Pharmacological Effects of Tramadol, an Opioid
Yıl 2023,
Cilt: 32 Sayı: 4, 206 - 214, 31.12.2023
Burçin Ün
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Ayper Pekmezekmek
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Betül Kalay
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Özlem Özü
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Ata Seçilmiş
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Tramadol, which shows chemical similarity with morphine, is an analgesic drug acting central nervous system. The analgesic potency of tramadol, a synthetic codein analog, is lower than morphine because of its weak µ-opioid receptor affinity. Although it is a frequently preferred drug in the treatment of acute and chronic pain, its abuse has been increasing recently. Tramadol also has a relaxing effect and is less addictive than other opioids. It is also commonly used in pregnant women. In this review, general information about the pharmacological properties, side effects and embryoteratogenicity of tramadol is given.
Kaynakça
- 1. Loeser JD, Treede R-D. The Kyoto protocol of IASP basic pain terminology. PAIN®. 2008;137(3):473-477.
- 2. Subedi M, Bajaj S, Kumar MS, Mayur Y. An overview of tramadol and its usage in pain management and future perspective. Biomedicine & Pharmacotherapy. 2019;111:443-451.
- 3. Kayaalp O, Uzbay T. İlaç Kötüye Kullanımı ve İlaç Bağımlılığı, Akılcı Tedavi yönünden Tıbbi Farmakoloji 13. baskı. 2. Cilt. s. 2012:846-868.
- 4. Camilleri M, Drossman D, Becker G, Webster L, Davies A, Mawe G. Emerging treatments in neurogastroenterology: a multidisciplinary working group consensus statement on opioid‐induced constipation. Neurogastroenterology & Motility. 2014;26(10):1386-1395.
- 5. Uzbay T. Hazdan Bağımlılığa, Destek Yayınları, 2018; 463, 128.
- 6. Corbett AD, Henderson G, McKnight AT, Paterson SJ. 75 years of opioid research: the exciting but vain quest for the Holy Grail. British journal of pharmacology. 2006;147(S1):S153-S162.
- 7. Ahlbeck K. Opioids: a two-faced Janus. Current medical research and opinion. 2011;27(2):439-448.
- 8. Milhorn HT, Milhorn HT. Opioids. Chemical Dependence: Diagnosis, Treatment, and Prevention. 1990:167-183.
- 9. Chhangani S. Handbook of Clinical Anesthesia. The Clinical Journal of Pain. 2001;17(4):380.
- 10. J Mistry C, Bawor M, Desai D, C Marsh D, Samaan Z. Genetics of opioid dependence: a review of the genetic contribution to opioid dependence. Current psychiatry reviews. 2014;10(2):156-167.
- 11. Hilal Dandan Randa LLB. Goodman ve Gilman’ın Farmakoloji ve Tedavi El Kitabı, çev: Remzi Erdem.
- 12. Clarke S, Zimmer A, Zimmer A, Hill R, Kitchen I. Region selective up-regulation of μ-, δ-and κ-opioid receptors but not opioid receptor-like 1 receptors in the brains of enkephalin and dynorphin knockout mice. Neuroscience. 2003;122(2):479-489.
- 13. Laycock H, Bantel C. Opioid mechanisms and opioid drugs. Anaesthesia & Intensive Care Medicine. 2019;20(8):450-455.
- 14. Bagley EE, Ingram SL. Endogenous opioid peptides in the descending pain modulatory circuit. Neuropharmacology. 2020;173:108131.
- 15. Zadina JE, Hackler L, Ge L-J, Kastin AJ. A potent and selective endogenous agonist for the µ-opiate receptor. Nature. 1997;386(6624):499-502.
- 16. Friedman A, Nabong L. Opioids: pharmacology, physiology, and clinical implications in pain medicine. Physical Medicine and Rehabilitation Clinics. 2020;31(2):289-303
- 17. Bodnar RJ. Endogenous opiates and behavior: 2012. Peptides. 2013;50:55-95.
- 18. Karkhanis AN, Al-Hasani R. Dynorphin and its role in alcohol use disorder. Brain research. 2020;1735:146742.
- 19. Tempfer C, Zeisler H, Heinzl H, Hefler L, Husslein P, Kainz C. Influence of acupuncture on maternal serum levels of interleukin-8, prostaglandin F2alpha, and beta-endorphin: a matched pair study. Obstetrics & Gynecology. 1998;92(2):245-248.
- 20. Reichlin S. Neuroendocrinology. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. 1998.
- 21. Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annual review of biochemistry. 2004;73(1):953-990.
- 22. Stein C, Schäfer M, Machelska H. Attacking pain at its source: new perspectives on opioids. Nature medicine. 2003;9(8):1003-1008.
- 23. Power I, Barratt S. Analgesic agents for the postoperative period: nonopioids. Surgical Clinics of North America. 1999;79(2):275-295.
- 24. Mizoguchi H, Narita M, Nagase H, Tseng LF. Activation of G-proteins in the mouse pons/medulla by β-endorphin is mediated by the stimulation of μ-and putative ε-receptors. Life Sciences. 2000;67(22):2733-2743.
