-title":"Approach to assessment and diagnosis of chronic pain","volume":"53","author":"Brunton","year":"2004","journal-title":"J. Fam. Pract."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ejphar.2014.12.022","article-title":"Effects of metabolites of the analgesic agent dipyrone (metamizol) on rostral ventromedial medulla cell activity in mice","volume":"748","author":"Maione","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/0006-8993(92)91082-P","article-title":"Localization of the central antinociceptive effects of diclofenac in the rat","volume":"590","author":"Bjorkman","year":"1992","journal-title":"Brain Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1159\/000139473","article-title":"Serotonin and opiate involvement in the antinociceptive effect of acetylsalicylic acid","volume":"54","author":"Pini","year":"1997","journal-title":"Pharmacology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.pain.2004.06.006","article-title":"Induction of opioid tolerance by lysine-acetylsalicylate in rats","volume":"111","author":"Tortorici","year":"2004","journal-title":"Pain"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.3390\/ph3051335","article-title":"NSAIDs, Opioids, Cannabinoids and the Control of Pain by the Central Nervous System","volume":"3","author":"Vanegas","year":"2010","journal-title":"Pharmaceuticals"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1186\/ar1794","article-title":"Cardiovascular and gastrointestinal effects of COX-2 inhibitors and NSAIDs: Achieving a balance","volume":"7","author":"Borer","year":"2005","journal-title":"Arthritis Res. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1097\/00000539-200106000-00044","article-title":"Propacetamol versus ketorolac for treatment of acute postoperative pain after total hip or knee replacement","volume":"92","author":"Zhou","year":"2001","journal-title":"Anesth. Analg."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1097\/01.ju.0000109961.69936.8e","article-title":"Ketorolac: Safe and effective analgesia for the management of renal cortical tumors with partial nephrectomy","volume":"171","author":"Diblasio","year":"2004","journal-title":"J. Urol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1213\/00000539-199403000-00017","article-title":"The effects of perioperative ketorolac infusion on postoperative pain and endocrine-metabolic response","volume":"78","author":"Varrassi","year":"1994","journal-title":"Anesth. Analg."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1510\/icvts.2010.239053","article-title":"Does the use of non-steroidal anti-inflammatory drugs after cardiac surgery increase the risk of renal failure?","volume":"11","author":"Acharya","year":"2010","journal-title":"Interact. Cardiovasc. Thorac. Surg."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1097\/00000542-200512000-00025","article-title":"Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials","volume":"103","author":"Elia","year":"2005","journal-title":"Anesthesiology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1001\/jama.296.13.jrv60011","article-title":"Cardiovascular risk and inhibition of cyclooxygenase: A systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2","volume":"296","author":"McGettigan","year":"2006","journal-title":"JAMA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1097\/00000542-200603000-00020","article-title":"Safety and efficacy of the cyclooxygenase-2 inhibitors parecoxib and valdecoxib after noncardiac surgery","volume":"104","author":"Nussmeier","year":"2006","journal-title":"Anesthesiology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/S0140-6736(05)17864-7","article-title":"Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: Nested case-control study","volume":"365","author":"Graham","year":"2005","journal-title":"Lancet"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1001\/jama.296.13.jrv60015","article-title":"Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: Meta-analysis of randomized trials","volume":"296","author":"Zhang","year":"2006","journal-title":"JAMA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/S0016-5085(89)80061-7","article-title":"Toward an epidemiology of gastropathy associated with nonsteroidal antiinflammatory drug use","volume":"96","author":"Fries","year":"1989","journal-title":"Gastroenterology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/S1474-4422(12)70189-8","article-title":"Subgrouping