Trends in Tramadol: Pharmacology, Metabolism, and Misuse

Karen Miotto, MD; Arthur K. Cho, PhD; Mohamed A. Khalil, MD; Kirsten Blanco, BS; Jun D. Sasaki, MD; Richard Rawson, PhD


Anesth Analg. 2017;124(1):44-51. 

In This Article


Tramadol has a unique mechanism of action. It inhibits the reuptake of norepinephrine and serotonin, resulting in antinociceptive activity similar to the SNRIs venlafaxine or duloxetine. In the United States, tramadol is available as an oral formulation generally prescribed for the treatment of chronic musculoskeletal and neuropathic pain, but it is also utilized off-label for on-demand therapy for erectile dysfunction. A growing number of patients will present with tramadol on their medication list as prescribers are moving away from chronic prototypic opioid treatment for nonmalignant pain. This review summarizes the essential knowledge on tramadol pharmacology, pharmacogenetics, drug interactions, and possible adverse events for the anesthesiologist. Key clinically significant findings are summarized in Table 3.

Genetic polymorphisms modulating CYP enzyme activities are the main source of variability in a patient's analgesic response to tramadol. CYP2D6 dependent and, to a lesser extent, CYP3A4 metabolic activation, are required for the full opioid analgesic effects. The clinical studies reviewed demonstrate that the opioid analgesic response rates to tramadol are significantly lower in PM compared with the other 3 phenotypic groups, IM, EM, and UM. Of clinical significance, patients who are PMs may report tramadol as ineffective for pain relief and request a stronger opioid. It is important to appreciate that this does not constitute drug seeking, rather an inability to convert tramadol to the active M1 opioid metabolite.

In addition to the metabolic activation of medication, the CYP2D6 enzyme families are inhibited or induced by drugs, resulting in clinically significant interactions that can cause unanticipated adverse reactions or therapeutic failures. One example is administering tramadol with medications that strongly inhibit CYP2D6, including the antidepressants fluoxetine or paroxetine, the antiemetic metoclopramide, or the antiarrhythmic and antiparasitic quinidine, which results in a net effect of changing an individual's apparent phenotype from an EM to a PM.[65]

A perioperative consideration is drug interactions with tramadol, particularly the number, types, and dosages of coadministered serotonergic medications. The risk of SS is increased with the concomitant use of medications that increase serotonin levels in the CNS or that inhibit the metabolism of tramadol (strong CYP2D6 inhibitors), as discussed. Drug classes implicated in SS include a long list of medications that are common in hospitalized patients, including antimigraine agents; triptans, antidepressants, buspirone, TCAs, MAOIs, antipsychotics; anticonvulsants; antiparkinsonian agents; and analgesics such as meperidine. The most notable risk is with the combinations of medications that increase serotonin by different mechanisms.[66] The manifestations of SS range from mild diarrhea and tremor to lethal symptoms of hyperpyrexia, muscle rigidity, and multiorgan failure. Monitoring for and counseling a patient about SS is prudent when starting a new serotonergic agent or when doses are increased.[40] In general, treatment of SS first involves supportive care and discontinuing the offending medications. Patients presenting with severe symptoms may need sedation, intubation, and paralyzation. Despite many antiemetic medications being serotonin antagonists, coadministration with tramadol does not increase the risk of SS because of the opposing effects; however, this interaction may decrease the effectiveness of the antiemetic.

An appreciation of the possibility of withdrawal is an early consideration when evaluating a patient taking tramadol. Withdrawal states are more frequent with abrupt cessation of high-dose, long-term use or in polysubstance users; however, symptoms have been reported in sensitive individuals at therapeutic dosages. In addition, in the preoperative period, tramadol and a serotonergic antidepressant may both need to be stopped, increasing the likelihood of a combined tramadol and antidepressant discontinuation syndrome. The antidepressants that carry the greatest risk for a discontinuation reaction in rank order include venlafaxine, paroxetine, sertraline, and fluvoxamine. In the cases where these medications cannot be tapered preoperatively, monitor patients for withdrawal and provide symptomatic treatment. If the withdrawal symptoms shown in Table 1 are present, they will subside once the patient is no longer nothing by mouth and can resume tramadol and the antidepressant.

Tramadol should also be considered for postoperative analgesia in surgical patients in which respiratory depression must be avoided, such as those with respiratory or cardiopulmonary compromise, obesity hypoventilation syndrome, smokers, or the elderly. The best candidates for tramadol treatment are those taking few serotonergic medications, perhaps have had a positive analgesic response to tramadol in the past, or are identified as UMs. In the practice of personalized medicine, several academic medical centers have developed clinical support services to assist health care providers in identifying CYP genotypes likely to have an optimal analgesic response to tramadol and alerting clinicians in the electronic medical records of significant drug-drug interactions. Pharmacogenomics testing offers better therapeutic outcomes, choice of treatment, and dose adjustments based on the patient's genotype. The Pharmacogenetics Working Group of the Royal Dutch Association for the Advancement of Pharmacy has developed tramadol dosing recommendations based on CYP profiles (Table 2).3

One review in the anesthesia literature suggests multimodal-action medications that block the reuptake of norepinephrine and/or serotonin may be effective in improving analgesia and functional outcome of postoperative pain in ambulatory surgery. Tramadol is often compared with another multimodal analgesic, tapentadol. Pharmacologically, tapentadol does not require metabolic activation, has greater affinity for μ-opioid receptors, and blocks reuptake of norepinephrine with limited serotonergic effects. In addition, as a weaker serotonin reuptake inhibitor, tapentadol carries less risk of precipitating SS. Although there are no head-to-head comparisons between the 2 medications, in a meta-analysis extracting data from historical studies, tapentadol was associated with slightly lower risks of constipation and nausea than tramadol.[67] The Poison Control Study data discussed determined that tramadol was associated with a higher rate of seizures and vomiting, whereas tapentadol was associated with reports more of respiratory depression, coma, and sedation. A limitation of this review is that the data on adverse effects, seizures, drug interactions, withdrawal, and abuse are compiled from case reports, many of which are not from the anesthesia literature and do not address oral tramadol in use for perioperative treatment of pain.

In conclusion, tramadol use is increasing worldwide. It is anticipated that clinical decision support systems will soon be available that draw on data from genetic analysis of opioid metabolism to assist clinicians in patient selection. A greater understanding of patient's metabolic profile and tramadol pharmacology will ensure the patient's optimal analgesic outcome. Finally, awareness that tramadol has an addiction liability is important for clinicians because abuse is prevalent among health care professionals and in geographic regions with high availability such as the Middle East.