- 25. Nandhu M, Naijil G, Smijin S, Jayanarayanan S, Paulose C. Opioid system functional regulation in neurological disease management. Journal of neuroscience research. 2010;88(15):3215-3221.
- 26. Maldonado R. The endogenous opioid system and drug addiction. Paper presented at: Annales pharmaceutiques francaises, 2010.
- 27. Atamer-Şimşek Ş. Opiat Reseptörleri. PsikofarmakolojideYenilikler Sempozyumu. 1991.
- 28. Cabıoğlu T. Endojen opioidler. Genel Tıp Dergisi. 2001;11(4):161-167.
- 29. Morgan Jr GE, Mikail MS. Clinical anesthesiology. Clinical anesthesiology; 1996:881-881.
- 30. Akgür SA, Coşkunol H. Bağımlılık yapan maddeler ve toksikolojisi: Ege Üniversitesi Yayınları; 2014.
- 31. Raffa RB, Friderichs E. Profile of Tramadol and Tramadol Analogues. Pain: CRC Press; 2003:752-763.
- 32. Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an'atypical'opioid analgesic. Journal of Pharmacology and Experimental Therapeutics. 1992;260(1):275-285.
- 33. Biasi G, Manca S, Manganelli S, Marcolongo R. Tramadol in the fibromyalgia syndrome: a controlled clinical trial versus placebo. International journal of clinical pharmacology research. 1998;18(1):13-19.
- 34. Herbert MK, Weis R, Holzer P. The enantiomers of tramadol and its major metabolite inhibit peristalsis in the guinea pig small intestine via differential mechanisms. BMC pharmacology. 2007;7(1):1-11.
- 35. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clinical pharmacokinetics. 2004;43:879-923.
- 36. Kuzucuoğlu T.YENİ OPİOİD ANALJEZİK TRAMADOL HYDROCHLORİD.
- 37. Lee CR, McTavish D, Sorkin EM. Tramadol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs. 1993;46:313-340.
- 38. Lintz W, Barth H, Osterloh G, Schmidt-Böthelt E. Bioavailability of enteral tramadol formulations. 1st communication: capsules. Arzneimittel-Forschung. 1986;36(8):1278-1283.
- 39. Lintz W, Becker R, Gerloff J, Terlinden R. Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations 4th communication: Drops (without ethanol). Arzneimittelforschung. 2000;50(02):99-108.
- 40. Lintz W, Barth H, Becker R, Frankus E, Schmidt-Böthelt E. Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 2nd communication: drops with ethanol. Arzneimittel-forschung. 1998;48(5):436-445.
- 41. Raffa R, Nayak R, Liao S, Minn F. The mechanism (s) of action and pharmacokinetics of tramadol hydrochloride. Rev Contemp Pharmacother. 1995;6:485-497.
- 42. Lintz W, Beier H, Gerloff J. Bioavailability of tramadol after im injection in comparison to iv infusion. International journal of clinical pharmacology and therapeutics. 1999;37(4):175-183.
- 43. Bamigbade T, Langford R. The clinical use of tramadol hydrochloride. Pain reviews. 1998;5:155-182.
- 44. Shipton E. Tramadol—present and future. Anaesthesia and intensive care. 2000;28(4):363-374.
- 45. Lintz W, Erlacin S, Frankus E, Uragg H. Biotransformation of tramadol in man and animal (author's transl). Arzneimittel-Forschung. 1981;31(11):1932-1943.
- 46. Duthie D. Remifentanil and tramadol. British Journal of Anaesthesia. 1998;81(1):51-57.
- 47. Pang W-W, Mok MS, Chang D-P, Huang M-H. Local anesthetic effect of tramadol, metoclopramide, and lidocaine following intradermal injection. Regional Anesthesia and Pain Medicine. 1998;23(6):580-583.
- 48. Roberts L, Morrow J. The pharmacological basis of therapeutics. New York. 2001.
- 49. Leeder JS, Kearns GL. Pharmacogenetics in pediatrics: implications for practice. Pediatric Clinics of North America. 1997;44(1):55-77.
- 50. Wilder-Smith CH, Hill L, Osler W, O'Keefe S. Effect of tramadol and morphine on pain and gastrointestinal motor function in patients with chronic pancreatitis. Digestive diseases and sciences. 1999;44:1107-1116.
- 51. Scott LJ, Perry CM. Tramadol: a review of its use in perioperative pain. Drugs. 2000;60:139-176.
- 52. Bourne MH. Analgesics for orthopedic postoperative pain. American Journal of Orthopedics (Belle Mead, NJ). 2004;33(3):128-135.
- 53. Harati Y, Gooch C, Swenson M, Edelman S, Greene D, Raskin P, Donofrio P, Cornblath D, Sachdeo R, Siu C. Double‐blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998;50(6):1842-1846.