of patients with neuropathic pain according to pain-related sensory abnormalities: A first step to a stratified treatment approach","volume":"11","author":"Baron","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_53","first-page":"CD008943","article-title":"Combination pharmacotherapy for the treatment of neuropathic pain in adults","volume":"2012","author":"Chaparro","year":"2012","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.1007\/s12325-019-01053-x","article-title":"Towards an Effective and Safe Treatment of Inflammatory Pain: A Delphi-Guided Expert Consensus","volume":"36","author":"Varrassi","year":"2019","journal-title":"Adv. Ther."},{"key":"ref_55","first-page":"284","article-title":"Multimodal analgesia and pharmacological synergy in pain management","volume":"46","year":"2020","journal-title":"Semergen"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0304-3959(97)00041-9","article-title":"Drug interactions in human neuropathic pain pharmacotherapy","volume":"73","author":"Virani","year":"1997","journal-title":"Pain"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Torres, N.B., and Altafini, C. (2016). Drug combinatorics and side effect estimation on the signed human drug-target network. BMC Syst. Biol., 10.","DOI":"10.1186\/s12918-016-0326-8"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1007\/s11916-014-0463-y","article-title":"Drug combinations in the treatment of neuropathic pain","volume":"18","author":"Eisenberg","year":"2014","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1016\/S1474-4422(13)70193-5","article-title":"Combination pharmacotherapy for management of chronic pain: From bench to bedside","volume":"12","author":"Gilron","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.jpain.2010.07.006","article-title":"Combination drug therapy for chronic pain: A call for more clinical studies","volume":"12","author":"Mao","year":"2011","journal-title":"J. Pain"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"514","DOI":"10.7326\/M16-2367","article-title":"Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain: A Clinical Practice Guideline From the American College of Physicians","volume":"166","author":"Qaseem","year":"2017","journal-title":"Ann. Intern. Med."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Berger, A., Sadosky, A., Dukes, E., Edelsberg, J., and Oster, G. (2012). Clinical characteristics and patterns of healthcare utilization in patients with painful neuropathic disorders in UK general practice: A retrospective cohort study. BMC Neurol., 12.","DOI":"10.1186\/1471-2377-12-8"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1097\/AJP.0000000000000879","article-title":"Prevalence, Characteristics, and Clinical Course of Neuropathic Pain in Primary Care Patients Consulting with Low Back-related Leg Pain","volume":"36","author":"Harrisson","year":"2020","journal-title":"Clin. J. Pain"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/j.ejpain.2006.10.004","article-title":"Clinical characteristics and pain management among patients with painful peripheral neuropathic disorders in general practice settings","volume":"11","author":"Gore","year":"2007","journal-title":"Eur. J. Pain"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"44","DOI":"10.2174\/1570159X1201140117162802","article-title":"Pregabalin in neuropathic pain: Evidences and possible mechanisms","volume":"12","author":"Verma","year":"2014","journal-title":"Curr. Neuropharmacol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1009950","DOI":"10.3389\/fphar.2022.1009950","article-title":"Risk of major adverse events associated with gabapentinoid and opioid combination therapy: A systematic review and meta-analysis","volume":"13","author":"Hahn","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1159\/000186502","article-title":"Controlled-release oxycodone and pregabalin in the treatment of neuropathic pain: Results of a multicenter Italian study","volume":"61","author":"Gatti","year":"2009","journal-title":"Eur. Neurol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"294","DOI":"10.14444\/7039","article-title":"The Impact of Intraoperative Local Ketorolac on Opioid Use in the Management of Postoperative Pain in Thoracolumbar Spinal Fusions: A Retrospective Cohort Study","volume":"14","author":"Lytle","year":"2020","journal-title":"Int. J. Spine Surg."