Amany I. Ahmed, Khalifa El-Dawy, Medhat M. Fawzy, Haytham A. Abdallah, Heba N. Abd Elsaid, Wessam O. Elmesslamy


In the Egyptian community, tramadol abuse is considered an increasingly alarming phenomenon. The popularity and massive use of tramadol especially among Egyptian youth contribute to alleged usages for treatment of premature ejaculation also for the extension of orgasm and also increase sexual pleasure as it available in many online drug media and stores. However, this abuser life on a blade of a knife and is susceptible to another sexual dysfunction, memory and learning disorder and different metabolic disorders. This literature consults the phenomenon of tramadol abuse and its relation to sexual function, memory learning disorder and other metabolic disorders. It could be concluded that the increase in the prevalence of tramadol HCl dependency over other substances in the Egyptian community, calls for paying more attention from family, health and educational institutes. Tramadol may apply a very useful intervention for treating premature ejaculation, but its abuse bad effect may supply a possible demonstration for the unexplained delayed fertility as well as behavioral and the associated psychological changes. Also it could involve malfunction of the cerebral cortex which includes deficits in memory and the reduction in cognitive function which appeared in chronic abusers of tramadol.

Key words: tramadol; abuse; apoptosis; oxidative stress; cognitive

Full Text:



(1) Babalonis S, Lofwall MR, Nuzzo PA, Siegel AJ, Walsh SL. Abuse liability and reinforcing efficacy of oral tramadol in humans. Drug Alcohol Depend. 2013; 129: 116–24.

(2) Stoops WW, Lofwall MR, Nuzzo PA, Craig LB, Siegel AJ, Walsh SL. Pharmacodynamic profile of tramadol in humans: Influence of naltrexone pretreatment. Psychopharmacology (Berl). 2012; 223: 427–38.

(3) Knisely JS, Campbell ED, Dawson KS, Schnoll SH. Tramadol post-marketing surveillance in health care professionals. Drug Alcohol Depend. 2002; 68: 15–22.

(4) Abdel-Hamid IA, Andersson K-E, Waldinger MD, Anis TH. Tramadol abuse and sexual function. SMR. 2016; 4: 235–46.

(5) Martyn-St James M, Cooper K, Kaltenthaler E, Dickinson K, Cantrell A, Wylie K, Frodsham L, Hood C. Tramadol for premature ejaculation: A systematic review and meta-analysis. BMC Urol. 2015; 15: 6.

(6) Alghobary M, El‐Bayoumy Y, Mostafa Y, Mahmoud EHM, Amr M. Evaluation of tramadol on demand vs. Daily paroxetine as a long‐term treatment of lifelong premature ejaculation. JSM. 2010; 7: 2860–7.

(7) El-Hadidy MA, El-Gilany A-H. Physical and sexual well-being during and after tramadol dependence. MECPsych. 2014; 21: 148-51.

(8) Abdellatief R, Elgamal D, Mohamed E. Effects of chronic tramadol administration on testicular tissue in rats: An experimental study. Andrologia. 2015; 47: 674–9.

(9) Al-Fannah J, Bourin M, Brands B, Buitrago R, Dodoo A, Elliott S, Mahlangu G, Noveria P, Pennings E, Razaghi E. Who expert committee on drug dependence thirty-sixth report introduction. Who expert committee on drug dependence: thirty-sixth report. 2015; 991: 1–50.

(10) Smith SM, Dart RC, Katz NP, Paillard F, Adams EH, Comer SD, Degroot A, Edwards RR, Haddox JD, Jaffe JH. Classification and definition of misuse, abuse, and related events in clinical trials: Acttion systematic review and recommendations. PAIN®. 2013; 154: 2287–96.

(11) Butler S. The immpact factor or immpact strikes again! Pain. 2013; 154: 2243–4.

(12) Sullivan M. Clarifying opioid misuse and abuse. Pain. 2013; 154: 2239–40.

