Detailed

Tramadol, an opioid analgesic along with being a weak serotonin and norepinephrine reuptake inhibitor, is also considered a weak agonist at the -opioid receptor [6; 7]. Clinically, tramadol has been shown to be used for pain reduction attributed to neuropathy, osteo- and rheumatoid arthritis and lower back pain [7]. Moreover, tramadol is also used in cancer pain [8]. In addition, pharmacologically, tramadol exists as two ‘versions’; with both exhibiting different mechanisms of action [1]. In addition, tramadol has also been noted to be a treatment in opioid withdrawal, premature ejaculation and anxiety disorders [7]. Recent data suggest that tramadol abuse is prevalent in 32 countries; according to the latest International Narcotics control Board Survey, in which 77 countries responded to tramadol [9]. In terms of Tramadol’s metabolism it is distributed throughout the body, with metabolism occurring in the liver [8; 2], and excretion via the kidneys [4]. As tramadol is usually administered as a racemic mixture – (+) and (-) tramadol – 10-30% of it, in its original form, is excreted in the urine [2]. Tramadol undergoes metabolism – via cytochrome 2D6 – into two metabolites: one is the therapeutically active desmethyl-tramadol (M1), the other is through demethylation to an inactive N-desmethyl-tramadol (M2) [2; 10]. The active tramadol metabolite (M1) half-life in the system is 5.5-9.5 hours [2]. Treatment for pain using oxycodone, considered a strong opioid analgesic, is only considered when treatment of tramadol in individuals has proven unsuccessful; or if individuals are non-respondent to the weak opioid [11; 12].

Dosage

Tramadol dose comes in many pharmaceutical forms [4]. For subcutaneous injection, tramadol a 50mg or 100mg dose in solution are available [4]. Therapeutic tramadol doses have been described as 50mg (orally) and 50-100mg (injection) [13]. Several studies have been reviewed and tramadol doses documented; these include a majority if oral tramadol administrations – capsules of 100mg, 200mg, 300mg and 400mg [4]. One study assessing the clinical equivalence of controlled-release oxycodone (20mg) and controlled-release tramadol (200mg) in a random, double-blind study in patients (54) undergoing breast cancer surgery found a similar analgesic effect from both oxycodone and tramadol [14]. Tramadol overdose has been attributed to the serotonin syndrome [1; 2]. This phenomena results from an excess serotonin at the 5-HT (serotonin) receptor, characterised by an alteration in one’s mental status and autonomic function [1]. Importantly, serotonin syndrome can affect individuals across all ages; from newborns to the elderly [1]. Effectively, overdosing on tramadol exhibits symptomology including central nervous system (CNS) depression, nausea, vomiting, tachycardia and seizure [1]. Serotonin syndrome, in a tramadol context, can be life-threatening.

Safety

Studies involving the evaluation of the pharmacokinetic and pharmacodynamic (PD) interactions of tramadol and mirogabalin, along with other central nervous system depressants, found that a co-administration of mirogabalin/tramadol increased the likelihood of nausea [15]. For use of tramadol in children, the Food and Drug Administration (FDA), in 2015, issued a boxed warning to describe a safe and effective prescription in children [16]. Tramadol has also been shown to decrease gene expression in genes in the hippocampus [17]. One study used tramadol (50mg/kg) to assess the neurotoxic effects associated with cognitive dysfunction [17]. In this work, Baghishani et al (2017) treated 35 rats with 50mg/kg tramadol and found this analgesic might contribute to disturbances in learning and memory [17]. Choo et al (2018) described tramadol tolerability, within the scope of a tramadol target dose [18]; this was suggested as being dependent on the varying doses of tramadol [18]. Tramadol withdrawal can include signs such as restlessness, agitation, anxiety and gastrointestinal discomfort [5].Tramadol dependence (addiction) has been noted as being of a low dependence (abuse) potential, with dependence based on long-term use. However, the WHO recognises that dependence differs from country and availability of tramadol [5].>

Side effects associated with (+) tramadol include nausea and vomiting [2]. According to a tramadol review by Grond et al (2004), the most common adverse effects arising from the use of tramadol – data from over 20 000 patients – included: nausea, dizziness, drowsiness, fatigue, sweating, vomiting and dry mouth [4]. Normal tramadol dose is 50-100mg, administered orally [19], however, at higher tramadol doses, sides effects such as nausea and vomiting occur more frequently and intravenous injection [19]. Interestingly, a single dose of tramadol can also cause adverse side effects; this has been reported in a patient in which a single-dose resulted in ataxia, dilatation of pupils, trembling, and dysphasia which ceased after discontinuing tramadol treatment [19]. Reported cases of tramadol and vomiting include two female patients who were administered an intravenous, 50mg tramadol dose [19]. Immunologically, tramadol has been shown to both suppress and stimulate natural killer cell activity and T-cell proliferation [4].

References

[1] Burton D. Beakley, Adam M. Kaye, and Alan D. Kaye, 2015. Tramadol, Pharmacology, Side Effects, and Serotonin Syndrome: A Review. Pain Physician 2015; 18:395-400.

[2] Ulrich Klotz, 2003. Tramadol − the Impact of its Pharmacokinetic and Pharmacodynamic Properties on the Clinical Management of Pain. Arzneim.-Forsch. Drug Res. 53, No. 10, 681−687.