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e447","DOI":"10.1097\/BPO.0000000000001345","article-title":"Perioperative Ketorolac for Supracondylar Humerus Fracture in Children Decreases Postoperative Pain, Opioid Usage, Hospitalization Cost, and Length-of-Stay","volume":"39","author":"Adams","year":"2019","journal-title":"J. Pediatr. Orthop."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1213\/ANE.0b013e31823cd524","article-title":"Ketorolac: Its role as part of a multimodal analgesic regimen","volume":"114","author":"White","year":"2012","journal-title":"Anesth. Analg."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1213\/ANE.0b013e3182334d68","article-title":"Perioperative single dose ketorolac to prevent postoperative pain: A meta-analysis of randomized trials","volume":"114","author":"Agarwal","year":"2012","journal-title":"Anesth. Analg."},{"key":"ref_72","first-page":"17","article-title":"A \u201cnovel\u201d association to treat pain: Tramadol\/dexketoprofen. The first drug of a \u201cnew pharmacological class\u201d","volume":"88","author":"Fornasari","year":"2017","journal-title":"Acta Biomed."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/S0002-9343(03)00116-5","article-title":"Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: A double-blind, randomized, placebo-controlled study","volume":"114","author":"Bennett","year":"2003","journal-title":"Am. J. Med."},{"key":"ref_74","first-page":"97","article-title":"Fluoxetin combined with cyclobenzaprine in the treatment of fibromyalgia","volume":"85","author":"Cantini","year":"1994","journal-title":"Minerva Med."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Calandre, E.P., Morillas-Arques, P., Molina-Barea, R., Rodriguez-Lopez, C.M., and Rico-Villademoros, F. (2011). Trazodone plus pregabalin combination in the treatment of fibromyalgia: A two-phase, 24-week, open-label uncontrolled study. BMC Musculoskelet. Disord., 12.","DOI":"10.1186\/1471-2474-12-95"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1002\/art.1780391111","article-title":"A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia","volume":"39","author":"Goldenberg","year":"1996","journal-title":"Arthritis Rheum."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1097\/00131402-200112000-00002","article-title":"Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy","volume":"3","author":"Simpson","year":"2001","journal-title":"J. Clin. Neuromuscul. Dis."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/j.ejpain.2007.12.010","article-title":"Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients","volume":"12","author":"Hanna","year":"2008","journal-title":"Eur. J. Pain."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s10195-009-0077-z","article-title":"Pregabalin, celecoxib, and their combination for treatment of chronic low-back pain","volume":"10","author":"Romano","year":"2009","journal-title":"J. Orthop. Traumatol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1001\/jama.280.21.1837","article-title":"Gabapentin for the treatment of postherpetic neuralgia: A randomized controlled trial","volume":"280","author":"Rowbotham","year":"1998","journal-title":"JAMA"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1007\/s00540-010-0913-6","article-title":"Low-dose gabapentin as useful adjuvant to opioids for neuropathic cancer pain when combined with low-dose imipramine","volume":"24","author":"Arai","year":"2010","journal-title":"J. Anesth."},{"key":"ref_82","first-page":"227","article-title":"Combination Therapy of Pregabalin with Tramadol for Treatment of Peripheral Neuropathy in Patients with Gynecological Cancer Receiving Taxane Containing Chemotherapy","volume":"44","author":"Nishikawa","year":"2017","journal-title":"Gan Kagaku Ryoho"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Afonso, A.S., Carnaval, T., and C\u00e9s, S.V. (2021). Combination Therapy for Neuropathic Pain: A Review of Recent Evidence. J. Clin. Med., 10.","DOI":"10.3390\/jcm10163533"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.jpain.2009.09.003","article-title":"A randomized, controlled trial of oxycodone versus placebo in patients with postherpetic neuralgia and painful diabetic neuropathy treated with pregabalin","volume":"11","author":"Zin","year":"2010","journal-title":"J. Pain"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/978-1-60327-323-7_4","article-title":"Animal