- 54. Sindrup SH, Andersen G, Madsen C, Smith T, Brøsen K, Jensen TS. Tramadol relieves pain and allodynia in polyneuropathy: a randomised, double-blind, controlled trial. Pain. 1999;83(1):85-90.
- 55. Wilder-Smith C, Hill L, Spargo K, Kalla A. Treatment of severe pain from osteoarthritis with slow-release tramadol or dihydrocodeine in combination with NSAID's: a randomised study comparing analgesia, antinociception and gastrointestinal effects. Pain. 2001;91(1-2):23-31.
- 56. Malonne H, Coffiner M, Sonet B, Sereno A, Vanderbist F. Efficacy and tolerability of sustained-release tramadolin the treatment of symptomatic osteoarthritis of the hip or knee: A multicenter, randomized, double-blind, placebo-controlled study. Clinical therapeutics. 2004;26(11):1774-1782.
- 57. Beltrán J, Martín-Mola E, Figueroa M, Granados J, Sanmartí R, Artigas R, Torres F, Forns M, Mauleón D. Comparison of dexketoprofen trometamol and ketoprofen in the treatment of osteoarthritis of the knee. The Journal of Clinical Pharmacology. 1998;38(S1):74S-80S.
- 58. Lewis KS, Han NH. Tramadol: a new centrally acting analgesic. American Journal of Health-System Pharmacy. 1997;54(6):643-652.
- 59. Leppert W. Tramadol as an analgesic for mild to moderate cancer pain. Pharmacological reports. 2009;61(6):978-992.
- 60. Reisli R. Kronik bel-boyun ağrılı hastada opioid analjezikler. TOTBİD Dergisi. 2017;16:139-147.
- 61. Teppema LJ, Olievier CN, Dahan A. Respiratory depression by tramadol: involvement of opioid receptors. ANESTHESIOLOGY-PHILADELPHIA THEN HAGERSTOWN-. 2000;93(3; SUPP/2):A1338-A1338
- 62. Nieuwenhuijs D, Bruce J, Drummond G, Warren P, Dahan A. Influence of oral tramadol on the dynamic ventilatory response to carbon dioxide in healthy volunteers. British journal of anaesthesia. 2001;87(6):860-865.
- 63. Warren P, Taylor J, Nicholson K, Wraith P, Drummond G. Influence of tramadol on the ventilatory response to hypoxia in humans. British journal of anaesthesia. 2000;85(2):211-216.
- 64. Tarkkila P, Tuominen M, Lindgren L. Comparison of respiratory effects of tramadol and pethidine. European journal of anaesthesiology. 1998;15(1):64-68.
- 65. Wu H, Wu G. In response: the cause of fatal respiratory depression is combination of clindamycin and fentanyl, rather than tramadol. Pain Physician. 2016;19(2):E362.
- 66. Houmes R-JM, Voets MA, Verkaaik A, Erdmann W, Lachmann B. Efficacy and safety of tramadol versus morphine for moderate and severe postoperative pain with special regard to respiratory depression. Anesthesia & Analgesia. 1992;74(4):510-514.
- 67. Barnung S, Treschow M, Borgbjerg F. Respiratory depression following oral tramadol in a patient with impaired renal function. Pain. 1997;71(1):111-112.
- 68. Barth H, Giertz H, Schmal A, Lorenz W. Anaphylactoid reactions and histamine release do not occur after application of the opioid tramadol. Agents and Actions. 1987;20(3-4):310-313.
- 69. Balcı C, Karabekir H, Sıvacı R, Toprak D, Ela Y, Pancaroğlu M. Lomber disk cerrahisi yapılan hastalarda postoperatif analjezide lornoksikam ve tramadolün hasta kontrollü analjezi yöntemi ile etkinliklerinin karşılaştırılması. Türk Anest Rean Der Dergisi. 2006;34(4):228-235.
- 70. Menteş Ö, Harlak A, Eryılmaz M, Balkan M, Kozak O, Arslan İ, Tufan CT. Laparoskopik kolesistektomi sonrası ağrı tedavisinde tramadolün devamlı infüzyon ve hasta kontrollü analjezi ile uygulanmasının karşılaştırılması. Gülhane Tıp Dergisi. 2009;51(1):6-10.
- 71. Eisenstein TK. The role of opioid receptors in immune system function. Frontiers in immunology. 2019;10:2904.
- 72. Tsai Y-C, Won S-J. Effects of tramadol on T lymphocyte proliferation and natural killer cell activity in rats with sciatic constriction injury. Pain. 2001;92(1-2):63-69.
- 73. Gaspani L, Bianchi M, Limiroli E, Panerai AE, Sacerdote P. The analgesic drug tramadol prevents the effect of surgery on natural killer cell activity and metastatic colonization in rats. Journal of neuroimmunology. 2002;129(1-2):18-24.
- 74. Sacerdote P, Bianchi M, Gaspani L, Manfredi B, Maucione A, Terno G, Ammatuna M, Panerai AE. The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients. Anesthesia & Analgesia. 2000;90(6):1411-1414.
