, Volume 235, Issue 9, pp 2631–2642 | Cite as

Acute tramadol enhances brain activity associated with reward anticipation in the nucleus accumbens

  • Yuki Asari
  • Yumiko Ikeda
  • Amane Tateno
  • Yoshiro Okubo
  • Takehiko Iijima
  • Hidenori SuzukiEmail author
Original Investigation



Tramadol is an analgesic with monoamine reuptake inhibition and μ-opioid receptor activation. Although tramadol has been widely used for treatment of various pain conditions, there is controversy over the risk of abuse potential. We examined the effects of tramadol on the reward system in humans using functional magnetic resonance imaging (fMRI) to assess the potential of tramadol for drug abuse or dependence.


A randomized, double-blind, placebo-controlled, crossover study was conducted for 19 healthy adults under tramadol or placebo. In association with subjective mood questionnaires, monetary incentive delay (MID) task was performed to assess the neural response to reward anticipation during fMRI. Subjective mood measures and blood oxygenation level-dependent (BOLD) signal during gain and loss anticipation were compared between tramadol and placebo.


Tramadol significantly reduced anxiety (Z = − 2.513, p = 0.012) and enhanced vigor (Z = − 2.725, p = 0.006) compared with placebo. By Mood Rating Scale, tramadol provoked contented (Z = − 2.316, p = 0.021), relaxed (Z = − 2.236, p = 0.025), and amicable feelings (Z = − 2.015, p = 0.044) as well as increased alertness (Z = − 1.972, p = 0.049) and contentedness domains (Z = − 2.174, p = 0.030) compared with placebo. Several brain regions including nucleus accumbens (NAc) were activated during gain anticipation in the MID task under both tramadol and placebo. Tramadol increased the %BOLD signal change in NAc at +¥500 cue significantly more than the placebo (Z = − 2.295, p = 0.022).


Tramadol enhances the reward system and thereby may have abuse potential or precipitate drug abuse in human.


Drug abuse fMRI Monetary incentive delay task Nucleus accumbens Reward system Tramadol 



The authors are entirely responsible for the scientific content of this paper. We are thankful to the Clinical Imaging Center for Healthcare, Nippon Medical School, for their support. In particular, we thank Koji Nagaya, Megumi Hongo, Koji Kanaya, Masaya Suda, Minoru Sakurai, Satoe Aoyama, and Aiko Abe for their technical assistance with the MRI examinations and Michiyo Tamura for research assistance. We also thank Dr. Gerz for his English editing of the manuscript.

Compliance with ethical standards

All participants gave written informed consent, and the study was approved by the ethics committee of Nippon Medical School (approval number 226018).

