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

Abstract and Introduction


Tramadol is a unique analgesic medication, available in variety of formulations, with both monoaminergic reuptake inhibitory and opioid receptor agonist activity increasingly prescribed worldwide as an alternative for high-affinity opioid medication in the treatment of acute and chronic pain. It is a prodrug that is metabolized by cytochrome P450 (CYP) enzymes CYP2D6 and CYP3A4 to its more potent opioid analgesic metabolites, particularly the O-demethylation product M1. The opioid analgesic potency of a given dose of tramadol is influenced by an individual's CYP genetics, with poor metabolizers experiencing little conversion to the active M1 opioid metabolite and individuals with a high metabolic profile, or ultra-metabolizers, experiencing the greatest opioid analgesic effects. The importance of the CYP metabolism has led to the adoption of computer clinical decision support with pharmacogenomics tools guiding tramadol treatment in major medical centers. Tramadol's simultaneous opioid agonist action and serotonin (5-HT) and norepinephrine reuptake inhibitory effects result in a unique side effect profile and important drug interactions that must be considered. Abrupt cessation of tramadol increases the risk for both opioid and serotonin–norepinephrine reuptake inhibitor withdrawal syndromes. This review provides updated important information on the pharmacology, pharmacokinetics, CYP genetic polymorphisms, drug interactions, toxicity, withdrawal, and illicit use of tramadol.


Tramadol has been well studied for the treatment of multiple types of chronic moderate to moderately severe pain conditions. Two Cochrane meta-analyses evaluating tramadol concluded that it is efficacious in neuropathic pain[1] and pain related to osteoarthritis.[2] There are also more recent positive Cochrane reviews for the treatment of low back pain and rheumatoid arthritis.[3,4] The evidence for its efficacy in the treatment of acute and postoperative pain is mixed,[5–7] although the analgesic response can be improved in combination with nonopioid analgesics. Most of the studies of acute pain have been done with parenteral preparations that are not available in the United States. In addition to the treatment of pain, there is evidence to support the off-label use of tramadol as on-demand treatment for premature ejaculation (PE).[8–10]

Tramadol was first developed in Germany in the late 1970s, and various formulations such as drops, sustained and extended-release preparations for oral use, suppositories for rectal use, and intramuscular, IV, and subcutaneous solutions have since been launched in more than 100 countries worldwide.[11] It was approved by the US Food and Drug Administration (FDA) in 1995 as the only nonscheduled opioid available. As with other opioids, the expansion of worldwide availability of tramadol has resulted in an increase in abuse and diversion. Consequently, a more restrictive scheduling has been adopted in many countries including the United States, where it became a Schedule IV substance in 2014.

Tramadol is a centrally acting synthetic opioid medication with monoaminergic actions similar to serotonin-norepinephrine reuptake inhibitors (SNRIs). Tramadol, as well as a similar dual-action analgesic, tapentadol, produce analgesia by affecting the nociceptive process and boosting the central modulation of pain.[12] A major difference between the 2 medications is that tapentadol exerts its effects without a pharmacologically active metabolite. In contrast, codeine and tramadol are prodrugs: codeine is metabolized into morphine, and the active metabolite of tramadol is O-desmethyltramadol (M1). Tramadol was originally thought to have a lower risk of constipation, respiratory depression, overdose, and addiction compared with other opioids, but CYP metabolic polymorphisms that will be described later in this review contribute to interesting phenotypic differences in the analgesic and side effect profile. The risk factors for serious adverse effects of tramadol, including serotonin syndrome and decreased seizure threshold, will also be discussed.

Use of tramadol for chronic pain or in the perioperative period requires an awareness of its unique pharmacology and special attention to the CYP450 polymorphism status, as well as an understanding of drug–drug interactions, to ensure adequate pain relief and avoidance of adverse drug effects. The emerging use of computer clinical decision support with pharmacogenomics tools guiding tramadol treatment is addressed. This review is timely because patients presenting to pain medicine treatment providers and for surgery are increasingly likely to have tramadol among their list of medications.