- 75. Murphy D, Sutton A, Prescott L, Murphy M. A comparison of the effects of tramadol and morphine on gastric emptying in man. Anaesthesia. 1997;52(12):1224-1229.
- 76. Crighton IM, Martin PH, Hobbs GJ, Cobby TF, Fletcher AJ, Stewart PD. A comparison of the effects of intravenous tramadol, codeine, and morphine on gastric emptying in human volunteers. Anesthesia & Analgesia. 1998;87(2):445-449.
- 77. Committee F. FDC Reports (Pink Sheet). Prescription Pharmaceuticals and Biotechnology. 1998;60:4-5.
- 78. Black E, Khor KE, Kennedy D, Chutatape A, Sharma S, Vancaillie T, Demirkol A. Medication use and pain management in pregnancy: a critical review. Pain Practice. 2019;19(8):875-899.
- 79. Vazzana M, Andreani T, Fangueiro J, Faggio C, Silva C, Santini A, Garcia M, Silva A, Souto E. Tramadol hydrochloride: pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems. Biomedicine & Pharmacotherapy. 2015;70:234-238.
- 80. Akhtar MF, Younas S, Saleem A, Baig MMFA, Sharif A, Abdel‐Daim MM, Rasul A, Saleem M. Maternotoxicity and fetotoxicity in Rattus norvegicus albinus exposed to tramadol during the late phase of pregnancy. Birth Defects Research. 2021;113(19):1407-1421.
- 81. AL–Essawi DA-HK. Fetal Teratogenic and Histopathological Influences of Tramadol on White Rat Fetuses. Annals of the Romanian Society for Cell Biology. 2021:4747-4760.
- 82. de Swart IW, de Vries LC, van Puijenbroek EP. Tramadol exposure in the first trimester of pregnancy: A case series. Reproductive Toxicology. 2015(57):226.
- 83. Källén B, Reis M. Use of tramadol in early pregnancy and congenital malformation risk. Reproductive Toxicology. 2015;58:246-251.
- 84. Argoff CE, Viscusi ER. The use of opioid analgesics for chronic pain: minimizing the risk for harm. The American Journal of Gastroenterology Supplements. 2014;2(1):3.
- 85. Benyamin R, Trescot AM, Datta S, Buenaventura RM, Adlaka R, Sehgal N, Glaser SE, Vallejo R. Opioid complications and side effects. Pain physician. 2008;11(2S):S105.
- 86. Stone P, Minton O. European Palliative Care Research collaborative pain guidelines. Central side-effects management: what is the evidence to support best practice in the management of sedation, cognitive impairment and myoclonus? Palliative medicine. 2011;25(5):431-441.
- 87. Gasse MC, Derby L, Vasilakis‐Scaramozza C, Jick H. Incidence of first‐time idiopathic seizures in users of tramadol. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2000;20(6):629-634.
- 88. Lee SH, Cho SY, Lee HG, Choi J, Yoon MH, Kim WM. Tramadol induced paradoxical hyperalgesia. Pain Physician. 2013;16(1):41.
- 89. Nestler EJ. Molecular neurobiology of addiction. American Journal on Addictions. 2001;10(3):201-217.
- 90. Minami K, Ogata J, Horishita T, Shiraishi M, Okamoto T, Sata T, Shigematsu A. Intramuscular tramadol increases gastric pH during anesthesia. Canadian Journal of Anesthesia. 2004;51(6):545.
- 91. Ülker GS. İlaç etkileşmeleri ve advers ilaç reaksiyonlarına yaklaşım. 2012.
- 92. Boyd IW. Tramadol and seizures. Medical Journal of Australia. 2005;182(11):595-596.
- 93. Beakley BD, Kaye AM, Kaye AD. Tramadol, pharmacology, side effects, and serotonin syndrome: a review. Pain physician. 2015;18(4):395.
- 94. Jeppesen U, Gram L, Vistisen K, Loft S, Poulsen HE, Brøsen K. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. European journal of clinical pharmacology. 1996;51:73-78.
- 95. Jovanović-Čupić V, Martinović Ž, Nešić N. Seizures associated with intoxication and abuse of tramadol. Clinical toxicology. 2006;44(2):143-146.
- 96. Ripple MG, Pestaner JP, Levine BS, Smialek JE. Lethal combination of tramadol and multiple drugs affecting serotonin. The American journal of forensic medicine and pathology. 2000;21(4):370-374.
- 97. Walsh SL, Babalonis S. The abuse potential of prescription opioids in humans—closing in on the first century of research. Non-medical and illicit use of psychoactive drugs. 2017:33-58.
- 98. Uzbay T. Nöropsikofarmakoloji: Rasyonel ilaç kullanımı: Medikal Yayıncılık; 2007.
- 99. Budd K, Langford R. Tramadol revisited. British journal of anaesthesia. 1999;82(4):493-495.