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Abdel-Ghany R, Nabil M, Abdel-Aal M, Barakat W (2015) Nalbuphine could decrease the rewarding effect induced by tramadol in mice while enhancing its antinociceptive activity. Eur J Pharmacol 758:11–15. CrossRefGoogle Scholar
  2. Babalonis S, Lofwall MR, Nuzzo PA, Siegel AJ, Walsh SL (2013) Abuse liability and reinforcing efficacy of oral tramadol in humans. Drug Alcohol Depend 129:116–124. CrossRefGoogle Scholar
  3. Balodis IM, Potenza MN (2015) Anticipatory reward processing in addicted populations: a focus on the monetary incentive delay task. Biol Psychiatry 77:434–444. CrossRefGoogle Scholar
  4. Barrot M (2015) Ineffective VTA disinhibition in protracted opiate withdrawal. Trends Neurosci 38:672–673. CrossRefGoogle Scholar
  5. Bassiony MM, Youssef UM, Hassan MS, Salah El-Deen GM, El-Gohari H, Abdelghani M, Abdalla A, Ibrahim DH (2017) Cognitive impairment and tramadol dependence. J Clin Psychopharmacol 37:61–66. CrossRefGoogle Scholar
  6. Beakley BD, Kaye AM, Kaye AD (2015) Tramadol, pharmacology, side effects, and serotonin syndrome: a review. Pain Physician 18:395–400Google Scholar
  7. Beck AT, Steer RA, Brown GK (1996) Manual for the Beck Depression Inventory, 2nd edn. Pearson, TexasGoogle Scholar
  8. Becker JB (2016) Sex differences in addiction. Dialogues Clin Neurosci 18:395–402PubMedPubMedCentralGoogle Scholar
  9. Bond A, Lader M (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47:211–218. CrossRefGoogle Scholar
  10. Bromberg-Martin ES, Matsumoto M, Hikosaka O (2010) Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 68:815–834. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Buckholtz JW, Treadway MT, Cowan RL, Woodward ND, Benning SD, Li R, Ansari MS, Baldwin RM, Schwartzman AN, Shelby ES, Smith CE, Cole D, Kessler RM, Zald DH (2010) Mesolimbic dopamine reward system hypersensitivity in individuals with psychopathic traits. Nat Neurosci 13:419–421. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Bustamante JC, Barrós-Loscertales A, Costumero V, Fuentes-Claramonte P, Rosell-Negre P, Ventura-Campos N, Llopis JJ, Ávila C (2014) Abstinence duration modulates striatal functioning during monetary reward processing in cocaine patients. Addict Biol 19:885–894. CrossRefGoogle Scholar
  13. Bymaster FP, Zhang W, Carter PA, Shaw J, Chernet E, Phebus L, Wong DT, Perry KW (2002) Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex. Psychopharmacology 160:353–361. CrossRefGoogle Scholar
  14. Castelli MP, Spiga S, Perra A, Madeddu C, Mulas G, Ennas MG, Gessa GL (2016) α2A adrenergic receptors highly expressed in mesoprefrontal dopamine neuron. Neuroscience 332:130–139. CrossRefGoogle Scholar
  15. De Deurwaerdère P, Di Giovanni G (2017) Serotonergic modulation of the activity of mesencephalic dopaminergic systems: therapeutic implications. Prog Neurobiol 151:175–236. CrossRefGoogle Scholar
  16. Delfs JM, Kong H, Mestek A, Chen Y, Yu L, Reisine T, Chesselet MF (1994) Expression of mu opioid receptor mRNA in rat brain: an in situ hybridization study at the single cell level. J Comp Neurol 345:46–68. CrossRefGoogle Scholar
  17. Delfs JM, Zhu Y, Druhan JP, Aston-Jones GS (1998) Origin of noradrenergic afferents to the shell subregion of the nucleus accumbens: anterograde and retrograde tract-tracing studies in the rat. Brain Res 806:127–140. CrossRefGoogle Scholar
  18. Di Mascio M, Di Giovanni G, Di Matteo V, Prisco S, Esposito E (1998) Selective serotonin reuptake inhibitors reduce the spontaneous activity of dopaminergic neurons in the ventral tegmental area. Brain Res Bull 46:547–554. CrossRefGoogle Scholar
