3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl] phenol hydrochloride

Current Scheduling Status
Year(s) and type of review / ECDD meetings
Drug Class
ECDD Recommendation
Critical review recommended
Recommendation (from TRS)
Substance identification
Tapentadol is chemically 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]- phenol hydrochloride. It has two chiral centres and is manufactured as a single (R,R)-stereoisomer.

Previous review
Tapentadol was pre-reviewed during the thirty-fifth meeting of ECDD and a recommendation was made for critical review.

Similarity to known substances and effects on the central nervous system
Tapentadol has some structural similarity to morphine and has shown agonist activity at the μ-opioid receptor and norepinephrine reuptake inhibition. It produces analgesia in acute and chronic pain states similar to that produced by oxycodone or morphine. Most reports of adverse events in humans have come from clinical trials, with nausea, dizziness, vomiting, somnolence and headache being the most commonly reported by patients. Respiratory depression with tapentadol has occurred rarely and had limited clinical relevance.

Dependence potential
Few published preclinical data on dependence potential for tapentadol exist, but animal studies have shown that tolerance and dependence developed in rats. There was a small amount of evidence of withdrawal in clinical studies in humans. Patients taking tapentadol were less likely to have withdrawal symptoms as assessed using the Clinical Opiate Withdrawal Scale than subjects taking oxycodone.

Actual abuse and/or evidence of likelihood of abuse
Based on the preclinical and clinical pharmacology of tapentadol, as well as anecdotal data, the potential for abuse with tapentadol is consistent with that of currently marketed drugs such as hydromorphone, oxycodone, morphine, and tramadol. Tapentadol has been marketed since 2008 without significant events or signs of abuse and currently is dispensed with tamper-resistant coatings. However, tapentadol has not yet appeared in many drug use surveys or surveillance reports, which limits the data regarding tapentadol abuse, dependence, diversion, recreational use, or poison control. Those data that are available suggest the potential for abuse of tapentadol to be similar to that of other μ-opioid agonists or slightly less. While three respondents to the WHO questionnaire confirmed recreational/harmful use of tapentadol, thirteen stated that there was no such use.

Therapeutic usefulness
Tapentadol is primarily prescribed and dispensed on an outpatient basis for osteoarthritis, joint pain or chronic pain states that have not responded to other medications.

Owing to the current insufficiency of data regarding dependence, abuse and risks to public health (including risks to the individual), the Committee recommended that tapentadol not be placed under international control at this time but be kept under surveillance.