Special Topics in Pain: Opioids

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Trends in Tramadol: Pharmacology, Metabolism, and Misuse.

Author(s): Miotto K, et al.
Journal: Anesth Analg. 2017; 124(1):44-51. 69 references.
Reprint: Karen Miotto, MD, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, 760 Westwood Plaza, Box 175919, Room B8-228, Los Angeles, CA 90095. Email: kmiotto@mednet.ucla.edu
Faculty Disclosure: Abstracted by N Walea, who has nothing to disclose.
Objective: Review and evaluate the latest advances and newest information in the area of Intravenous Agents; Review and evaluate the latest advances and newest information in the area of Opioids; Review and evaluate the latest advances and newest information in the area of Psychopharmacologics


Editor’s Note: Tramadol is a complex drug with opioid and SNRI properties making it a good choice for moderate to severe pain but there is a possibility of the \serotonin syndrome with drug interactions over a wide range of agents in different classes-antimigraine agents; triptans, antidepressants, buspirone, TCAs, MAOls, antipsychotics; anticonvulsants; antiparkinsonian agents; and analgesics such as meperidine. Manifestations of SS range from mild diarrhea and tremor to lethal symptoms of hyperpyrexia, muscle rigidity, and multiorgan failure. Multiple metabolizer styles sometimes lead to claims of being an ineffective analgesic.

Sources of variability in a patient's analgesic response to tramadol are the genetic polymorphisms modulating CYP enzyme activities. CYP2D6 dependent and, to a lesser extent, CYP3A4 metabolic activation, are required for the full opioid analgesic effects. Clinical studies demonstrate that the analgesic response rates to tramadol are significantly lower in poor metabolizers (PM) compared with the other 3 phenotypic groups, intermediate metabolizers (IM), extensive metabolizers (EM; the most common type), and very high ultra-metabolizers (UM). PM patients 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.

Class:  Pharmacology: Tramadol

Tramadol use is increasing worldwide. It has been well studied for the treatment of multiple types of chronic moderate to moderately severe pain conditions. Meta-analyses evaluating tramadol concluded that it is efficacious in neuropathic pain, pain related to osteoarthritis and rheumatoid arthritis and treatment of low back pain.  

The mechanism of action of tramadol is unique. It inhibits the reuptake of norepinephrine and serotonin, resulting in antinociceptive activity similar to the serotonin-norepinephrine reuptake inhibitors (SNRls) venlafaxine or duloxetine.

The main sources of variability in a patient's analgesic response to tramadol are the genetic polymorphisms modulating CYP enzyme activities. CYP2D6 dependent and, to a lesser extent, CYP3A4 metabolic activation, are required for the full opioid analgesic effects. Clinical studies demonstrate that the analgesic response rates to tramadol are significantly lower in poor metabolizers (PM) compared with the other three phenotypic groups, intermediate metabolizers (IM), extensive metabolizers (EM; the most common type), and very high ultra-metabolizers (UM). PM patients 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.

Drug interactions with tramadol are a perioperative consideration, particularly the number, types, and dosages of coadministered serotonergic medications. The risk of serotonin syndrome (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, MAOls, antipsychotics; anticonvulsants; antiparkinsonian agents; and analgesics such as meperidine. Manifestations of SS range from mild diarrhea and tremor to lethal symptoms of hyperpyrexia, muscle rigidity, and multiorgan failure. In general, treatment of SS first involves supportive care and discontinuing the offending medications.

Tramadol should 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.

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 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. In the cases where these medications cannot be tapered preoperatively, monitor patients for withdrawal and provide symptomatic treatment.

Despite previous assumptions that tramadol did not have an addiction liability, various English- and Arabic-language studies concluded that tramadol produces desirable euphoric, stimulant, and relaxing effects that increase its abuse potential. The most frequent abusers of tramadol are those with easy access and history of substance abuse, patients with chronic pain, and health professionals. Although rarely a primary drug of choice, a review of physician health program records showed that tramadol was the third most frequently mentioned opioid and it exceeded the abuse liability of fentanyl, oxycodone, and hydromorphone in this group of physicians. Increased monitoring is necessary in patients with a history of tramadol abuse or dependence because they are more likely to exhibit toxidromes and continue use to avoid opioid and SNRl withdrawal,

Important Points:
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.

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