Summary for UKPID


    Anne Prince, BSc (Hons) MRPharmS

    National Poisons Information Service (Newcastle Centre)
    Regional Drug & Therapeutics Centre
    Wolfson Building
    Claremont Place
    Newcastle upon Tyne
    NE1 4LP

    This monograph has been produced by staff of a National Poisons
    Information Service Centre in the United Kingdom.  The work was
    commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review group: Directors of the UK National Poisons Information


    Tramadol Hydrochloride

    Type of product

         opioid analgesic with agonist activity


         tramadol hydrochloride tablets/capsules 50 mg, injection 100 mg
         and sustained release tablets 100 mg, 150 mg, 200 mg


         The fatal dose is not known. Two children aged 5 weeks and 6
         months presented with coma, miosis and respiratory depression
         after rectal administration of 100 mg but recovered after
         treatment with naloxone.


         Progressive depression of the central nervous system leading to
         deep coma, cyanosis and marked reduction of the respiratory rate
         before respiratory arrest occurs.

         Pin point pupils, nausea and vomiting in less severs cases.

         Hypotension, tachycardia, hallucinations and rhabdomyolosis have
         been reported.


    1. Give naloxone IV(1.2 mg for an adult and 0.01mg/kg body weight for
    children) if coma or respiratory depression are present. Repeat the
    dose if there is no response after 2 minutes.

    2. Observe patient for recurrence of CNS and respiratory depression.
    The plasma half life of naloxone is shorter than that of most opioids
    and repeated doses may be required. Intravenous infusions may be
    necessary where repeated doses have been required.

    3. Establish clear airway, adequate ventilation and oxygenation if
    there is no response to naloxone.

    4. Assisted ventilation with positive end expiratory pressure may be
    necessary if pulmonary oedema is a complication.

    5. Empty the stomach if indicated.(This would not be suggested by the
    Newcastle Poisons Centre)

    6. Other supportive measures as indicated by the patients progress.

    Brand name

         Zydol , Zydol SR ,Tramake


         Tramadol hydrochloride

    Chemical group/family

         Opioid-type analgesic
         BNF 4.7.2

    Reference Number

         CAS 27203-92-5 (tramadol)
         CAS 22204-88-2 (tramadol HCl)
         CAS 36282-47-0 (tramadol HCl)

    Product licence numbers

         08821/0005 (Zydol caps)
         08821/0004 (Zydol amps)


         Searle Pharmaceuticals
         PO Box 53,
         Lane End Rd,
         High Wycombe,
         HP12 4HL
         Tel 01494 521124


         Capsules 50 mg, pack size 100 capsules
         Slow release tablets; 100 mg, 150 mg, 200 mg
         Pack size 60 tablets.
         Injection; 50 mg/ml (2ml amp)
         Pack size 5 ampoules.

    Physio-chemical properties1

    Chemical structure
         (+/-) - trans-2- Dimethyl-nomethyl-1-(3-
         methoxyphenyl)cyclohexanol hydrochloride

    Molecular Weight



         Tramadol is indicated for the management (treatment and
         prevention) of moderate to severe pain

    Therapeutic Dose (Data Sheet)

    Adults and children over 12 years

         Oral -         50 mg to 100 mg followed not more frequently than
                        4 hourly. A total daily dose of more than 400 mg
                        is not generally required.

         IV/IM -        For post operative pain an initial dose of 100 mg
                        is given. During the next 60 minutes 50 mg can be
                        given every 10-20 minutess upto a total dose of
                        250 mg. Maximum 600 mg daily.

    Children under 12 years

         Not recommended.


         Usual dose

    Renal Impairment

         Severe         not recommended
         Moderate       increase the dosage interval to 12 hours

    Hepatic Impairment

         Severe         increase the dosage interval to 12 hours


    Head injury, epilepsy, raised intracranial pressure, patients on other
    respiratory depressant drugs.


    Known sensitivity to tramadol
    Patients taking MAOI's or within two weeks of stopping.


    There are no published data on the outcome of human pregnancy after
    tramadol exposure in the first trimester. Tramadol has been used
    during labour with no significant adverse effects on the

    Animal studies have not demonstrated any increase in fetal
    malformation. Tramadol should not be given to pregnant women as there
    is inadequate evidence available on its safety.