models of acute and chronic inflammatory and nociceptive pain","volume":"617","author":"Honore","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"5.4","DOI":"10.1002\/0471141755.ph0504s56","article-title":"Models of inflammation: Carrageenan- or complete Freund\u2019s Adjuvant (CFA)-induced edema and hypersensitivity in the rat","volume":"56","author":"Fehrenbacher","year":"2012","journal-title":"Curr. Protoc. Pharmacol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/0304-3959(95)01441-1","article-title":"Characterization of a rat model of incisional pain","volume":"64","author":"Brennan","year":"1996","journal-title":"Pain"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1093\/ilar.40.3.111","article-title":"Inflammatory Models of Pain and Hyperalgesia","volume":"40","author":"Ren","year":"1999","journal-title":"ILAR J."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"867786","DOI":"10.3389\/fpain.2022.867786","article-title":"Editorial: Preclinical Animal Models and Measures of Pain: Improving Predictive Validity for Analgesic Drug Development","volume":"3","author":"Negus","year":"2022","journal-title":"Front. Pain Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1111\/jphp.12584","article-title":"Antihyperalgesic effects of dexketoprofen and tramadol in a model of postoperative pain in mice\u2014Effects on glial cell activation","volume":"68","author":"Puig","year":"2016","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1093\/bja\/aev457","article-title":"Randomized clinical trial of dexketoprofen\/tramadol 25 mg\/75 mg in moderate-to-severe pain after total hip arthroplasty","volume":"116","author":"McQuay","year":"2016","journal-title":"Br. J. Anaesth."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Moore, R.A., McQuay, H.J., Tomaszewski, J., Raba, G., Tutunaru, D., Lietuviete, N., Galad, J., Hagymasy, L., Melka, D., and Kotarski, J. (2016). Dexketoprofen\/tramadol 25 mg\/75 mg: Randomised double-blind trial in moderate-to-severe acute pain after abdominal hysterectomy. BMC Anesthesiol., 16.","DOI":"10.1186\/s12871-016-0174-5"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1186\/s10194-015-0541-5","article-title":"Dexketoprofen\/tramadol: Randomised double-blind trial and confirmation of empirical theory of combination analgesics in acute pain","volume":"16","author":"Moore","year":"2015","journal-title":"J. Headache Pain"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/j.1472-8206.2008.00636.x","article-title":"Effects of tramadol and dexketoprofen on analgesia and gastrointestinal transit in mice","volume":"23","author":"Miranda","year":"2009","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1111\/j.1472-8206.2010.00922.x","article-title":"Antinociceptive and anti-exudative synergism between dexketoprofen and tramadol in a model of inflammatory pain in mice","volume":"26","author":"Miranda","year":"2012","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1097\/JCMA.0000000000000115","article-title":"Synergistic symptom-specific effects of ketorolac-tramadol and ketorolac-pregabalin in a rat model of peripheral neuropathy","volume":"82","author":"Lin","year":"2019","journal-title":"J. Chin. Med. Assoc."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1097\/00000542-200211000-00033","article-title":"Gabapentin and pregabalin can interact synergistically with naproxen to produce antihyperalgesia","volume":"97","author":"Hurley","year":"2002","journal-title":"Anesthesiology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1097\/00000542-199910000-00021","article-title":"Evaluation of interaction between gabapentin and ibuprofen on the formalin test in rats","volume":"91","author":"Yoon","year":"1999","journal-title":"Anesthesiology"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.pbb.2010.11.007","article-title":"Pharmacological interaction between oxcarbazepine and two COX inhibitors in a rat model of inflammatory hyperalgesia","volume":"97","author":"Tomic","year":"2011","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1213\/ANE.0b013e31824e5da3","article-title":"Gabapentin augments the antihyperalgesic effects of diclofenac sodium through spinal action in a rat postoperative pain model","volume":"115","author":"Narai","year":"2012","journal-title":"Anesth. Analg."