Tramadol

2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexan-1-ol

Overview

Tramadol belongs to Opioids.

Key safety note: Tramadol is often perceived as a 'mild' opioid, but its dual mechanism gives it risks ordinary opioids do not have.[6]
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.
  • Pain relief with mild opioid effects: relaxation, mild mood lift or euphoria (partly serotonergic/noradrenergic) and drowsiness.
  • Common adverse effects: nausea, dizziness, dry mouth, sweating, constipation and headache.
  • Dose- and interaction-dependent dangers: seizures, serotonin syndrome, and, with other depressants, respiratory depression.
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- and extended-release) and injectable, prescribed and dose-adjusted by a clinician. Figures are therapeutic (prescribing) context, not a recreational guide.. Tramadol is dosed to the lowest effective level. The maximum is 400 mg/day (lower in the elderly and in renal/hepatic impairment). Because the active metabolite depends on CYP2D6, effect and toxicity vary between people. It should not be combined with serotonergic drugs, other opioids, alcohol or sedatives, and the seizure risk rises with higher doses and certain co-medications.

Dose ranges

Moderate–severe pain (adult)

50–100 mg every 4–6 h as needed

Maximum (adult)

400 mg/day

Elderly / renal or hepatic impairment

Reduced dose and/or longer interval

Duration

onset

≈1 h (immediate-release)

total

≈4–6 h (IR), extended-release once–twice daily

after effects

Withdrawal on stopping regular use (opioid + SSRI-like)

Chemical & Physical Properties
FormulaC16H25NO2
Molar mass263.38 g/mol
StateSolid (usually the hydrochloride salt, white crystalline powder, freely water-soluble)
Melting point178–181 °C (hydrochloride salt)
Boiling pointunavailable: true. reason: the only figure available is a software prediction (~406 °C at 1 atm), which is not physically meaningful: tramadol is a crystalline solid that thermally decomposes (pyrolyses) well before boiling, so no reliable experimental boiling point exists
DensityNot reported
Vapor pressureNot reported
pKa9.41
LogP1.34
SolubilityHydrochloride salt: freely soluble in water, Free base: ≈0.75 g/L in water
Refractive indexNot reported
Identifiers & Synonyms
CAS27203-92-5
CAS (enantiomer)
PubChem CID33741
InChIKeyTVYLLZQTGLZFBW-ZBFHGGJFSA-N
InChIInChI=1S/C16H25NO2/c1-17(2)12-14-7-4-5-10-16(14,18)13-8-6-9-15(11-13)19-3/h6,8-9,11,14,18H,4-5,7,10,12H2,1-3H3/t14-,16+/m1/s1
SMILESCN(C)C[C@H]1CCCC[C@@]1(C2=CC(=CC=C2)OC)O

Synonyms

  • Ultram
  • Tramal
  • Tramadol
  • Zydol
Pharmacodynamics & Biochemistry

Tramadol (Ultram, Tramal, Zydol) is an atypical, centrally-acting analgesic with two mechanisms working together: it is a weak agonist at the μ-opioid receptor (MOR) and, at the same time, a serotonin–noradrenaline reuptake inhibitor (SNRI). The monoaminergic action contributes much of the pain relief, which is why its analgesia is only partly reversed by naloxone. It is given as a racemate whose two enantiomers are complementary: (1R,2R)-(+)-tramadol carries most of the opioid activity and inhibits serotonin reuptake, while (1S,2S)-(−)-tramadol mainly inhibits noradrenaline reuptake. The opioid component is delivered largely not by tramadol itself but by its metabolite. Tramadol is a weak MOR ligand: at the cloned human μ-receptor its Kᵢ is about 2.4 µM, but the CYP2D6-generated metabolite O-desmethyltramadol (M1) binds roughly 700-fold more tightly (Kᵢ ≈ 3.4 nM) with high, morphine-like intrinsic activity, and accounts for most of the opioid effect. Tramadol has negligible affinity at the δ- and κ-opioid receptors (Kᵢ >10 µM). Its serotonin- and noradrenaline-reuptake inhibition sits in the low-micromolar range. Because M1 formation depends on CYP2D6, the response varies with genetics and interactions: CYP2D6 poor metabolisers get less analgesia, while ultra-rapid metabolisers produce more M1 and are at higher risk of opioid toxicity: a particular danger in children. The dual mechanism also gives tramadol two class-atypical hazards beyond ordinary opioid effects: it lowers the seizure threshold, and its serotonergic action can precipitate serotonin syndrome (see safety).