    Breast Feeding2

    Tramadol and its metabolites are found in small amounts in human
    breast milk and it is thought that an infant could ingest 0.1% of the
    dose given to the mother. The Data Sheet states that tramadol should
    not be administered to breast feeding mothers.


    Physical and psychological dependence is a potential risk, although
    tramadol is at present, less abused as a single drug than conventional
    opioids. Cases of abuse and dependence have occurred.

    Hazard / risk classification:


         68% after a single oral dose
         90-100% following multiple doses

    Volume of distribution
         203L (IV)


    Elimination half life

         28L/h (IV)

    Protein binding


    In single and repeated dose studies (rodents and dogs) doses 10 times
    those used in man produce signs of hepatotoxicity. Symptoms of
    toxicity are typical of opioids and include restlessness, ataxia,
    vomiting, tremor, dyspnoea and convulsions.

    Epidemiology of poisoning5

    No specific figures available for tramadol however in 1992 (the latest
    year for which figures are currently available) 226 deaths (190 male,
    36 female) were attributed to opiates and related narcotics. This
    represents 11.4% of deaths from poisoning by drugs, medicaments and

    biological substances. 144 deaths (130 male, 14 female) were due to
    accidental poisoning, 32 (20 male, 12 female) to suicide and self-
    inflicted injury,(female) to homicide and injury purposely inflicted
    by other persons, and 49 to injury undetermined whether accidentally
    or purposely inflicted. Tramadol has a lower respiratory depressant
    effect than other opioids and may have a lower abuse potential.

    Adverse Effects2

    Nausea, vomiting, dry mouth. Tiredness, fatigue, drowsiness,
    solmonence, dizziness, headache, confusion, hallucinations and
    infrequently respiratory depression. Rarely convulsions, dependence
    and dysphoria .


    Other CNS depressant drugs, Carbamazepine lithium, SSRIs and tricyclic

    Mechanism of Action/Toxicity

    Tramadol is a centrally acting analgesic which acts at opiate
    receptors and toxic effects are usually extensions of its
    pharmacological activity.

    Features of Poisoning



    Overdose effects of tramadol are usually extensions of its
    pharmacological activity and include miosis, vomiting, siezures, coma,
    and cardiovascular collapse. The effects are similar to other opioids
    but effects on respiratory depression and smooth muscle are usually
    less pronounced with tramadol.


    Cardiovascular collapse can occur


    Severe overdoses can result in respiratory depression and pulmonary


    Cerebral depression and seizures can result from tramadol overdose


    Gastrointestinal effects are common. Nausea, vomiting, constipation,
    abdominal pain, flatulance and xerostomia can occur


    Urinary retention or frequency may occur


    Erythema, pruritis and diaphoresis occur infrequently



    Give a dose of activated charcoal if presentation is within 1-2 hours
    of ingestion. Gastric aspiration or lavage may be indicated if
    presentation is soon after ingestion in a patient known to have taken
    large quantities. Gastric aspiration may be appropriate if the patient
    is comatose provided the airway is protected.

    Supportive Care

    Support respiratory and cardiovascular functions as necessary and
    ensure a clear airway.


    Administer IV fluids.


    Treatment is based on clinical presentation rather than on specific
    laboratory data. Monitor arterial blood gases, pulmonary function and
    chest X ray for patients with significant exposure.


    Administer IV diazepam bolus (dose: adult: 5-10 mg initially which may
    be repeated every 15 minutes PRN upto 30 mg. Child: 0.25 to 0.4
    mg/kg/dose upto 10 mg/dose.

    Pulmonary oedema (non cardiogenic)

    Maintain ventilation and oxygenation with close arterial blood gas
    monitoring. Early use of PEEP and mechanical ventilation may be needed
    to maintain PO2 greater than 50mmHg with FIO2 less than 60%.


    Give naloxone, preferably intravenously, if respiratory depression or
    coma are present (1.2 mg for an adult and 0.01 mg/kg body weight for
    children). Repeat dose if there is no response within 2 minutes.
    Failure of a definite opioid overdose to respond suggests that another
    CNS depressant drug or brain damage is present. The plasma half life
    of naloxone is shorter than that of most opioids and therefore
    repeated doses may be necessary. If a large dose has been taken and
    relapse occurs set up an infusion (5 x 400 mcg ampoules naloxone = 2
    mg in 500ml 5% dextrose) at a rate = 2/3 of the dose needed to wake
    patient up per hour.