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1016\/j.lfs.2006.07.025","article-title":"Examination of the interaction between peripheral diclofenac and gabapentin on the 5% formalin test in rats","volume":"79","author":"Picazo","year":"2006","journal-title":"Life Sci."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1002\/ddr.21300","article-title":"Antinociceptive Interactions between Meloxicam and Gabapentin in Neuropathic Pain Depend on the Ratio used in Combination in Rats","volume":"77","year":"2016","journal-title":"Drug Dev. Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"3469","DOI":"10.2147\/JPR.S383981","article-title":"Efficacy of Combination Therapy with Pregabalin in Neuropathic Pain: A Preclinical Study in the Rat L5 Spinal Nerve Ligation Model","volume":"15","author":"Nozawa","year":"2022","journal-title":"J. Pain Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.jpainsymman.2006.11.013","article-title":"Gabapentin and an opioid combination versus opioid alone for the management of neuropathic cancer pain: A randomized open trial","volume":"34","author":"Keskinbora","year":"2007","journal-title":"J. Pain. Symptom Manag."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.pbb.2009.01.013","article-title":"Anti-nociceptive synergism of morphine and gabapentin in neuropathic pain induced by chronic constriction injury","volume":"92","year":"2009","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.3892\/etm.2017.4102","article-title":"Morphine and pregabalin in the treatment of neuropathic pain","volume":"13","author":"Wang","year":"2017","journal-title":"Exp. Ther. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1016\/S0140-6736(09)61081-3","article-title":"Nortriptyline and gabapentin, alone and in combination for neuropathic pain: A double-blind, randomised controlled crossover trial","volume":"374","author":"Gilron","year":"2009","journal-title":"Lancet"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/S0140-6736(22)01472-6","article-title":"Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): A multicentre, double-blind, randomised crossover trial","volume":"400","author":"Tesfaye","year":"2022","journal-title":"Lancet"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2616","DOI":"10.1016\/j.pain.2013.05.043","article-title":"Duloxetine and pregabalin: High-dose monotherapy or their combination? The \u201cCOMBO-DN study\u201d\u2014A multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain","volume":"154","author":"Tesfaye","year":"2013","journal-title":"Pain"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"437","DOI":"10.4103\/aian.AIAN_144_18","article-title":"Pregabalin and Amitriptyline as Monotherapy or as Low-Dose Combination in Patients of Neuropathic Pain: A Randomized, Controlled Trial to Evaluate Efficacy and Safety in an Eastern India Teaching Hospital","volume":"22","author":"Chakrabarty","year":"2019","journal-title":"Ann. Indian. Acad. Neurol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1213\/ANE.0000000000001561","article-title":"Metformin Synergizes with Conventional and Adjuvant Analgesic Drugs to Reduce Inflammatory Hyperalgesia in Rats","volume":"124","author":"Pecikoza","year":"2017","journal-title":"Anesth. Analg."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1139\/cjpp-2016-0306","article-title":"Synergistic interaction between diclofenac and pyrilamine on nociception, inflammation, and gastric damage in rats","volume":"95","author":"Ortiz","year":"2017","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1002\/ddr.21401","article-title":"Synergistic Interaction of Matricaria Chamomilla Extract with Diclofenac and Indomethacin on Carrageenan-Induced Paw Inflammation in Rats","volume":"78","author":"Ortiz","year":"2017","journal-title":"Drug Dev. Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1002\/ddr.21418","article-title":"Pharmacological interaction of alpha-bisabolol and diclofenac on nociception, inflammation, and gastric integrity in rats","volume":"79","author":"Ortiz","year":"2018","journal-title":"Drug Dev. Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/ddr.21418","article-title":"Synergistic interaction between docosahexaenoic acid and diclofenac on inflammation, nociception, and gastric security models in rats","volume":"79","author":"Ortiz","year":"2018","journal-title":"Drug Dev. Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/j.ejpain.2006.07.006","article-title":"Ameliorative effect of combined administration of inducible nitric oxide synthase inhibitor with cyclooxygenase-2 inhibitors in neuropathic pain in rats","volume":"11","author":"Dudhgaonkar","year":"2007","journal-title":"Eur. J. Pain"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1159\/000101390","article-title":"Isobolographic analyses of the gabapentin-metamizol combination after local peripheral, intrathecal and oral administration in the rat","volume":"79","author":"Herrera","year":"2007","journal-title":"Pharmacology"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1213\/ANE.0b013e3181cbd8da","article-title":"Synergistic interactions between paracetamol and oxcarbazepine in somatic and visceral pain models in rodents","volume":"110","author":"Tomic","year":"2010","journal-title":"Anesth. Analg."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1053\/eujp.2002.0329","article-title":"Gabapentin and pregabalin suppress tactile allodynia and potentiate spinal cord stimulation in a model of neuropathy","volume":"6","author":"Wallin","year":"2002","journal-title":"Eur. J. Pain"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/j.neuropharm.2005.12.002","article-title":"Antihyperalgesic effects of local injections of anandamide, ibuprofen, rofecoxib and their combinations in a model of neuropathic pain","volume":"50","author":"Guindon","year":"2006","journal-title":"Neuropharmacology"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.pain.2005.12.007","article-title":"Local interactions between anandamide, an endocannabinoid, and ibuprofen, a nonsteroidal anti-inflammatory drug, in acute and inflammatory pain","volume":"121","author":"Guindon","year":"2006","journal-title":"Pain"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1213\/01.ane.0000194587.94260.1d","article-title":"The additive antinociceptive interaction between WIN 55,212-2, a cannabinoid agonist, and ketorolac","volume":"102","author":"Ulugol","year":"2006","journal-title":"Anesth. Analg."},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Diaz-Reval, M.I., Cardenas, Y., Huerta, M., Trujillo, X., Sanchez-Pastor, E.A., Gonzalez-Trujano, M.E., Virgen-Ortiz, A., and Perez-Hernandez, M.G. (2022). Activation of Peripheral Cannabinoid Receptors Synergizes the Effect of Systemic Ibuprofen in a Pain Model in Rat. Pharmaceuticals, 15.","DOI":"10.3390\/ph15080910"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"2521","DOI":"10.1111\/bph.13534","article-title":"Opioid and cannabinoid synergy in a mouse neuropathic pain model","volume":"173","author":"Kazantzis","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"509","DOI":"10.2478\/acph-2022-0037","article-title":"Synergistic action between a synthetic cannabinoid compound and tramadol in neuropathic pain rats","volume":"72","author":"Regla","year":"2022","journal-title":"Acta Pharm."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.neuropharm.2016.12.008","article-title":"Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists","volume":"116","author":"Grenald","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Evans, A.A., Jesus, C.H.A., Martins, L.L., Fukuyama, A.H., Gasparin, A.T., Crippa, J.A., Zuardi, A.W., Hallak, J.E.C., Genaro, K., and de Castro Junior, C.J. (2023). Pharmacological Interaction between Cannabidiol and Tramadol on Experimental Diabetic Neuropathic Pain: An Isobolographic Analysis. Cannabis Cannabinoid Res., ahead of print.","DOI":"10.1089\/can.2021.0242"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1097\/00000539-200012000-00037","article-title":"The efficacy of intrathecal morphine and clonidine in the treatment of pain after spinal cord injury","volume":"91","author":"Siddall","year":"2000","journal-title":"Anesth. Analg."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"245","DOI":"10.36076\/ppj.2010\/13\/245","article-title":"Multi-day low dose ketamine infusion as adjuvant to oral gabapentin in spinal cord injury related chronic pain: A prospective, randomized, double blind trial","volume":"13","author":"Amr","year":"2010","journal-title":"Pain Physician"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.phrs.2007.04.006","article-title":"Protein kinase C in pain: Involvement of multiple isoforms","volume":"55","author":"Velazquez","year":"2007","journal-title":"Pharmacol. Res."