(13) Radbruch L, Glaeske G, Grond S, Münchberg F, Scherbaum N, Storz E, Tholen K, Zagermann-Muncke P, Zieglgänsberger W, Hoffmann-Menzel H. Topical review on the abuse and misuse potential of tramadol and tilidine in germany. Subst Abus. 2013; 34: 313–20.

(14) Sairam Atluri G, ManchikantI L. Assessment of the trends in medical use and misuse of opioid analgesics from 2004 to 2011. ASIPP. 2014; 17: E119-E28.

(15) O'connor EC, Mead AN. Tramadol acts as a weak reinforcer in the rat self-administration model, consistent with its low abuse liability in humans. Pharmacol., Biochem. Behav. 2010; 96: 279–86.

(16) Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL. Opioid and nonopioid components independently contribute to the mech-anism of action of tramadol, an'atypical'opioid ana-lgesic. J Pharmacol Exp Ther. 1992; 260: 275–85.

(17) Hamdi E, Gawad T, Khoweiled A, Sidrak AE, Amer D, Mamdouh R, Fathi H, Loza N. Lifetime prevalence of alcohol and substance use in egypt: A community survey. Subst Abus. 2013; 34: 97–104.

(18) Mohamed NR, Hammad SA, El Hamrawy LG, Rajab AZ, El Bahy MS, Soltan MR. Dual diagnosis and psychosocial correlates in substance abuse in menoufia, egypt. Menoufia Med J. 2013; 26: 114.

(19) Bassiony MM, Salah El-Deen GM, Yousef U, Raya Y, Abdel-Ghani MM, El-Gohari H, Atwa SA. Adolescent tramadol use and abuse in egypt. The Am j drug . alco. abuse. 2015; 41: 206–11.

(20) Asaad T, Barakat D, Elwasify M, Aziz KA, Elwasify M, El-Gabry DA. Screening for obstructive sleep apnoea in patients with treatment-resistant depression: A case–control study. MECPsych. 2018; 25: 57–63.

(21) Brownfield WR. International narcotics control strategy report: Volume i: Drug and chemical control: DIANE Publishing; 2011.

(22) Salem EA, Delk JR, Wilson SK, Bissada NK, Hellstrom WJ, Cleves MA. 1043: Tramadol hcl has promise in on demand use to treat premature ejaculation. JU. 2007; 177: 345.

(23) Mohamed NR, El Hamrawy LG, Shalaby AS, El Bahy MS, Allah MMA. An epidemiological study of tramadol hcl dependence in an outpatient addiction clinic at heliopolis psychiatric hospital. Menoufia Med J. 2015; 28: 591.

(24) Hatata HA, Khalil A, Asaad T. Dual diagnosis in substance use disorders. An Egyptian study MD thesis Egypt: Faculty of Medicine, Ain Shams University. 2004.

(25) Organization WH. Neuroscience of psychoactive substance use and dependence: WHO; 2004.

(26) Abolmagd S, Nasr A, Erfan S, Mamdouh R, El-Lawendi M. A group of egyptian addicts: Users view for addiction causes and its impact on self and family. EJ P. 2004; 23: 145–58.

(27) Okasha A. Long term strategy of addressing narcotics-an arab-egyptian perspective. Read at the Royal College of Psychiatrists in Jordan, Amman. 2000.

(28) Hafeiz H. Socio-demographic correlates and pattern of drug abuse in eastern saudi arabia. Drug Alcohol Depend. 1995; 38: 255–9.

(29) Kaye AD. Tramadol, pharmacology, side effects, and serotonin syndrome: A review. ASIPP. 2015; 18: 395–400.

(30) Lintz W, Barth H, Becker R, Frankus E, Schmidt-Böthelt E. Pharmacokinetics of tramadol and bioavailability of enteral tramadol formula-tions. 2nd communication: Drops with ethanol. Arzneimittelforschung. 1998; 48: 436–45.

(31) Zhang H, Zhao Y, Wang X, Zhang Q. Bioavailability of tramadol hydrochloride after administration via different routes in rats. Biopharm Drug Dispos. 2014; 35: 525–31.

