Summary for UKPID
Tramadol
Anne Prince, BSc (Hons) MRPharmS
National Poisons Information Service (Newcastle Centre)
Regional Drug & Therapeutics Centre
Wolfson Building
Claremont Place
Newcastle upon Tyne
NE1 4LP
UK
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
Service.
Summary
Tramadol Hydrochloride
Type of product
opioid analgesic with agonist activity
Ingredients
tramadol hydrochloride tablets/capsules 50 mg, injection 100 mg
and sustained release tablets 100 mg, 150 mg, 200 mg
Toxicity
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.
Features
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.
Management
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
Generic
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)
Manufacturer/supplier
Searle Pharmaceuticals
PO Box 53,
Lane End Rd,
High Wycombe,
Bucks.
HP12 4HL
Tel 01494 521124
Presentation
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
C16H25NO2,HCL
Molecular Weight
299.8
Uses2
Indications
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.
Elderly
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
Precautions
Head injury, epilepsy, raised intracranial pressure, patients on other
respiratory depressant drugs.
Contraindications
Known sensitivity to tramadol
Patients taking MAOI's or within two weeks of stopping.
Pregnancy3
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
fetus/neonate.
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.
Abuses
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:
Pharmacokinetics4
Bioavailability
68% after a single oral dose
90-100% following multiple doses
Volume of distribution
203L (IV)
Metabolism
85%
Elimination half life
5hr
Clearance
28L/h (IV)
Protein binding
20%
Toxicokinetics2
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 .
Interactions
Other CNS depressant drugs, Carbamazepine lithium, SSRIs and tricyclic
antidepressants.
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
(Toxbase/Poisondex)
Summary
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
Cardiovascular collapse can occur
Respiratory
Severe overdoses can result in respiratory depression and pulmonary
oedema
Neurologic
Cerebral depression and seizures can result from tramadol overdose
Gastrointestinal
Gastrointestinal effects are common. Nausea, vomiting, constipation,
abdominal pain, flatulance and xerostomia can occur
Genitourinary
Urinary retention or frequency may occur
Dermatologic
Erythema, pruritis and diaphoresis occur infrequently
Management
Decontamination
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.
Hypotension
Administer IV fluids.
Monitor
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.
Seizures
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%.
Antidotes
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
haemofiltration.
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
Author
Anne Prince, BSc (Hons) MRPharmS
National Poisons Information Service (Newcastle Centre)
Regional Drug & Therapeutics Centre
Wolfson Building
Claremont Place
Newcastle upon Tyne
NE1 4LP
UK
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
References
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
(2):313-340;1993.5
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
(1):128-130
7. Deepak K, Sachdeva and B Tilman Jolly. Tramadol overdose
requiring prolonged opioid antagonism. American Journal of
Emergency Medicine 1997;15(2):217-218.