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.