(32) Raber M, Schulz H-U, Schürer M, Krupp S, Momberger H. Pharmacokinetic properties of tramadol sustained release capsules. Arzneimittel-forschung. 1999; 49: 594–8.

(33) Cnota PJ, Nowak H, Tagarro I, Erb K, Schürer M, Schulz H-U, Maus J. Tramadol sr formulations. Clin Drug Investig. 2005; 25: 435–43.

(34) Stamer U, Musshoff F, Kobilay M, Madea B, Hoeft A, Stuber F. Concentrations of tramadol and o‐desmethyltramadol enantiomers in different cyp2d6 genotypes. Clin Pharmacol Ther. 2007; 82: 41–7.

(35) Wu W, McKown L, Liao S. Metabolism of the analgesic drug ultram® (tramadol hydrochloride) in humans: Api-ms and ms/ms characterization of metabolites. Xenobiotica. 2002; 32: 411–25.

(36) Gong L, Stamer UM, Tzvetkov MV, Altman RB, Klein TE. Pharmgkb summary: Tramadol pathway. Pharmacogenet Genomics. 2014; 24: 374.

(37) Lintz W, Erlacin S, Frankus E, Uragg H. Biotransformation of tramadol in man and animal (author's transl). Arzneimittelforschung. 1981; 31: 1932–43.

(38) Lintz W, Barth H, Osterloh G, Schmidt-Böthelt E. Bioavailability of enteral tramadol formulations. 1st communication: Capsules. Arzneimittelforschung. 1986; 36: 1278–83.

(39) Vazzana M, Andreani T, Fangueiro J, Faggio C, Silva C, Santini A, Garcia M, Silva A, Souto E. Tramadol hydrochloride: Pharmaco-kinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems. Biomed Pharmacother. 2015; 70: 234–8.

(40) Minami K, Ogata J, Uezono Y. What is the main mechanism of tramadol? Naunyn-Schmiedeberg's archives of pharmacology. 2015; 388: 999-1007.

(41) Raffa RB. Basic pharmacology relevant to drug abuse assessment: Tramadol as example. J Clin Pharm Ther. 2008; 33: 101–8.

(42) Epstein DH, Preston KL, Jasinski DR. Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: Lessons from tramadol. Biol Psychol. 2006; 73: 90–9.

(43) Smith HS, editor Opioid metabolism. Mayo Clin Proc; 2009: Elsevier.

(44) Camí J, Lamas X, Farre M. Acute effects of tramadol in methadone-maintained volunteers. Drugs. 1994; 47: 39–43.

(45) Duke AN, Bigelow GE, Lanier RK, Strain EC. Discriminative stimulus effects of tramadol in humans. J Pharmacol Exp Ther. 2011; 338: 255–62.

(46) Gobbi M, Mennini T. Release studies with rat brain cortical synaptosomes indicate that tramadol is a 5-hydroxytryptamine uptake blocker and not a 5-hydroxytryptamine releaser. Eur J Pharmacol. 1999; 370: 23–6.

(47) Franceschini D, Lipartiti M, Giusti P. Effect of acute and chronic tramadol on [3h]-norepinephrine-uptake in rat cortical synaptosomes. Prog Neuropsychopharmacol Biol Psychiatry. 1999; 23: 485-96.

(48) Ogata J, Minami K, Uezono Y, Okamoto T, Shiraishi M, Shigematsu A, Ueta Y. The inhibitory effects of tramadol on 5-hydroxytryptamine type 2c receptors expressed in xenopus oocytes. Anesth Analg. 2004; 98: 1401–6.

(49) Shiraishi M, Minami K, Uezono Y, Yanagihara N, Shigematsu A, Shibuya I. Inhibitory effects of tramadol on nicotinic acetylcholine receptors in adrenal chromaffin cells and in xenopus oocytes expressing α7 receptors. Br J Pharmacol. 2002; 136: 207–16.

(50) Hara K, Minami K, Sata T. The effects of tramadol and its metabolite on glycine, γ-aminobutyric acida, and n-methyl-d-aspartate receptors expressed in xenopus oocytes. Anesth Analg. 2005; 100: 1400–5.