Bir Opioid Olan Tramadolün Farmakolojik Etkileri
Yıl 2023,
Cilt: 32 Sayı: 4, 206 - 214, 31.12.2023
Burçin Ün
,
Ayper Pekmezekmek
,
Betül Kalay
,
Özlem Özü
,
Ata Seçilmiş
Öz
Tramadol, yapıca kodeine benzeyen, sentetik bir opiod olan santral etkili analjeziktir. Analjezik etkisini selektif zayıf µ-opioid reseptör affinitesiyle göstermektedir. Ayrıca gebelerde kullanımı da yaygındır. Akut ve kronik ağrı tedavilerinde sıklıkla tercih edilen bir ilaç olmasına rağmen son zamanlarda kötüye kullanımı da giderek artmaktadır. Tramadol, rahatlatıcı bir etkiye de sahip olup diğer opioidlere göre bağımlılık yapma potansiyeli daha düşüktür. Gebelerde analjezik etkisi nedeniyle yaygın olarak kullanıldığı halde embriyoteratonejitesi hakkında yeterli çalışma yapılmamıştır.
Kaynakça
- 1. Loeser JD, Treede R-D. The Kyoto protocol of IASP basic pain terminology. PAIN®. 2008;137(3):473-477.
- 2. Subedi M, Bajaj S, Kumar MS, Mayur Y. An overview of tramadol and its usage in pain management and future perspective. Biomedicine & Pharmacotherapy. 2019;111:443-451.
- 3. Kayaalp O, Uzbay T. İlaç Kötüye Kullanımı ve İlaç Bağımlılığı, Akılcı Tedavi yönünden Tıbbi Farmakoloji 13. baskı. 2. Cilt. s. 2012:846-868.
- 4. Camilleri M, Drossman D, Becker G, Webster L, Davies A, Mawe G. Emerging treatments in neurogastroenterology: a multidisciplinary working group consensus statement on opioid‐induced constipation. Neurogastroenterology & Motility. 2014;26(10):1386-1395.
- 5. Uzbay T. Hazdan Bağımlılığa, Destek Yayınları, 2018; 463, 128.
- 6. Corbett AD, Henderson G, McKnight AT, Paterson SJ. 75 years of opioid research: the exciting but vain quest for the Holy Grail. British journal of pharmacology. 2006;147(S1):S153-S162.
- 7. Ahlbeck K. Opioids: a two-faced Janus. Current medical research and opinion. 2011;27(2):439-448.
- 8. Milhorn HT, Milhorn HT. Opioids. Chemical Dependence: Diagnosis, Treatment, and Prevention. 1990:167-183.
- 9. Chhangani S. Handbook of Clinical Anesthesia. The Clinical Journal of Pain. 2001;17(4):380.
- 10. J Mistry C, Bawor M, Desai D, C Marsh D, Samaan Z. Genetics of opioid dependence: a review of the genetic contribution to opioid dependence. Current psychiatry reviews. 2014;10(2):156-167.
- 11. Hilal Dandan Randa LLB. Goodman ve Gilman’ın Farmakoloji ve Tedavi El Kitabı, çev: Remzi Erdem.
- 12. Clarke S, Zimmer A, Zimmer A, Hill R, Kitchen I. Region selective up-regulation of μ-, δ-and κ-opioid receptors but not opioid receptor-like 1 receptors in the brains of enkephalin and dynorphin knockout mice. Neuroscience. 2003;122(2):479-489.
- 13. Laycock H, Bantel C. Opioid mechanisms and opioid drugs. Anaesthesia & Intensive Care Medicine. 2019;20(8):450-455.
- 14. Bagley EE, Ingram SL. Endogenous opioid peptides in the descending pain modulatory circuit. Neuropharmacology. 2020;173:108131.
- 15. Zadina JE, Hackler L, Ge L-J, Kastin AJ. A potent and selective endogenous agonist for the µ-opiate receptor. Nature. 1997;386(6624):499-502.
- 16. Friedman A, Nabong L. Opioids: pharmacology, physiology, and clinical implications in pain medicine. Physical Medicine and Rehabilitation Clinics. 2020;31(2):289-303
- 17. Bodnar RJ. Endogenous opiates and behavior: 2012. Peptides. 2013;50:55-95.
- 18. Karkhanis AN, Al-Hasani R. Dynorphin and its role in alcohol use disorder. Brain research. 2020;1735:146742.
- 19. Tempfer C, Zeisler H, Heinzl H, Hefler L, Husslein P, Kainz C. Influence of acupuncture on maternal serum levels of interleukin-8, prostaglandin F2alpha, and beta-endorphin: a matched pair study. Obstetrics & Gynecology. 1998;92(2):245-248.
- 20. Reichlin S. Neuroendocrinology. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. 1998.
- 21. Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annual review of biochemistry. 2004;73(1):953-990.
- 22. Stein C, Schäfer M, Machelska H. Attacking pain at its source: new perspectives on opioids. Nature medicine. 2003;9(8):1003-1008.
- 23. Power I, Barratt S. Analgesic agents for the postoperative period: nonopioids. Surgical Clinics of North America. 1999;79(2):275-295.
