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| Treatment for Tramadol Overdose |
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A 24-year-old man presents to the ED after experiencing a seizure. The only medication he has currently been taking is tramadol, which he was prescribed for an injury that occurred a few weeks ago. After his admission to the ED, it was learned that his bottle of 40 tablets filled yesterday is currently empty. The seizure had resolved on its own before reaching the ED, so no anticonvulsant agents were administered. He claims that he was not experiencing appropriate pain relief with the prescribed dosage so he took the tablets more frequently in an attempt to relieve the pain.
After years of successful usage in Germany, tramadol was approved by the FDA in 1995 (1) for the treatment of acute and chronic pain, as well as cancer-related pain. It can also be used as an adjunct to anesthesia, which is a non-FDA labeled indication (2). The main advantage seen by bringing the drug into the U.S. market was its low abuse potential compared to opioid analgesics. A 2006 study found that tramadol posed no more of an abuse potential than NSAIDs in patients without a history of alcohol or substance abuse (3). This was seen as a valuable benefit due to the fact that pain is often undertreated and physicians are less likely to prescribe controlled analgesics out of concern for developing dependence and abuse potential. (4)
Its widespread use in painful conditions is due to the following:
Tramadol is a centrally-acting analgesic with a dual mechanism of action:
Adults (17+ years of age):
For moderate to moderately severe chronic pain not requiring rapid onset of analgesic effect, the following titration method is used to help improve tolerability of tramadol therapy: administer 25mg/day in the morning and add a separate 25mg dose every 3 days to reach 100mg/day (25mg 4 times/day). Thereafter, increase the total daily dose by 50mg/day every 3 days to reach 200mg/day (50mg 4 times/day). After titration, administer 50 to 100mg every 4 to 6 hours as needed for pain relief, not exceeding 400mg/day.
For patients that require rapid onset of pain relief and for whom the benefits outweigh the risk of discontinuation due to adverse effects from higher initial dosing, administer 50 to 100mg every 4 to 6 hours as needed for pain relief, not exceeding 400mg/day.
For extended-release tablets, dosing should begin at 100mg/day, increasing by 100mg every 5 days to relieve pain. Total daily dosage should not exceed 300mg, as clinical benefit has not been observed beyond that amount.
Elderly Population:
Caution should be used when selecting a dose for patients 65 years of age or older. Doses should be administered at the low end of the dosing range, taking into consideration the likelihood of decreased hepatic, renal, or cardiac function as well as concomitant disease or other drug therapy. For patients 75 years of age or older, maximum daily dosage of regular release tramadol should not exceed 300mg/day.
Renal impairment:
In patients with a creatinine clearance (CrCl) less than 30mL/min, the dosing interval should be increased to 12 hours and the total daily dose should not exceed 200mg. Tramadol extended-release tablets should not be used in renally impaired patients (CrCl < 30mL/min).
Hepatic impairment:
The recommended dosage for adults with cirrhosis is 50mg every 12 hours. Tramadol ER should not be used in severe hepatic impairment (Child-Pugh class C).
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Absorption:
Tramadol is rapidly and almost completely absorbed after oral administration. The mean bioavailability is approximately 75%. The peak plasma concentrations of racemic tramadol and the metabolite M1 occurs at 2 and 3 hours, respectively. Steady state is achieved within 2 days with 4-times-daily dosing. Absorption is not affected by food.
Distribution:
Tramadol has a volume of distribution of approximately 2.7L/kg. Plasma protein binding is approximately 20%.
Metabolism:
Tramadol is extensively metabolized following oral administration. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. One metabolite, M1, is pharmacologically active and its formation is dependent on the 2D6 isoenzyme of CYP-450. Therefore, therapeutic response may be affected by enzyme inhibition.
Excretion:
After metabolism by the liver, the metabolites of tramadol are eliminated primarily by the kidney. Approximately 30% is excreted as unchanged drug, whereas 60% is excreted as metabolites. The remainder is eliminated either as unidentified or unextractable metabolites. The mean half-lives of racemic tramadol and M1 are approximately 6 and 7 hours, respectively.
Pharmacology of Extended-Release (ER) Tramadol (11):
Tramadol ER tablets have diffusion-controlled semi-permeable coatings that provide in vivo drug release independent of gastrointestinal pH changes. Sustained-release tablets release the active ingredient over a period of 12 hours and reach peak concentrations after 4.9 hours. Administration is once daily, most commonly in the morning.