  19. Dremencov E, El Mansari M, Blier P (2009) Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area. J Psychiatry Neurosci 34:223–229PubMedPubMedCentralGoogle Scholar
  20. Epstein DH, Preston KL, Jasinski DR (2006) Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: lessons from tramadol. Biol Psychol 73:90–99. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Faron-Górecka A, Kuśmider M, Inan SY, Siwanowicz J, Dziedzicka-Wasylewska M (2004a) Effects of tramadol on α2-adrenergic receptors in the rat brain. Brain Res 1016:263–267. CrossRefGoogle Scholar
  22. Faron-Górecka A, Kuśmider M, Inan SY, Siwanowicz J, Piwowarczyk T, Dziedzicka-Wasylewska M (2004b) Long-term exposure of rats to tramadol alters brain dopamine and α1-adrenoceptor function that may be related to antidepressant potency. Eur J Pharmacol 501:103–110. CrossRefGoogle Scholar
  23. Frink MC, Hennies HH, Englberger W, Haurand M, Wilffert B (1996) Influence of tramadol on neurotransmitter systems of the rat brain. Arzneimittelforschung 46:1029–1036Google Scholar
  24. Funayama T, Ikeda Y, Tateno A, Takahashi H, Okubo Y, Fukayama H, Suzuki H (2014) Modafinil augments brain activation associated with reward anticipation in the nucleus accumbens. Psychopharmacology 231:3217–3228. CrossRefGoogle Scholar
  25. Garzón M, Pickel VM (2001) Plasmalemmal μ-opioid receptor distribution mainly in nondopaminergic neurons in the rat ventral tegmental area. Synapse 41:311–328. CrossRefGoogle Scholar
  26. Gianoulakis C (2009) Endogenous opioids and addiction to alcohol and other drugs of abuse. Curr Top Med Chem 9:999–1015. CrossRefGoogle Scholar
  27. Goertz RB, Wanat MJ, Gomez JA, Brown ZJ, Phillips PE, Paladini CA (2015) Cocaine increases dopaminergic neuron and motor activity via midbrain α1 adrenergic signaling. Neuropsychopharmacology 40:1151–1162. CrossRefGoogle Scholar
  28. Grenhoff J, Svensson TH (1993) Prazosin modulates the firing pattern of dopamine neurons in rat ventral tegmental area. Eur J Pharmacol 233:79–84. CrossRefGoogle Scholar
  29. Grond S, Sablotzki A (2004) Clinical pharmacology of tramadol. Clin Pharmacokinet 43:879–923. CrossRefGoogle Scholar
  30. Haber SN, Knutson B (2010) The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology 35:4–26. CrossRefGoogle Scholar
  31. Hall FS, Sora I, Uhl GR (2001) Ethanol consumption and reward are decreased in μ-opiate receptor knockout mice. Psychopharmacology 154:43–49. CrossRefGoogle Scholar
  32. Hayes DJ, Greenshaw AJ (2011) 5-HT receptors and reward-related behaviour: a review. Neurosci Biobehav Rev 35:1419–1449. CrossRefGoogle Scholar
  33. Hervé D, Pickel VM, Joh TH, Beaudet A (1987) Serotonin axon terminals in the ventral tegmental area of the rat: fine structure and synaptic input to dopaminergic neurons. Brain Res 435:71–83. CrossRefGoogle Scholar
  34. Hidano T, Fukuhara M, Iwawaki M, Soga S, Spielberger CD (2000) State-trait anxiety inventory—form JYZ. Jitsumukyoiku Shuppan, TokyoGoogle Scholar
  35. Howell LL, Cunningham KA (2015) Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder. Pharmacol Rev 67:176–197. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Hui-Chen L, Yang Y, Na W, Ming D, Jian-Fang L, Hong-Yuan X (2004) Pharmacokinetics of the enantiomers of trans-tramadol and its active metabolite, trans-O-demethyltramadol, in healthy male and female Chinese volunteers. Chirality 16:112–118. CrossRefGoogle Scholar
