Tapentadol

3-[(2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl]phenol

Overview

Tapentadol belongs to Opioids.

Key safety note: Tapentadol is an effective opioid analgesic, but it carries the core opioid dangers: dose-dependent respiratory depression that can be fatal (greatly increased by alcohol, benzodiazepines, gabapentinoids or other depressants), tolerance, physical dependence with a withdrawal syndrome, and genuine misuse potential: hence its controlled-drug status.[4][3][5]
Effects
Subjective effects vary. What a substance feels like depends on dose, individual physiology, mindset, and setting. The points below describe commonly reported effects, not guaranteed, uniform, or desirable outcomes.
  • Opioid analgesia with the typical μ-agonist effects, pain relief, sedation, sometimes euphoria, nausea and itching, though constipation tends to be milder than with conventional opioids.
  • The noradrenergic component can raise heart rate and blood pressure and contributes to efficacy in neuropathic pain. It also underlies the seizure and serotonin-syndrome cautions.
  • At higher or recreational doses: euphoria and sedation as with other opioids, with dose-dependent respiratory depression. Misuse and dependence potential are real, which is why it is a controlled drug.
Dosing & duration
Harm-reduction note: These are commonly cited reference ranges, not a recommendation or a “safe” dose. Potency, purity, body chemistry, tolerance, and drug combinations vary widely. Start low, go slow, wait for full effects before redosing, and never assume an unknown product matches these figures. Missing data is not evidence of safety.

Oral (immediate-release tablets and extended-release / prolonged-release tablets).. Tapentadol is a controlled (Schedule II / BtM) opioid analgesic. The figures below are clinical reference doses, not recreational guidance. Like all μ-opioid agonists it causes dose-dependent respiratory depression that can be fatal, greatly increased by alcohol, benzodiazepines, gabapentinoids or other depressants, and tolerance and physical dependence develop with regular use. Its added noradrenergic action brings a lowered seizure threshold and a serotonin-syndrome risk when combined with serotonergic drugs or MAOIs. Opioid respiratory depression is reversed by naloxone (the noradrenergic effects are not).

Dose ranges

Immediate-release

50–100 mg every 4–6 h (max ≈600 mg/day)

Extended-release

50–250 mg every 12 h (max 500 mg/day)

Duration

onset

≈30 minutes (immediate-release)

total

Immediate-release ≈4–6 h, extended-release ≈12 h

after effects

Sedation, with regular use, tolerance, dependence and an opioid withdrawal syndrome

Chemical & Physical Properties
FormulaC14H23NO
Molar mass221.34 g/mol
StateSolid (usually the hydrochloride salt, crystalline)
Melting point202–205 °C (base), 168–179 °C (hydrochloride)
Boiling pointNot reported
DensityNot reported
Vapor pressureNot reported
pKapKa1 ≈9.3–9.6 (tertiary amine), pKa2 ≈10.3–10.45 (phenol)
LogP2.87 (experimental)
SolubilityHydrochloride soluble in acetone, acetonitrile and isopropanol
Refractive indexNot reported
Identifiers & Synonyms
CAS175591-23-8
CAS (enantiomer)
PubChem CID9838022
InChIKeyKWTWDQCKEHXFFR-SMDDNHRTSA-N
InChIInChI=1S/C14H23NO/c1-5-14(11(2)10-15(3)4)12-7-6-8-13(16)9-12/h6-9,11,14,16H,5,10H2,1-4H3/t11-,14+/m0/s1
SMILESCC[C@@H](C1=CC(=CC=C1)O)[C@@H](C)CN(C)C

Synonyms

  • Nucynta
  • Palexia
Pharmacodynamics & Biochemistry

Tapentadol is a centrally acting analgesic with a dual mechanism in a single molecule: it is a moderate μ-opioid receptor (MOR) agonist and a noradrenaline (norepinephrine) reuptake inhibitor (NRI). The two actions are synergistic for pain relief, and the clinically used drug is the (R,R)-enantiomer. Its MOR affinity is relatively low (human Ki ≈150 nM, roughly 50× weaker than morphine), so a substantial part of its analgesia comes from the noradrenergic component. This balance is thought to give effective analgesia, particularly for neuropathic pain, with somewhat fewer classic opioid effects (notably less constipation) at equianalgesic doses. Unlike tramadol, tapentadol is NOT a prodrug: it is directly active and does not depend on CYP2D6 metabolism to form an active metabolite, so its effect is more predictable and less affected by CYP2D6 genotype or interactions. It also has minimal serotonin-reuptake activity, giving a lower, though not zero, serotonin-syndrome risk than tramadol.