    Elimination Techniques

    Tramadol is minimally eliminated from the serum by haemodialysis or

    Case Data

    1. A six month old infant was inadvertently administered 100 mg of
    tramadol rectally. Tramadol concentrations in the serum, CFS, and
    urine were in the toxic range(>20 mcg/ml). The infant developed
    seizures, severe somnolence, miosis, and respiratory depression.
    Seizures were controlled with diazepam, while artificial ventilation
    and intravenous naloxone were initiated to reverse respiratory
    depression. The infant recovered rapidly with no further sequelae.4

    2. A 5 week old infant was mistakenly given 100 mg( 27mg/kg) tramadol
    rectally and developed severe cerebral depression with subsequent
    respiratory depression. Both symptoms were successfully treated with
    intravenous naloxone over the next 48 hours.4

    3. A 41 year old man was found dead in a hotel room. He was previously
    diagnosed with depression. Multiple containers of medication were
    found at the scene. Autopsy findings included fully developed rigor
    mortis and pulmonary edema with haemorrhage. Toxicological analysis of
    different body fluids was performed and the following results obtained
    in the blood (mg/L): moclobemide (59.76), clomipramine (I.69),
    tramadol (10.89), diazepam (2.08), nordiazepam (0.82) and caffeine
    (9.64). A fatal serotonin syndrome presumably developed as a result of
    meclobemide-clomipramine interaction. Tramadol could have a
    synergistic effect on the syndrome. The forensic pathologists ruled
    that the the cause of death was multiple drug intoxication resulting
    in serotonin syndrome and that the manner of death was suicide6.

    4.A 36 year old HIV positive man believed to have taken up to 110 x 50
    mg tramadol tablets was found unresponsive. On arrival at hospital he
    was given 2 mg of intravenous naloxone and immediately became awake
    and was able to answer questions. Within 30 minutes the patient became
    increasingly drowsy with shallow respirations. He again responded to 2
    mg of intravenous naloxone. In the next 10 minutes, he became 

    responsive to pain only. At this point after he again responded to 2
    mg naloxone, a continuous infusion of naloxone was initiated at 6
    mg/hour. This was titrated up to 12 mg/hour because of increasing
    lethargy. The patient was also given 1g/kg of activated charcoal
    orally. Four hours after his arrival at the hospital a slow wean from
    the naloxone drip was initiated; this was completed approximately 16
    hours later without any further depression of respiratory or mental
    status. The patient was discharged from hospital 1 day later.7


    Anne Prince, BSc (Hons) MRPharmS

    National Poisons Information Service (Newcastle Centre)
    Regional Drug & Therapeutics Centre
    Wolfson Building
    Claremont Place
    Newcastle upon Tyne
    NE1 4LP

    This monograph was produced by the staff of the Newcastle Centre of
    the National Poisons Information Service in the United Kingdom. The
    work was commissioned and funded by the UK Departments of Health, and
    was designed as a source of detailed information for use by poisons
    information centres.

    Peer review was undertaken by the Directors of the UK National Poisons
    Information Service.

    Last updated February 1997


    1.   Martindale. The Extra Pharmacopoeia, 31st Edition, Pharmaceutical
         Press 1996.

    2.   ABPI. Compendium of Data Sheets and Summaries of Product
         Characteristics. Datapharm Publications Ltd 1996-1997.

    3.   NTIS National Teratology Information Service.

    4.   C.R. Lee, D. McTavish and Sorkin M.E. Tramadol: A preliminary
         review of its pharmacological and pharmacokinetic properties and
         therapeutic potential in acute and chronic pain states. Drugs 46

    5.   DH4 no.18 Department of Health Document 1992.

    6.   Hernandez AF et al. Fatal moclobemide overdose or death caused by
         serotonin syndrome? Journal of Forensic Sciences 1995;40

    7.   Deepak K, Sachdeva and B Tilman Jolly. Tramadol overdose
         requiring prolonged opioid antagonism. American Journal of
         Emergency Medicine 1997;15(2):217-218.