  37. Ichikawa J, Meltzer HY (1995) Effect of antidepressants on striatal and accumbens extracellular dopamine levels. Eur J Pharmacol 281:255–261. CrossRefGoogle Scholar
  38. Jalabert M, Bourdy R, Courtin J, Veinante P, Manzoni OJ, Barrot M, Georges F (2011) Neuronal circuits underlying acute morphine action on dopamine neurons. Proc Natl Acad Sci U S A 108:16446–16450. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Kawahara H, Kawahara Y, Westerink BH (2001) The noradrenaline-dopamine interaction in the rat medial prefrontal cortex studied by multi-probe microdialysis. Eur J Pharmacol 418:177–186. CrossRefGoogle Scholar
  40. Knutson B, Adams CM, Fong GW, Hommer D (2001) Anticipation of increasing monetary reward selectively recruits nucleus accumbens. J Neurosci 21:RC159CrossRefGoogle Scholar
  41. Knutson B, Bjork JM, Fong GW, Hommer D, Mattay VS, Weinberger DR (2004) Amphetamine modulates human incentive processing. Neuron 43:261–269. CrossRefGoogle Scholar
  42. Knutson B, Bhanji JP, Cooney RE, Atlas LY, Gotlib IH (2008) Neural responses to monetary incentives in major depression. Biol Psychiatry 63:686–692. CrossRefGoogle Scholar
  43. Kojima M, Furukawa TA (2003) Japanese manual of the Beck Depression Inventory, 2nd edn. Nihon Bunka Kagakusha, TokyoGoogle Scholar
  44. McNair DM, Lorr M, Droppleman LF (1992) Profile of mood states. Educational and industrial testing service, San DiegoGoogle Scholar
  45. Mejías-Aponte CA, Drouin C, Aston-Jones G (2009) Adrenergic and noradrenergic innervation of the midbrain ventral tegmental area and retrorubral field: prominent inputs from medullary homeostatic centers. J Neurosci 29:3613–3626. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Minami K, Ogata J, Uezono Y (2015) What is the main mechanism of tramadol? Naunyn Schmiedeberg's Arch Pharmacol 388:999–1007. CrossRefGoogle Scholar
  47. Miotto K, Cho AK, Khalil MA, Blanco K, Sasaki JD, Rawson R (2017) Trends in tramadol: pharmacology, metabolism, and misuse. Anesth Analg 124:44–51. CrossRefGoogle Scholar
  48. Mitrano DA, Schroeder JP, Smith Y, Cortright JJ, Bubula N, Vezina P, Weinshenker D (2012) Alpha-1 adrenergic receptors are localized on presynaptic elements in the nucleus accumbens and regulate mesolimbic dopamine transmission. Neuropsychopharmacology 37:2161–2172. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Munro CA, McCaul ME, Wong DF, Oswald LM, Zhou Y, Brasic J, Kuwabara H, Kumar A, Alexander M, Ye W, Wand GS (2006) Sex differences in striatal dopamine release in healthy adults. Biol Psychiatry 59:966–974. CrossRefGoogle Scholar
  50. Murai T, Yoshida Y, Koide S, Takada K, Misaki T, Koshikawa N, Cools AR (1998) Clonidine reduces dopamine and increases GABA in the nucleus accumbens: an in vivo microdialysis study. Pharmacol Biochem Behav 60:695–701. CrossRefGoogle Scholar
  51. Nakamura A, Narita M, Miyoshi K, Shindo K, Okutsu D, Suzuki M, Higashiyama K, Suzuki T (2008) Changes in the rewarding effects induced by tramadol and its active metabolite M1 after sciatic nerve injury in mice. Psychopharmacology 200:307–316. CrossRefGoogle Scholar
  52. Nasser HM, Calu DJ, Schoenbaum G, Sharpe MJ (2017) The dopamine prediction error: contributions to associative models of reward learning. Front Psychol 8:244. CrossRefPubMedPubMedCentralGoogle Scholar
  53. Nestor LJ, Murphy A, McGonigle J, Orban C, Reed L, Taylor E, Flechais R, Paterson LM, Smith D, Bullmore ET, Ersche KD, Suckling J, Tait R, Elliott R, Deakin B, Rabiner I, Lingford-Hughes A, Nutt DJ, Sahakian B, Robbins TW, ICCAM Consortium (2017) Acute naltrexone does not remediate fronto-striatal disturbances in alcoholic and alcoholic polysubstance-dependent populations during a monetary incentive delay task. Addict Biol 22:1576–1589. CrossRefGoogle Scholar
