ADME and toxicity considerations for tramadol: from basic research to clinical implications

ABSTRACT

Introduction

Tramadol is widely being used in chronic pain management for improving patients’ life quality and reducing trauma. Although it is listed in several medicinal guidelines, its use is controversial because of the conflicting results obtained in pharmacokinetic/pharmacodynamic studies. This multi-receptor drug acts as µ₁ opioid receptor agonist, monoamine reuptake inhibitor, and inhibitor of ligand-gated ion channels and some special protein-coupled receptors.

Areas covered

This review provides a comprehensive view on the pharmacokinetic, pharmacodynamic, and toxicity of tramadol with a deep look on its side effects, biochemical and pathological changes, and possible drug interactions. In addition, the main ways of tramadol poisoning management describe according to in vivo and clinical trial studies.

Expert opinion

Given the broad spectrum of targets, increasing the cases of overdoses and toxicity, and probable drugs interaction, it is necessary to take another look at the pharmacology of tramadol. Regarding the adverse effects of tramadol on different tissues, especially the nervous system and liver tissue, more attentions to tramadol metabolites, their interaction with other drugs, and active agents seem critical. Seizure as the most cited effect of tramadol and its destructive effects on tissues would alleviate by co-administration with drugs with antioxidant properties.

KEYWORDS:

• Tramadol
• opioid
• µ₁ receptor
• analgesic
• toxicity

Article highlights

• The ADMET (absorption, distribution, metabolism, excretion, and toxicity) of a tramadol are studied. Tramadol elimination half-life is about 5 h, and it is mainly excreted by kidneys and faces. O-desmethyltramadol (M1) is the main metabolite of tramadol. Its production rate and tramadol tolerance is directly related to the genetic variation in CYP450.

• Opioid receptors activation, monoamine transporters, G-protein-coupled receptors (GPCRs), muscarinic and nicotinic receptors, GABA receptors, NMDA receptors, and voltage dependent receptors are the main tramadol sites of action.

• The main side effects of tramadol in the terms of clinical and apparent side effects, biochemical, and pathological changes are discussed. Seizures, serotonin syndrome, headache, vertigo, hyperglycemia, hypotonicity, and acidosis are the general side effects of tramadol. Besides in some cases the low level of glucose and high CO2 concentration in blood and respiratory depression in coordination with adverse effects at pathological levels to the lung, kidney, testicular tissues, and CNS are indicated.

• Poisoning management protocols for tramadol overdose are investigated. Naloxone, antioxidants, caffeine, ethimazole, morphine, acetaminophen, and benzodiazepines are mainly used together for both managing tramadol poisoning or as pain killer.

• Tramadol drug interaction as one of the main cause of tramadol related to side effects and deaths were explained by a few examples.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.