- 24. Mizoguchi H, Narita M, Nagase H, Tseng LF. Activation of G-proteins in the mouse pons/medulla by β-endorphin is mediated by the stimulation of μ-and putative ε-receptors. Life Sciences. 2000;67(22):2733-2743.
- 25. Nandhu M, Naijil G, Smijin S, Jayanarayanan S, Paulose C. Opioid system functional regulation in neurological disease management. Journal of neuroscience research. 2010;88(15):3215-3221.
- 26. Maldonado R. The endogenous opioid system and drug addiction. Paper presented at: Annales pharmaceutiques francaises, 2010.
- 27. Atamer-Şimşek Ş. Opiat Reseptörleri. PsikofarmakolojideYenilikler Sempozyumu. 1991.
- 28. Cabıoğlu T. Endojen opioidler. Genel Tıp Dergisi. 2001;11(4):161-167.
- 29. Morgan Jr GE, Mikail MS. Clinical anesthesiology. Clinical anesthesiology; 1996:881-881.
- 30. Akgür SA, Coşkunol H. Bağımlılık yapan maddeler ve toksikolojisi: Ege Üniversitesi Yayınları; 2014.
- 31. Raffa RB, Friderichs E. Profile of Tramadol and Tramadol Analogues. Pain: CRC Press; 2003:752-763.
- 32. Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an'atypical'opioid analgesic. Journal of Pharmacology and Experimental Therapeutics. 1992;260(1):275-285.
- 33. Biasi G, Manca S, Manganelli S, Marcolongo R. Tramadol in the fibromyalgia syndrome: a controlled clinical trial versus placebo. International journal of clinical pharmacology research. 1998;18(1):13-19.
- 34. Herbert MK, Weis R, Holzer P. The enantiomers of tramadol and its major metabolite inhibit peristalsis in the guinea pig small intestine via differential mechanisms. BMC pharmacology. 2007;7(1):1-11.
- 35. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clinical pharmacokinetics. 2004;43:879-923.
- 36. Kuzucuoğlu T.YENİ OPİOİD ANALJEZİK TRAMADOL HYDROCHLORİD.
- 37. Lee CR, McTavish D, Sorkin EM. Tramadol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs. 1993;46:313-340.
- 38. Lintz W, Barth H, Osterloh G, Schmidt-Böthelt E. Bioavailability of enteral tramadol formulations. 1st communication: capsules. Arzneimittel-Forschung. 1986;36(8):1278-1283.
- 39. Lintz W, Becker R, Gerloff J, Terlinden R. Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations 4th communication: Drops (without ethanol). Arzneimittelforschung. 2000;50(02):99-108.
- 40. Lintz W, Barth H, Becker R, Frankus E, Schmidt-Böthelt E. Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 2nd communication: drops with ethanol. Arzneimittel-forschung. 1998;48(5):436-445.
- 41. Raffa R, Nayak R, Liao S, Minn F. The mechanism (s) of action and pharmacokinetics of tramadol hydrochloride. Rev Contemp Pharmacother. 1995;6:485-497.
- 42. Lintz W, Beier H, Gerloff J. Bioavailability of tramadol after im injection in comparison to iv infusion. International journal of clinical pharmacology and therapeutics. 1999;37(4):175-183.
- 43. Bamigbade T, Langford R. The clinical use of tramadol hydrochloride. Pain reviews. 1998;5:155-182.
- 44. Shipton E. Tramadol—present and future. Anaesthesia and intensive care. 2000;28(4):363-374.
- 45. Lintz W, Erlacin S, Frankus E, Uragg H. Biotransformation of tramadol in man and animal (author's transl). Arzneimittel-Forschung. 1981;31(11):1932-1943.
- 46. Duthie D. Remifentanil and tramadol. British Journal of Anaesthesia. 1998;81(1):51-57.
- 47. Pang W-W, Mok MS, Chang D-P, Huang M-H. Local anesthetic effect of tramadol, metoclopramide, and lidocaine following intradermal injection. Regional Anesthesia and Pain Medicine. 1998;23(6):580-583.
- 48. Roberts L, Morrow J. The pharmacological basis of therapeutics. New York. 2001.
- 49. Leeder JS, Kearns GL. Pharmacogenetics in pediatrics: implications for practice. Pediatric Clinics of North America. 1997;44(1):55-77.
- 50. Wilder-Smith CH, Hill L, Osler W, O'Keefe S. Effect of tramadol and morphine on pain and gastrointestinal motor function in patients with chronic pancreatitis. Digestive diseases and sciences. 1999;44:1107-1116.
- 51. Scott LJ, Perry CM. Tramadol: a review of its use in perioperative pain. Drugs. 2000;60:139-176.
- 52. Bourne MH. Analgesics for orthopedic postoperative pain. American Journal of Orthopedics (Belle Mead, NJ). 2004;33(3):128-135.
- 53. Harati Y, Gooch C, Swenson M, Edelman S, Greene D, Raskin P, Donofrio P, Cornblath D, Sachdeo R, Siu C. Double‐blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998;50(6):1842-1846.