(51) Nakamura M, Minami K, Uezono Y, Horishita T, Ogata J, Shiraishi M, Okamoto T, Terada T, Sata T. The effects of the tramadol metabolite o-desmethyl tramadol on muscarinic receptor-induced responses in xenopus oocytes expressing cloned m1 or m3 receptors. Anesth Analg. 2005; 101: 180–6.

(52) Mostafa G, Mohamad MF, Bakry RM, Farrag WS. Effect of tramadol and ropivacaine infiltration on plasma catecholamine and postoperative pain. J Am sci. 2011; 7: 473–79.

(53) Miyano K, Minami K, Yokoyama T, Ohbuchi K, Yamaguchi T, Murakami S, Shiraishi S, Yamamoto M, Matoba M, Uezono Y. Tramadol and its metabolite m1 selectively suppress transient receptor potential ankyrin 1 activity, but not transient receptor potential vanilloid 1 activity. Anesth Analg. 2015; 120: 790–8.

(54) Isiordia‐Espinoza MA, Pozos‐Guillén A, Pérez‐Urizar J, Chavarría‐Bolaños D. Involvement of nitric oxide and atp‐sensitive potassium channels in the peripheral antinoceptive action of a tramadol–dexketoprofen combination in the formalin test. Drug dev res. 2014; 75: 449–54.

(55) Marincsák R, Tóth BI, Czifra G, Szabó T, Kovács L, Bíró T. The analgesic drug, tramadol, acts as an agonist of the transient receptor potential vanilloid-1. Anesth Analg. 2008; 106: 1890–6.

(56) Bodera P, Stankiewicz W, Zawada K, Antkowiak B, Paluch M, Kieliszek J, Kalicki B, Bartosiński A, Wawer I. Changes in antioxidant capacity of blood due to mutual action of electromagnetic field (1800 mhz) and opioid drug (tramadol) in animal model of persistent in-flammatory state. Pharmacol Rep. 2013; 65: 421–8.

(57) Bajic D, Berde CB, Commons KG. Periaqueductal gray neuroplasticity following chronic morphine varies with age: Role of oxidative stress. Neuroscience. 2012; 226: 165–77.

(58) Sharifipour M, Izadpanah E, Nikkhoo B, Zare S, Abdolmaleki A, Hassanzadeh K, Moradi F, Hassanzadeh K. A new pharmacological role for donepezil: Attenuation of morphine-induced tolerance and apoptosis in rat central nervous system. J Biomed Sci. 2014; 21: 6.

(59) Hassanzadeh K, Habibi-asl B, Farajnia S, Roshangar L. Minocycline prevents morphine indu-ced apoptosis in rat cerebral cortex and lumbar spin-al cord: A possible mechanism for attenuating mor-phine tolerance. Neurotox Res. 2011; 19: 649–59.

(60) Popovic M, Janicijevic-Hudomal S, Kaurinovic B, Rasic J, Trivic S, Vojnović M. Antioxidant effects of some drugs on immobilization stress combined with cold restraint stress. Molecules. 2009; 14: 4505–16.

(61) (61) Zhang, Y Z, Qiu-Sheng P, Jing Z, Rong-Liang. Oxidative damage of biomolecules in mouse liver induced by morphine and protected by antioxidants. Basic clin pharmacol toxicol.2004; 95: 53–58

(62) Ghoneim FM, Khalaf HA, Elsamanoudy AZ, Helaly AN. Effect of chronic usage of tramadol on motor cerebral cortex and testicular tissues of adult male albino rats and the effect of its withdrawal: Histological, immunohistochemical and biochemical study. Int J Clin Exp Pathol. 2014; 7: 7323.

(63) Nna V, Akpan U, Osim E. Hyperpro-lactinemia contributes to reproductive deficit in male rats chronically administered pde5 inhibitors (sildenafil and tadalafil) and opioid (tramadol). APJR. 2016; 5: 381–6.

(64) Lemarie A, Grimm S. Mutations in the heme b-binding residue of sdhc inhibit assembly of respiratory chain complex ii in mammalian cells. Mitochondrion. 2009; 9: 254–60.