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"3595903","DOI":"10.1155\/2017\/3595903","article-title":"Gabapentin Inhibits Protein Kinase C Epsilon Translocation in Cultured Sensory Neurons with Additive Effects When Coapplied with Paracetamol (Acetaminophen)","volume":"2017","author":"Vellani","year":"2017","journal-title":"Sci. World J."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1002\/dmrr.1225","article-title":"Painful diabetic peripheral neuropathy: Consensus recommendations on diagnosis, assessment and management","volume":"27","author":"Tesfaye","year":"2011","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1002\/ejp.1148","article-title":"Current evidence of cannabinoid-based analgesia obtained in preclinical and human experimental settings","volume":"22","author":"Lotsch","year":"2018","journal-title":"Eur. J. Pain"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13052-023-01445-4","article-title":"Paracetamol and ibuprofen combination for the management of acute mild-to-moderate pain in children: Expert consensus using the Nominal Group Technique (NGT)","volume":"49","author":"Parri","year":"2023","journal-title":"Ital. J. Pediatr."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s40263-020-00777-7","article-title":"Efficacy and Safety of Ibuprofen Plus Paracetamol in a Fixed-Dose Combination for Acute Postoperative Pain in Adults: Meta-Analysis and a Trial Sequential Analysis","volume":"35","author":"Abushanab","year":"2021","journal-title":"CNS Drugs"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.pmrj.2015.09.010","article-title":"A Medication Combination for the Treatment of Central Poststroke Pain via the Adjuvant Use of Prednisone with Gabapentin: A Case Report","volume":"8","author":"Batlle","year":"2016","journal-title":"PM R."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1111\/pan.13517","article-title":"Analgesic effectiveness, pharmacokinetics, and safety of a paracetamol\/ibuprofen fixed-dose combination in children undergoing adenotonsillectomy: A randomized, single-blind, parallel group trial","volume":"28","author":"Playne","year":"2018","journal-title":"Paediatr. Anaesth."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.ajps.2020.06.004","article-title":"Drug-drug cocrystals: Opportunities and challenges","volume":"16","author":"Wang","year":"2021","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"305","DOI":"10.15171\/bi.2018.33","article-title":"Recent advances in improving oral drug bioavailability by cocrystals","volume":"8","author":"Emami","year":"2018","journal-title":"Bioimpacts"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"3577","DOI":"10.1021\/acs.cgd.0c00106","article-title":"Generation and Evaluation of Pharmacologically Relevant Drug\u2013Drug Cocrystal for Gout Therapy","volume":"20","author":"Modani","year":"2020","journal-title":"Cryst. Growth Des."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.1002\/jps.22434","article-title":"Coformer selection in pharmaceutical cocrystal development: A case study of a meloxicam aspirin cocrystal that exhibits enhanced solubility and pharmacokinetics","volume":"100","author":"Cheney","year":"2011","journal-title":"J. Pharm. Sci."},{"key":"ref_142","unstructured":"Buschmann, H.H., Carandell, L.S., Buchholz, J.B., Bertan, J.C.C., and Artero, J.R. (2013). Co-Crystals of Duloxetine and Naproxen. (EP2291345B1)."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"e02946","DOI":"10.1016\/j.heliyon.2019.e02946","article-title":"Cocrystal construction between the ethyl ester with parent drug of diclofenac: Structural, stability, and anti-inflammatory study","volume":"5","author":"Nugrahani","year":"2019","journal-title":"Heliyon"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijpharm.2017.09.012","article-title":"Levetiracetam + nonsteroidal anti-inflammatory drug binary systems: A contribution to the development of new solid dosage forms","volume":"533","author":"Machado","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"2679","DOI":"10.2147\/JPR.S208082","article-title":"Co-crystals as a new approach to multimodal analgesia and the treatment of pain","volume":"12","author":"Almansa","year":"2019","journal-title":"J. Pain Res."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1021\/acs.cgd.6b01848","article-title":"Co-crystal of Tramadol Hydrochloride\u2013Celecoxib (ctc): A Novel API\u2212API Co-crystal for the Treatment of Pain","volume":"17","author":"Almansa","year":"2017","journal-title":"Cryst. Growth Des."