- 54. Sindrup SH, Andersen G, Madsen C, Smith T, Brøsen K, Jensen TS. Tramadol relieves pain and allodynia in polyneuropathy: a randomised, double-blind, controlled trial. Pain. 1999;83(1):85-90.
- 55. Wilder-Smith C, Hill L, Spargo K, Kalla A. Treatment of severe pain from osteoarthritis with slow-release tramadol or dihydrocodeine in combination with NSAID's: a randomised study comparing analgesia, antinociception and gastrointestinal effects. Pain. 2001;91(1-2):23-31.
- 56. Malonne H, Coffiner M, Sonet B, Sereno A, Vanderbist F. Efficacy and tolerability of sustained-release tramadolin the treatment of symptomatic osteoarthritis of the hip or knee: A multicenter, randomized, double-blind, placebo-controlled study. Clinical therapeutics. 2004;26(11):1774-1782.
- 57. Beltrán J, Martín-Mola E, Figueroa M, Granados J, Sanmartí R, Artigas R, Torres F, Forns M, Mauleón D. Comparison of dexketoprofen trometamol and ketoprofen in the treatment of osteoarthritis of the knee. The Journal of Clinical Pharmacology. 1998;38(S1):74S-80S.
- 58. Lewis KS, Han NH. Tramadol: a new centrally acting analgesic. American Journal of Health-System Pharmacy. 1997;54(6):643-652.
- 59. Leppert W. Tramadol as an analgesic for mild to moderate cancer pain. Pharmacological reports. 2009;61(6):978-992.
- 60. Reisli R. Kronik bel-boyun ağrılı hastada opioid analjezikler. TOTBİD Dergisi. 2017;16:139-147.
- 61. Teppema LJ, Olievier CN, Dahan A. Respiratory depression by tramadol: involvement of opioid receptors. ANESTHESIOLOGY-PHILADELPHIA THEN HAGERSTOWN-. 2000;93(3; SUPP/2):A1338-A1338
- 62. Nieuwenhuijs D, Bruce J, Drummond G, Warren P, Dahan A. Influence of oral tramadol on the dynamic ventilatory response to carbon dioxide in healthy volunteers. British journal of anaesthesia. 2001;87(6):860-865.
- 63. Warren P, Taylor J, Nicholson K, Wraith P, Drummond G. Influence of tramadol on the ventilatory response to hypoxia in humans. British journal of anaesthesia. 2000;85(2):211-216.
- 64. Tarkkila P, Tuominen M, Lindgren L. Comparison of respiratory effects of tramadol and pethidine. European journal of anaesthesiology. 1998;15(1):64-68.
- 65. Wu H, Wu G. In response: the cause of fatal respiratory depression is combination of clindamycin and fentanyl, rather than tramadol. Pain Physician. 2016;19(2):E362.
- 66. Houmes R-JM, Voets MA, Verkaaik A, Erdmann W, Lachmann B. Efficacy and safety of tramadol versus morphine for moderate and severe postoperative pain with special regard to respiratory depression. Anesthesia & Analgesia. 1992;74(4):510-514.
- 67. Barnung S, Treschow M, Borgbjerg F. Respiratory depression following oral tramadol in a patient with impaired renal function. Pain. 1997;71(1):111-112.
- 68. Barth H, Giertz H, Schmal A, Lorenz W. Anaphylactoid reactions and histamine release do not occur after application of the opioid tramadol. Agents and Actions. 1987;20(3-4):310-313.
- 69. Balcı C, Karabekir H, Sıvacı R, Toprak D, Ela Y, Pancaroğlu M. Lomber disk cerrahisi yapılan hastalarda postoperatif analjezide lornoksikam ve tramadolün hasta kontrollü analjezi yöntemi ile etkinliklerinin karşılaştırılması. Türk Anest Rean Der Dergisi. 2006;34(4):228-235.
- 70. Menteş Ö, Harlak A, Eryılmaz M, Balkan M, Kozak O, Arslan İ, Tufan CT. Laparoskopik kolesistektomi sonrası ağrı tedavisinde tramadolün devamlı infüzyon ve hasta kontrollü analjezi ile uygulanmasının karşılaştırılması. Gülhane Tıp Dergisi. 2009;51(1):6-10.
- 71. Eisenstein TK. The role of opioid receptors in immune system function. Frontiers in immunology. 2019;10:2904.
- 72. Tsai Y-C, Won S-J. Effects of tramadol on T lymphocyte proliferation and natural killer cell activity in rats with sciatic constriction injury. Pain. 2001;92(1-2):63-69.
- 73. Gaspani L, Bianchi M, Limiroli E, Panerai AE, Sacerdote P. The analgesic drug tramadol prevents the effect of surgery on natural killer cell activity and metastatic colonization in rats. Journal of neuroimmunology. 2002;129(1-2):18-24.