Tramadol has been known to be associated with the development of physical as well as psychological dependence, which may result in withdrawal symptoms upon the abrupt discontinuation of the drug. This agent is unique in that it has two mechanisms of action which may both contribute to its dependence and withdrawal properties. It has weak activity at the opioid receptor as well as serotonin and norepinephrine reuptake inhibition properties. Case reports of tramadol withdrawal to date have described anxiety and restlessness, autonomic dysfunction, abdominal cramping, diarrhea, and myoclonic activity of the extremeties. These symptoms, which are consistent with opioid withdrawal, have dramatically improved with resumption of mu-receptor activity. Although there is improvement seen after the administration of morphine, most cases show that complete resolution only occurs upon readministration of tramadol. This suggests that activity other than at the mu-receptor may also be responsible for dependency.(12) Dependence and withdrawal syndrome have been seen in chronic pain patients after abrupt discontinuation despite dosing within therapeutic range (up to 400mg/day) and regardless of past history of drug abuse (7). Patients should be advised to take tramadol as scheduled and to stop gradually, especially after long treatment periods. Physicians should consider the potential for physical dependence when they prescribe tramadol for pain (9).
Although it possesses opioid agonist properties, tramadol does not appear to produce significant respiratory depression or cardiovascular effects in most patients when taken therapeutically. However in toxic doses, serious effects that may be seen include respiratory depression, hypertension, tachycardia, seizures, coma, and others.
Review of clinical effects seen with tramadol toxicity by body system (13):
Central Nervous System:
CNS/respiratory depression, nausea/vomiting, seizures, dizziness, agitation, confusion, headache, hallucinations
Cardiac:
tachycardia, bradycardia, hypertension, hypotension
Other:
miosis, diaphoresis, hypokalemia, blurred vision, tachypnea, rash, pruritis, abdominal pain, edema, erythema, facial numbness, movement disorders (tremors, jerking, shivering, shaking), ataxia
Toxicity of tramadol usually occurs with dosages of 500mg or higher. In a 2005 study that observed 190 cases of tramadol overdose, CNS depression was the most common symptom seen (27.4% of the cases), followed by nausea/vomiting (21.1%), tachycardia (17.4%), and seizures (13.7%) (13). The smallest amount of tramadol associated with seizure was 200mg and 84.6% of seizures occurred within 6 hours of ingestion. Symptoms resolved within 24 hours in most of the symptomatic patients. Accidental ingestions by children were generally well tolerated, primarily causing sedation. Seizures appear to occur much more commonly in tramadol abuse than in therapeutic use. In a study focusing on the occurrence of seizures in abusers, it was found that tonic-clonic seizures occurred in 31 of 57 patients with 55% of those cases experiencing multiple seizures. Conversely, a retrospective surveillance study found that less than 1% of first time tramadol users experienced seizures (14). Mild serotonin syndrome may be seen in tramadol overdose with possible symptoms including agitation, confusion, tachycardia, and hypertension (15). Other symptoms that are likely to be seen in more severe cases of serotonin syndrome (usually when used in combination with another serotonergic agent) include cognitive-behavioral changes, neuromuscular hyperactivity, marked rigidity, trismus, rhabdomyolysis, coma, DIC, right heart failure, and disturbances of electrolytes, transaminases and creatinine kinase. Differential diagnoses to be ruled out include neuroleptic malignant syndrome, sepsis, hepatic encephalopathy, heat stroke, myocardial necrosis, delirium tremens and anticholinergic reactions (17).
Treatment for Tramadol Overdose
When treating tramadol overdosage, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. Although an opioid antagonist (e.g. naloxone) will reverse some, but not all, manifestations of tramadol overdosage, the risk of seizures also is increased with naloxone administration (16). In animals, seizures following toxic doses of tramadol could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Hemodialysis is unlikely to be helpful in a tramadol overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period (16).
The following guidelines are exemplary of the supportive treatment that may be required for tramadol overdose (8).
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Written by:
Mathew Hume, Pharm.D,11/2007
Reviewed by:
George M. Bosse, M.D. 11/2007
Henry A. Spiller M.S., D.ABAT 11/2007
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