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/448400a","article-title":"The pain game","volume":"448","author":"Wadman","year":"2007","journal-title":"Nature"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1056\/NEJMoa1611593","article-title":"Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis","volume":"375","author":"Nissen","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.ejphar.2018.06.022","article-title":"Administration of a co-crystal of tramadol and celecoxib in a 1:1 molecular ratio produces synergistic antinociceptive effects in a postoperative pain model in rats","volume":"833","author":"Merlos","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"2718","DOI":"10.1111\/bcp.13395","article-title":"Single-dose pharmacokinetics of co-crystal of tramadol-celecoxib: Results of a four-way randomized open-label phase I clinical trial in healthy subjects","volume":"83","author":"Videla","year":"2017","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/papr.13136","article-title":"Celecoxib-tramadol co-crystal in patients with moderate-to-severe pain following bunionectomy with osteotomy: A phase 3, randomized, double-blind, factorial, active- and placebo-controlled trial","volume":"23","author":"Viscusi","year":"2023","journal-title":"Pain Pract."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1002\/ejp.2021","article-title":"Efficacy and safety of co-crystal of tramadol-celecoxib (CTC) in acute moderate-to-severe pain after abdominal hysterectomy: A randomized, double-blind, phase 3 trial (STARDOM2)","volume":"26","author":"Langford","year":"2022","journal-title":"Eur. J. Pain"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s40268-018-0235-y","article-title":"Co-crystal of Tramadol-Celecoxib in Patients with Moderate to Severe Acute Post-surgical Oral Pain: A Dose-Finding, Randomised, Double-Blind, Placebo- and Active-Controlled, Multicentre, Phase II Trial","volume":"18","author":"Videla","year":"2018","journal-title":"Drugs R&D"},{"key":"ref_154","unstructured":"Esteve Pharmaceuticals (2023, November 01). Seglentis: Prescribing Information 2021. Available online: https:\/\/www.kowapharma.com\/documents\/SEGLENTIS_Prescribing_Information.pdf."},{"key":"ref_155","doi-asserted-by":"crossref","unstructured":"Aramini, A., Bianchini, G., Lillini, S., Tomassetti, M., Pacchiarotti, N., Canestrari, D., Cocchiaro, P., Novelli, R., Dragani, M.C., and Palmerio, F. (2023). Ketoprofen, lysine and gabapentin co-crystal magnifies synergistic efficacy and tolerability of the constituent drugs: Pre-clinical evidences towards an innovative therapeutic approach for neuroinflammatory pain. Biomed. Pharmacother., 163.","DOI":"10.1016\/j.biopha.2023.114845"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1002\/jps.24647","article-title":"Gastrointestinal Behavior of Weakly Acidic BCS Class II Drugs in Man\u2014Case Study of Diclofenac Potassium","volume":"105","author":"Brouwers","year":"2016","journal-title":"J. Pharm. Sci."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.drudis.2018.11.023","article-title":"Pharmaceutical cocrystals: From serendipity to design to application","volume":"24","author":"Kavanagh","year":"2019","journal-title":"Drug Discov. Today"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1152\/physrev.00004.2008","article-title":"Prostaglandins, NSAIDs, and gastric mucosal protection: Why doesn\u2019t the stomach digest itself?","volume":"88","author":"Wallace","year":"2008","journal-title":"Physiol. Rev."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.phrs.2009.06.002","article-title":"Ibuprofen-arginine generates nitric oxide and has enhanced anti-inflammatory effects","volume":"60","author":"Perrotta","year":"2009","journal-title":"Pharmacol. Res."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/12\/1802\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:40:00Z","timestamp":1760132400000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/12\/1802"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,16]]},"references-count":159,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["biom13121802"],"URL":"https:\/\/doi.org\/10.3390\/biom13121802","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,16]]}}}