Biological targets

  • MOR
  • SERT
  • NET

Binding & functional measurements

TargetMeasurementSpecies
μ-opioid receptorKi 2,400 ± 1,100 nMHuman
Pharmacokinetics
BioavailabilityOral ≈70% (rising with repeated dosing)
Tmax≈1.5–2 h
Half-life≈6 h (M1 ≈7–9 h)
VdNot reported
Protein bindingNot reported
MetabolismHepatic CYP2D6 to active M1. CYP3A4 to inactive metabolites
ExcretionRenal
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

Tramadol is often perceived as a 'mild' opioid, but its dual mechanism gives it risks ordinary opioids do not have. It lowers the seizure threshold and can cause convulsions even at therapeutic doses, seizures occur in roughly half of acute tramadol overdoses, and the risk rises with antidepressants, bupropion and other seizure-threshold-lowering drugs. Its serotonergic action can trigger serotonin syndrome, especially combined with SSRIs, SNRIs, MAOIs, triptans or other serotonergic agents. On top of these it carries the usual opioid dangers: dose-dependent respiratory depression (dangerous with alcohol, benzodiazepines and other CNS depressants, and unpredictable in CYP2D6 ultra-rapid metabolisers and in children: the basis for regulatory restrictions in under-12s), constipation, and physical dependence. Its withdrawal is atypical too: alongside ordinary opioid withdrawal it can produce SSRI-discontinuation-like symptoms (paraesthesia, 'brain zaps', tinnitus) and sometimes hallucinations, paranoia and severe anxiety, and it can last longer than withdrawal from conventional opioids. Naloxone only partially reverses an overdose (and can itself raise seizure risk). Overdose is genuinely dangerous, particularly with other depressants.[6]

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

SSRIs, SNRIs, MAOIs, Triptans, Other serotonergic drugs Risk of serotonin syndrome, with MAOIs contraindicated within 14 days (also tricyclics, linezolid and St John's wort).[6]
Drugs that lower the seizure threshold Antidepressants, bupropion, antipsychotics or stimulants add seizure risk.[6]
Strong CYP2D6 inhibitors (e.g. paroxetine, fluoxetine) Paroxetine, fluoxetine or quinidine reduce M1 formation and opioid analgesia, while ultra-rapid metabolisers risk toxicity.[6][4]
Alcohol, Benzodiazepines Additive respiratory depression and sedation (opioid boxed warning).[6]

Contraindications

Concurrent MAOI, SSRI/SNRI or other serotonergic medication concurrent or recent (within 14 days) MAOI use.[6]
Current or prior seizure disorder uncontrolled epilepsy or seizure disorder.[6]
Significant respiratory depression or acute severe asthma severe respiratory depression or acute severe asthma.[6]
Combining with alcohol or other CNS depressants acute intoxication with alcohol, hypnotics, opioids or psychotropics.[6]
Children (age-restricted; respiratory-depression risk) children under 12, and under 18 after tonsillectomy or adenoidectomy.[6]
Pregnancy or breastfeeding and caution in the elderly.[6]
Usage & Context
  • A prescription analgesic for moderate to moderately-severe acute and chronic pain, positioned between simple analgesics and stronger opioids (about one-tenth the potency of morphine).
  • Also used off-label for premature ejaculation (exploiting its serotonergic action) and, occasionally, refractory restless-legs syndrome.
  • Widely misused: its opioid-plus-SNRI effect and a historically 'low-risk' reputation drove non-medical use, prompting scheduling in the US and UK in 2014.
Sources & Evidence

Further Information