- 74. Sacerdote P, Bianchi M, Gaspani L, Manfredi B, Maucione A, Terno G, Ammatuna M, Panerai AE. The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients. Anesthesia & Analgesia. 2000;90(6):1411-1414.
- 75. Murphy D, Sutton A, Prescott L, Murphy M. A comparison of the effects of tramadol and morphine on gastric emptying in man. Anaesthesia. 1997;52(12):1224-1229.
- 76. Crighton IM, Martin PH, Hobbs GJ, Cobby TF, Fletcher AJ, Stewart PD. A comparison of the effects of intravenous tramadol, codeine, and morphine on gastric emptying in human volunteers. Anesthesia & Analgesia. 1998;87(2):445-449.
- 77. Committee F. FDC Reports (Pink Sheet). Prescription Pharmaceuticals and Biotechnology. 1998;60:4-5.
- 78. Black E, Khor KE, Kennedy D, Chutatape A, Sharma S, Vancaillie T, Demirkol A. Medication use and pain management in pregnancy: a critical review. Pain Practice. 2019;19(8):875-899.
- 79. Vazzana M, Andreani T, Fangueiro J, Faggio C, Silva C, Santini A, Garcia M, Silva A, Souto E. Tramadol hydrochloride: pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems. Biomedicine & Pharmacotherapy. 2015;70:234-238.
- 80. Akhtar MF, Younas S, Saleem A, Baig MMFA, Sharif A, Abdel‐Daim MM, Rasul A, Saleem M. Maternotoxicity and fetotoxicity in Rattus norvegicus albinus exposed to tramadol during the late phase of pregnancy. Birth Defects Research. 2021;113(19):1407-1421.
- 81. AL–Essawi DA-HK. Fetal Teratogenic and Histopathological Influences of Tramadol on White Rat Fetuses. Annals of the Romanian Society for Cell Biology. 2021:4747-4760.
- 82. de Swart IW, de Vries LC, van Puijenbroek EP. Tramadol exposure in the first trimester of pregnancy: A case series. Reproductive Toxicology. 2015(57):226.
- 83. Källén B, Reis M. Use of tramadol in early pregnancy and congenital malformation risk. Reproductive Toxicology. 2015;58:246-251.
- 84. Argoff CE, Viscusi ER. The use of opioid analgesics for chronic pain: minimizing the risk for harm. The American Journal of Gastroenterology Supplements. 2014;2(1):3.
- 85. Benyamin R, Trescot AM, Datta S, Buenaventura RM, Adlaka R, Sehgal N, Glaser SE, Vallejo R. Opioid complications and side effects. Pain physician. 2008;11(2S):S105.
- 86. Stone P, Minton O. European Palliative Care Research collaborative pain guidelines. Central side-effects management: what is the evidence to support best practice in the management of sedation, cognitive impairment and myoclonus? Palliative medicine. 2011;25(5):431-441.
- 87. Gasse MC, Derby L, Vasilakis‐Scaramozza C, Jick H. Incidence of first‐time idiopathic seizures in users of tramadol. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2000;20(6):629-634.
- 88. Lee SH, Cho SY, Lee HG, Choi J, Yoon MH, Kim WM. Tramadol induced paradoxical hyperalgesia. Pain Physician. 2013;16(1):41.
- 89. Nestler EJ. Molecular neurobiology of addiction. American Journal on Addictions. 2001;10(3):201-217.
- 90. Minami K, Ogata J, Horishita T, Shiraishi M, Okamoto T, Sata T, Shigematsu A. Intramuscular tramadol increases gastric pH during anesthesia. Canadian Journal of Anesthesia. 2004;51(6):545.
- 91. Ülker GS. İlaç etkileşmeleri ve advers ilaç reaksiyonlarına yaklaşım. 2012.
- 92. Boyd IW. Tramadol and seizures. Medical Journal of Australia. 2005;182(11):595-596.
- 93. Beakley BD, Kaye AM, Kaye AD. Tramadol, pharmacology, side effects, and serotonin syndrome: a review. Pain physician. 2015;18(4):395.
- 94. Jeppesen U, Gram L, Vistisen K, Loft S, Poulsen HE, Brøsen K. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. European journal of clinical pharmacology. 1996;51:73-78.
- 95. Jovanović-Čupić V, Martinović Ž, Nešić N. Seizures associated with intoxication and abuse of tramadol. Clinical toxicology. 2006;44(2):143-146.
- 96. Ripple MG, Pestaner JP, Levine BS, Smialek JE. Lethal combination of tramadol and multiple drugs affecting serotonin. The American journal of forensic medicine and pathology. 2000;21(4):370-374.
- 97. Walsh SL, Babalonis S. The abuse potential of prescription opioids in humans—closing in on the first century of research. Non-medical and illicit use of psychoactive drugs. 2017:33-58.
- 98. Uzbay T. Nöropsikofarmakoloji: Rasyonel ilaç kullanımı: Medikal Yayıncılık; 2007.
- 99. Budd K, Langford R. Tramadol revisited. British journal of anaesthesia. 1999;82(4):493-495.