Biological targets

  • MOR
  • NET

Binding & functional measurements

TargetMeasurementSpecies
Noradrenaline transporterKi 8,800 ± 1,170 nMHuman
δ-opioid receptorKi 970 ± 10 nMRat
κ-opioid receptorKi 910 ± 90 nMRat
μ-opioid receptorEC50 670 ± 150 nM
Emax 88%		Human
μ-opioid receptorKi 96 ± 9.0 nMRat
Noradrenaline transporterKi 480 ± 110 nMRat
Serotonin transporterKi 5,280 ± 580 nMHuman
Serotonin transporterKi 2,370 ± 540 nMRat
Pharmacokinetics
BioavailabilityOral ~32% (extensive first-pass), ~20% plasma-protein bound
TmaxImmediate-release ~1.25 h (onset ~30 min)
Half-life≈4–5 h (immediate-release)
VdNot reported
Protein bindingNot reported
MetabolismMainly hepatic glucuronidation (UGT) to inactive metabolites (minor CYP2C9/2C19/2D6). NOT a CYP2D6-dependent prodrug
ExcretionRenal (~99% as metabolites)
Toxicology & Safety
Harm-reduction note: Toxicity and risk depend on dose, route, purity, combinations, setting, and individual health factors. Missing harms should never be interpreted as evidence of safety.

Not reported

Tapentadol is an effective opioid analgesic, but it carries the core opioid dangers: dose-dependent respiratory depression that can be fatal (greatly increased by alcohol, benzodiazepines, gabapentinoids or other depressants), tolerance, physical dependence with a withdrawal syndrome, and genuine misuse potential: hence its controlled-drug status. Its noradrenergic action adds a lowered seizure threshold and, with serotonergic drugs or MAOIs, a risk of serotonin syndrome (lower than tramadol's, but real). Constipation and some opioid side effects tend to be milder than with conventional opioids. Opioid respiratory depression is reversible with naloxone, but naloxone does not reverse the noradrenergic effects.[4][3][5]

Legal Status
Legal note: Legal status can change over time and may vary by country, region, formulation, analogue status, prescription context, and enforcement practice. Always confirm with current official sources before relying on this section.
Interactions & Contraindications

Drug interactions

MAOIs Contraindicated: the combined opioid and noradrenergic action risks hypertensive crisis and serotonin toxicity.[4]
Alcohol, Benzodiazepines, Gabapentinoids (gabapentin, pregabalin), Opioids Additive sedation and potentially fatal respiratory depression.[4][5]
SSRIs, SNRIs, Triptans, Tramadol Additive serotonin-syndrome risk, lower than with tramadol but not absent.[4]
Drugs that lower the seizure threshold Additive seizure risk.[5]

Contraindications

Significant respiratory depression or acute severe asthma including acute or severe bronchial asthma.[4]
Paralytic ileus or gastrointestinal obstruction paralytic ileus.[4]
Concurrent MAOI, SSRI/SNRI or other serotonergic medication concurrent or recent (within 14 days) MAOI use.[4]
Combining with alcohol or other CNS depressants caution with other CNS depressants and with serotonergic drugs.[4]
Current or prior seizure disorder history of seizures or epilepsy (tapentadol lowers the seizure threshold).[5]
History of stimulant or substance use disorder opioid dependence or misuse risk.[4]
Kidney or liver impairment severe impairment (dose adjustment or avoidance).[4]
Usage & Context
  • A prescription opioid analgesic (Nucynta, Palexia) for moderate-to-severe acute and chronic pain, including neuropathic pain (e.g. diabetic peripheral neuropathy), where its dual opioid + noradrenergic action is advantageous.
  • As a controlled opioid it is also misused and diverted for euphoria. Its abuse and dependence potential is the reason for its Schedule II (US) / controlled-drug status internationally.
Sources & Evidence

Further Information