(65) Mohamed TM, Ghaffar HMA, El Husseiny RM. Effects of tramadol, clonazepam, and their combination on brain mitochondrial complexes. Toxicol Ind Health. 2015; 31: 1325–33.

(66) Butterfield DA, Castegna A, Lauderback CM, Drake J. Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in alzheimer’s disease brain contribute to neuronal death. Neurobiol Aging. 2002; 23: 655–64.

(67) Abdel-Zaher AO, Abdel-Rahman MS, ELwasei FM. Protective effect of nigella sativa oil against tramadol-induced tolerance and dependence in mice: Role of nitric oxide and oxidative stress. Neurotoxicology. 2011; 32: 725–33.

(68) Butterfield DA, Reed T, Newman SF, Sultana R. Roles of amyloid β-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of alzheimer's disease and mild cognitive impairment. Free Radic Biol Med. 2007; 43: 658–77.

(69) Kanter M. Nigella sativa and derived thy-moquinone prevents hippocampal neurodegenera-tion after chronic toluene exposure in rats. Neuro-chem Res. 2008; 33: 579.

(70) Rabei HM. The immunological and histopathological changes of tramadol, tramadol/acetaminophen and acetaminophen in male albino rats: Comparative study. The Egyptian Journal of Hospital Medicine. 2011; 31: 1–56.

(71) Alici HA, Ozmen I, Cesur M, Sahin F. Effect of the spinal drug tramadol on the fatty acid compositions of rabbit spinal cord and brain. Biol Pharm Bull. 2003; 26: 1403–6.

(72) Ahmed MA, Kurkar A. Effects of opioid (tramadol) treatment on testicular functions in adult male rats: The role of nitric oxide and oxidative str-ess. Clin Exp Pharmacol Physiol. 2014; 41: 317–23.

(73) Liu L-W, Lu J, Wang X-H, Fu S-K, Li Q, Lin F-Q. Neuronal apoptosis in morphine addiction and its molecular mechanism. Int J Clin Exp Med. 2013; 6: 540.

(74) Atici S, Cinel L, Cinel I, Doruk N, Aktekin M, Akca A, Camdeviren H, Oral U. Opioid neurotoxicity: Comparison of morphine and tramadol in an experimental rat model. Int J Neurosci. 2004; 114: 1001–11.

(75) Heidari Z, Mahmoudzadeh-Sagheb H, Kohan F. A quantitative and qualitative study of rat testis following administration of methadone and buprenorphine. Int J High Risk Behav Addict. 2012; 1: 12–5.

(76) Azmy SM, El-Rahman SSA, Nada SA, Salam OMA, El-Yamany MF, Nassar NN. Does nicotine impact tramadol abuse? Insights from neurochemical and neurobehavioral changes in mice. Neurotoxicology. 2018.

(77) Lees G. Inhibition of sodium-potassium-atpase: A potentially ubiquitous mechanism contri-buting to central nervous system neuropathology. Brain Res Rev. 1991; 16: 283–300.

(78) Elwy AE-HM, Tabl G. Impact of tramadol and morphine abuse on the activities of acetylcholine esterase, Na+/K+-atpase and related parameters in cerebral cortices of male adult rats. Electron physician. 2017; 9: 4027.

(79) de Souza Wyse AT, Streck EL, Worm P, Wajner A, Ritter F, Netto CA. Preconditioning prevents the inhibition of Na+, K+-atpase activity after brain ischemia. Neurochem Res. 2000; 25: 971–5.

(80) Horvat A, Momic T, Petrovic S, Nikezic G, Demajo M. Selective inhibition of brain Na, K-atpase by drugs. Physiol Res. 2006; 55: 325.

(81) Baghishani F, Mohammadipour A, Hosseinzadeh H, Hosseini M, Ebrahimzadeh-bideskan A. The effects of tramadol administration on hippocampal cell apoptosis, learning and memory in adult rats and neuroprotective effects of crocin. Metab Brain Dis. 2018: 1–10.