  54. Nogami T, Takano H, Arakawa R, Ichimiya T, Fujiwara H, Kimura Y, Kodaka F, Sasaki T, Takahata K, Suzuki M, Nagashima T, Mori T, Shimada H, Fukuda H, Sekine M, Tateno A, Takahashi H, Ito H, Okubo Y, Suhara T (2013) Occupancy of serotonin and norepinephrine transporter by milnacipran in patients with major depressive disorder: a positron emission tomography study with [11C]DASB and (S,S)-[18F]FMeNER-D2. Int J Neuropsychopharmacol 16:937–943. CrossRefGoogle Scholar
  55. Ogawa K, Tateno A, Arakawa R, Sakayori T, Ikeda Y, Suzuki H, Okubo Y (2014) Occupancy of serotonin transporter by tramadol: a positron emission tomography study with [11C]DASB. Int J Neuropsychopharmacol 17:845–850. CrossRefGoogle Scholar
  56. Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113. CrossRefGoogle Scholar
  57. Ossewaarde L, Verkes RJ, Hermans EJ, Kooijman SC, Urner M, Tendolkar I, van Wingen GA, Fernández G (2011) Two-week administration of the combined serotonin-noradrenaline reuptake inhibitor duloxetine augments functioning of mesolimbic incentive processing circuits. Biol Psychiatry 70:568–574. CrossRefGoogle Scholar
  58. Preston KL, Jasinski DR, Testa M (1991) Abuse potential and pharmacological comparison of tramadol and morphine. Drug Alcohol Depend 27:7–17. CrossRefGoogle Scholar
  59. Quelch DR, Mick I, McGonigle J, Ramos AC, Flechais RSA, Bolstridge M, Rabiner E, Wall MB, Newbould RD, Steiniger-Brach B, van den Berg F, Boyce M, Østergaard Nilausen D, Breuning Sluth L, Meulien D, von der Goltz C, Nutt D, Lingford-Hughes A (2017) Nalmefene reduces reward anticipation in alcohol dependence: an experimental functional magnetic resonance imaging study. Biol Psychiatry 81:941–948. CrossRefGoogle Scholar
  60. Reed B, Butelman ER, Kreek MJ (2017) Endogenous opioid system in addiction and addiction-related behaviors. Curr Opin Behav Sci 13:196–202. CrossRefGoogle Scholar
  61. Rommelfanger KS, Mitrano DA, Smith Y, Weinshenker D (2009) Light and electron microscopic localization of alpha-1 adrenergic receptor immunoreactivity in the rat striatum and ventral midbrain. Neuroscience 158:1530–1540. CrossRefGoogle Scholar
  62. Russo SJ, Nestler EJ (2013) The brain reward circuitry in mood disorders. Nat Rev Neurosci 14:609–625. CrossRefGoogle Scholar
  63. Saji K, Ikeda Y, Kim W, Shingai Y, Tateno A, Takahashi H, Okubo Y, Fukayama H, Suzuki H (2013) Acute NK1 receptor antagonist administration affects reward incentive anticipation processing in healthy volunteers. Int J Neuropsychopharmacol 16:1461–1471. CrossRefGoogle Scholar
  64. Schott BH, Minuzzi L, Krebs RM, Elmenhorst D, Lang M, Winz OH, Seidenbecher CI, Coenen HH, Heinze HJ, Zilles K, Düzel E, Bauer A (2008) Mesolimbic functional magnetic resonance imaging activations during reward anticipation correlate with reward-related ventral striatal dopamine release. J Neurosci 28:14311–14319. CrossRefGoogle Scholar
  65. Schouw ML, De Ruiter MB, Kaag AM, van den Brink W, Lindauer RJ, Reneman L (2013) Dopaminergic dysfunction in abstinent dexamphetamine users: results from a pharmacological fMRI study using a reward anticipation task and a methylphenidate challenge. Drug Alcohol Depend 130:52–60. CrossRefGoogle Scholar
  66. Schultz W (1997) Dopamine neurons and their role in reward mechanisms. Curr Opin Neurobiol 7:191–197. CrossRefGoogle Scholar