[3] W. N. Wu, L. A. McKown & S. Liao, 2008. Metabolism of the analgesic drug ULTRAM ® (tramadol hydrochloride) in humans: API-MS and MS/MS characterization of metabolites. Xenobiotica, 2002, vol. 32, no. 5, 411±425.

[4] Stefan Grond and Armin Sablotzki, 2004. Clinical Pharmacology of Tramadol. Clin Pharmacokinet 2004; 43 (13): 879-92.

[5] World Health Organisastion, 2014. Expert Committee on Drug Dependence Thirty‐sixth Meeting. Tramadol

Update Review Report Agenda item 6.1.

[6] A. G. A. Farag, M. A. Basha, S. A. Amin, N. F. Elnaidany, N. G. Elhelbawy, M. M. T. Mostafa, S. A. Khodier, R. A. Ibrahem, R. Z. Mahfouz, 2018. Tramadol (opioid) abuse is associated with a dose- and time-dependent poor sperm quality and hyperprolactinaemia in young men. Andrologia. 2018;50:e13026.

[7] Xameer Hassamal, KarenMiotto,WilliamDale, Tai Danovitch, 2018. Tramadol: Understanding the Risk of Serotonin Syndrome and Seizures. The American Journal of Medicine, Vol 131, No 1.

[8] J. Faria, J. Barbosa, R. Moreira, O. Queiro, F. Carvalho, R.J. Dinis-Oliveira, 2018. Comparative pharmacology and toxicology of tramadol and tapentadol. European Journal of Pain, 22 (2018) 827—844. doi:10.1002/ejp.1196.

[9] Amany I. Ahmed, Khalifa El-Dawy, Medhat M. Fawzy, Haytham A. Abdallah, Heba N. Abd elsaid, Wessam O. Elmesslamy, 2018. RETROSPECTIVE REVIEW OF TRAMADOL ABUSE. Slov Vet Res 2018; 55 (Suppl 20): 471–83. DOI 10.26873/SVR-677-2018.

[10] UM Stamer, F Musshoff, M Kobilay, B Madea, A Hoeft and F Stuber, 2007. Concentrations of Tramadol and O-desmethyltramadol Enantiomers in Different CYP2D6 Genotypes. Clinical Pharmacology & Therapeutics, volume 82, number 1. DOI:10.1038/sj.clpt.6100152.

[11] Wojciech Leppert, 2010. Role of oxycodone and oxycodone/naloxone in cancer pain management. Pharmacological Reports, 62, 578-591.

[12] Eija Kalso, 2005. Oxycodone. Journal of Pain and Symptom Management, Vol. 29 No. 5S.

[13] S Shadnia, K Soltaninejad, K Heydari, G Sasanian and M Abdollahi, 2008. Tramadol intoxication: a review of 114 cases. Human & Experimental Toxicology (2008) 27: 201–205.

[14] Sandra Kampe, Karsten Wolter, Mathias Warm, Oguzhan Dagtekin, Sasan Shaheen, Susanne Landwehr, 2009. Pharmacology 2009;84:276–281 DOI: 10.1159/000242998.

[15] Mendel Jansen, Jeanne Mendell, Alexander Currie, James Dow, Ling He, Domenico Merante, Victor Dishy, Hitoshi Ishizuka, and Hamim Zahir, 2018. Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Mirogabalin When Coadministered With Lorazepam, Zolpidem, Tramadol, or Ethanol: Results From Drug-Drug Interaction Studies in Healthy Subjects. Clinical Pharmacology in Drug Development 2018, 7(6).

[16] Frédérique Rodieux, Laszlo Vutskits, Klara M. Posfay-Barbe, Walid Habre, Valérie Piguet, Jules A. Desmeules and Caroline F. Samer, 2018. When the Safe Alternative Is Not That Safe: Tramadol Prescribing in Children. Frontiers in Pharmacology, Volume 9, Article 148. DOI: 10.3389/fphar.2018.00148.

[17] Farideh Baghishani & Abbas Mohammadipour & Hossain Hosseinzadeh & Mahmoud Hosseini & Alireza Ebrahimzadeh-bideskan, 2018. The effects of tramadol administration on hippocampal cell apoptosis, learning and memory in adult rats and neuroprotective effects of crocin. Metabolic Brain Disease (2018) 33:907–916. https://doi.org/10.1007/s11011-018-0194-6.

[18] Kim Hoon Choo, Rishya A/L Manikam, Khadijah Poh Yuen Yoong and Vanitha A/P Kandasamy, 2018. Prophylactic metoclopramide use in trauma patients given tramadol: A randomised, double-blinded, placebo-controlled trial. Hong Kong Journal of Emergency Medicine 1–8.

[19] Arbind Kumar R, Elna Paul, Aishwarya TV, 2018. Tramadol Induced Vomiting. PTB Reports, 2018; 4(2): 19-20.

[20] Hazem M. Abu-Shawish, Nasser Abu Ghalwa, Faried R. Zaggout, Salman M. Saadeh, Ayoub R. Al-Dalou, Anwar A. Abou Assi, 2010. Improved determination of tramadol hydrochloride in biological fluids and pharmaceutical preparations utilizing a modified carbon paste electrode. Biochemical Engineering Journal 48 (2010) 237–245. doi:10.1016/j.bej.2009.10.019.