(82) Baghishani F, Mohammadipour A, Hosseinzadeh H, Hosseini M, Ebrahimzadeh-bideskan A. The effects of tramadol administration on hippocampal cell apoptosis, learning and memory in adult rats and neuroprotective effects of crocin. Metab Brain Dis. 2018; 33: 907–16.

(83) Senay EC, Adams EH, Geller A, Inciardi JA, Munoz A, Schnoll SH, Woody GE, Cicero TJ. Physical dependence on ultram® (tramadol hydrochloride): Both opioid-like and atypical withdrawal symptoms occur. Drug Alcohol Depend. 2003; 69: 233–41.

(84) Inass E, Hassan M, Fouad G, El-Komey F. Toxic effects of paroxetine on sexual and reproductive functions of rats. Egyptian Journal of Hospital Medicine. 2005; 21: 16–32.

(85) Loughrey M, Loughrey C, Johnston S, O’Rourke D. Fatal hepatic failure following accidental tramadol overdose. Forensic Sci Int. 2003; 134: 232–3.

(86) Elkhateeb A, El Khishin I, Megahed O, Mazen F. Effect of nigella sativa linn oil on tramadol-induced hepato-and nephrotoxicity in ad-ult male albino rats. Toxicol Rep. 2015; 2: 512–9.

(87) Atici S, Cinel I, Cinel L, Doruk N, Eskandari G, Oral U. Liver and kidney toxicity in chronic use of opioids: An experimental long term treatment model. J Biosci. 2005; 30: 245–52.

(88) Awadalla EA, Salah-Eldin A-E. Histopathological and molecular studies on tramadol mediated hepato-renal toxicity in rats. J Pharm Biol Sci. 2015; 10: 90–102.

(89) Boshra V. Evaluation of osteoporosis risk associated with chronic use of morphine, fentanyl and tramadol in adult female rats. Curr drug saf. 2011; 6: 159–63.

(90) Garcia AN, Salloum IM. Polysomnogra-phic sleep disturbances in nicotine, caffeine, alc-ohol, cocaine, opioid, and cannabis use: A focused review. Am j addict. 2015; 24: 590–8.

(91) Bohra MH, Kaushik C, Temple D, Chung SA, Shapiro CM. Weighing the balance: How analgesics used in chronic pain influence sleep? Br j pain. 2014; 8: 107–18.

(92) Pattinson K. Opioids and the control of respiration. Br J Anaesth. 2008; 100: 747–58.

(93) Panagiotou I, Mystakidou K. Non-analgesic effects of opioids: Opioids’ effects on sleep (including sleep apnea). Curr Pharm Des. 2012; 18: 6025–33.

(94) Walder B, Tramer M, Blois R. The effects of two single doses of tramadol on sleep: A randomized, cross-over trial in healthy volunteers. Eur J Anaesthesiol. 2001; 18: 36–42.

(95) Hassanian-Moghaddam H, Kolahi A, editors. Tramadol intoxication/abuse: A new issue on high-access population. Sixth Annual Congress of Asia Pacific Association of Medical Toxicology; 2007.

(96) Tjäderborn M, Jönsson AK, Hägg S, Ahlner J. Fatal unintentional intoxications with tramadol during 1995–2005. Forensic Sci Int. 2007; 173: 107–11.

(97) Simonsen KW, Edvardsen HME, Thelander G, Ojanperä I, Thordardottir S, Andersen LV, Kriikku P, Vindenes V, Christoffersen D, Delaveris GJM. Fatal poisoning in drug addicts in the nordic countries in 2012. Forensic Sci Int. 2015; 248: 172–80.

(98) Awadalla EA, Salah-Eldin A-E. Molecular and histological changes in cerebral cortex and lung tissues under the effect of tramadol treatment. Biomed Pharmacother. 2016; 82: 269–80.

(99) Alizadeh-Ghamsari A, Dadpour B, Najari F. Pathological findings of tramadol on liver tissue in the cadaver referred to legal medicine organization of tehran 2008-2013. I JMTFM. 2016; 6: 59–64.



  • There are currently no refbacks.