  67. Skipper GE, Fletcher C, Rocha-Judd R, Brase D (2004) Tramadol abuse and dependence among physicians. JAMA 292:1818–1819. CrossRefGoogle Scholar
  68. Soyka M, Backmund M, Hasemann S (2004) Tramadol use and dependence in chronic noncancer pain patients. Pharmacopsychiatry 37:191–192. CrossRefGoogle Scholar
  69. Spielberger CD (1983) Manual for the state-trait anxiety inventory, STAI-form Y. Consulting Psychologists Press, CaliforniaGoogle Scholar
  70. Talairach J, Tournoux P (1988) Co-planar Stereotaxic Atlas of the human brain: 3-dimensional proportional system—an approach to cerebral imaging. Thieme Medical Publishers, New YorkGoogle Scholar
  71. Vazzana M, Andreani T, Fangueiro J, Faggio C, Silva C, Santini A, Garcia ML, Silva AM, Souto EB (2015) Tramadol hydrochloride: pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems. Biomed Pharmacother 70:234–238. CrossRefGoogle Scholar
  72. Volkow ND, Morales M (2015) The brain on drugs: from reward to addiction. Cell 162:712–725. CrossRefPubMedPubMedCentralGoogle Scholar
  73. Volkow ND, Koob GF, McLellan AT (2016) Neurobiologic advances from the brain disease model of addiction. N Engl J Med 374:363–371. CrossRefPubMedPubMedCentralGoogle Scholar
  74. Winstock AR, Borschmann R, Bell J (2014) The non-medical use of tramadol in the UK: findings from a large community sample. Int J Clin Pract 68:1147–1151. CrossRefGoogle Scholar
  75. Wuo-Silva R, Fukushiro DF, Borçoi AR, Fernandes HA, Procópio-Souza R, Hollais AW, Santos R, Ribeiro LT, Corrêa JM, Talhati F, Saito LP, Aramini TC, Kameda SR, Bittencourt LR, Tufik S, Frussa-Filho R (2011) Addictive potential of modafinil and cross-sensitization with cocaine: a pre-clinical study. Addiction Biol 16:565–579. CrossRefGoogle Scholar
  76. Wuo-Silva R, Fukushiro DF, Hollais AW, Santos-Baldaia R, Mári-Kawamoto E, Berro LF, Yokoyama TS, Lopes-Silva LB, Bizerra CS, Procópio-Souza R, Hashiguchi D, Figueiredo LA, Costa JL, Frussa-Filho R, Longo BM (2016) Modafinil induces rapid-onset behavioral sensitization and cross-sensitization with cocaine in mice: implications for the addictive potential of modafinil. Front Pharmacol 7:420. CrossRefPubMedPubMedCentralGoogle Scholar
  77. Yacubian J, Gläscher J, Schroeder K, Sommer T, Braus DF, Büchel C (2006) Dissociable systems for gain- and loss-related value predictions and errors of prediction in the human brain. J Neurosci 26:9530–9537. CrossRefGoogle Scholar
  78. Yates WR, Nguyen MH, Warnock JK (2001) Tramadol dependence with no history of substance abuse. Am J Psychiatry 158:964. CrossRefGoogle Scholar
  79. Zacny JP (2005) Profiling the subjective, psychomotor, and physiological effects of tramadol in recreational drug users. Drug Alcohol Depend 80:273–278. CrossRefGoogle Scholar
  80. Zhou X, Liu J (2015) Fluorescence detection of tramadol in healthy Chinese volunteers by high-performance liquid chromatography and bioequivalence assessment. Drug Des Devel Ther 9:1225–1231. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Yuki Asari
    • 1
  • Yumiko Ikeda
    • 2
  • Amane Tateno
    • 3
  • Yoshiro Okubo
    • 3
  • Takehiko Iijima
    • 1
  • Hidenori Suzuki
    • 2
    Email author
  1. 1.Department of Perioperative Medicine, Division of AnesthesiologyShowa University School of DentistryTokyoJapan
  2. 2.Department of Pharmacology, Graduate School of MedicineNippon Medical SchoolTokyoJapan
  3. 3.Department of Neuropsychiatry, Graduate School of MedicineNippon Medical SchoolTokyoJapan

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