Published: October 2007

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Serious Reactions with Tramadol: Seizures and Serotonin Syndrome

Information on this subject has been updated. Read the most recent information.

Prescriber Update 28(1): 11-13.
October 2007

Ruth Savage, Medical Assessor, New Zealand Pharmacovigilance Centre, Dunedin

Seizures can occur with tramadol, particularly if high doses are used or there is concomitant use of medicines that lower the seizure threshold.  The use of tramadol with serotonergic medicines can increase the risk of serotonin syndrome.  To reduce the likelihood of these serious reactions occurring, prescribe the lowest effective doses of tramadol and avoid its use in patients with a history of seizure disorders.  In patients with risk factors for seizures or serotonin syndrome, it may be prudent to consider other analgesics instead of tramadol.

Tramadol is a centrally-acting analgesic indicated for moderate to severe pain.¹  It stimulates opioid receptors, and inhibits noradrenaline and serotonin reuptake.  Seizures and serotonin syndrome are amongst the more commonly reported serious adverse reactions attributed to tramadol in the CARM and the WHO International Drug Monitoring databases.

Clinical features of serotonin syndrome

Symptoms and signs of serotonin syndrome include at least three of the following: agitation, ataxia, increased sweating, diarrhoea, fever, hyperreflexia, myoclonus, or shivering.  The syndrome usually occurs after initiating or increasing the dose of a serotonergic medicine.

Medicines known to cause serotonin syndrome

Table 1: Agents causing serotonin syndrome2
Antidepressants	mirtazapine, monoamine oxidase inhibitors (including moclobemide), SSRIs, tricyclics, venlafaxine
Antiparkinson agents	amantadine, bromocriptine, carbergoline, levodopa, pergolide, selegiline
Illicit drugs	cocaine, hallucinogenic amphetamines such as MDMA (ecstasy), LSD, etc.
Migraine therapy	dihydroergotamine, naratriptan, sumatriptan, zolmitriptan
Other agents	bupropion, carbamazepine, lithium, morphine, pethidine, reserpine, sibutramine, St. John's wort, tramadol

Local reports of serotonin syndrome with tramadol

The CARM database holds three reports of serotonin syndrome occurring in patients taking tramadol.  In each case serotonin syndrome occurred after extra serotonergic medicine was taken, as follows: tramadol dose increased in a patient taking tramadol, paroxetine and thioridazine; tramadol added to long-term treatment with amitriptyline and high-dose fluoxetine (60mg daily); citalopram recommenced after patient started tramadol.  In the latter case, the tramadol was commenced in hospital where the patient's history of citalopram use was not recorded.

Tramadol can induce seizures especially at high doses

In the last five years, tramadol has been the most commonly implicated medicine in reports of seizures to CARM.  A total of ten reports were received to December 2006, involving eight females and two males with an age range of 15 to 49 years.  Ten patients were given tramadol orally and five intravenously.  Seizures have been reported in patients receiving tramadol at recommended dose levels.  However, reports to CARM indicate that high doses, co-prescribed medicines and a history of epilepsy may increase the likelihood of seizures with tramadol.

Three patients who had seizures were given greater than the maximum recommended dose.  One took 600mg orally over 12 hours; another, following a general anaesthetic and cyclizine, was given 50mg intravenously, followed five minutes later by 250mg intravenously as a single dose.  The third received an intravenous dose of 300mg; this patient had renal failure.  The box below shows recommended doses for tramadol and dose adjustments for patients with renal impairment.

Other medicines or history of seizures may further increase seizure risk

In the CARM reports, three patients were taking a tricyclic antidepressant (TCA) as well as tramadol.  One was also taking an antipsychotic medicine, and one an SSRI.  Two of these patients experienced seizures when the dose of tramadol was increased.  One of these took tramadol daily but had seizures on four occasions when the dose was increased.  The third patient developed seizures after tramadol was given following a general anaesthetic.

Three other patients developed seizures when tramadol was given intravenously following, or with, pethidine and/or cyclizine.  One other patient with a history of seizures experienced a marked increase in seizure frequency within 24 hours of starting oral tramadol 400mg daily.  He was not taking potentially interacting medicines.

Reducing the risk of serotonin syndrome and seizures with tramadol

The dose of tramadol should not exceed the recommended maximum daily dose or the recommended dose for a single administration - see box below.

To reduce the likelihood of serotonin syndrome occurring, avoid co-prescribing tramadol with the medicines listed in Table 1, if possible.  Tramadol is contraindicated in patients who are taking monoamine oxidase inhibitors or who have taken them within the last 14 days.¹  Prescribers also need to be aware that co-prescription of tramadol with tricyclic antidepressants, selective serotonin re-uptake inhibitors and antipsychotics can lower the seizure threshold.¹  Prescribers should bear in mind the potential risks of serotonin syndrome and seizures when making a clinical decision to use tramadol.

Seizures have been reported with high doses of pethidine,³ morphine,⁴ cyclizine,⁵ and ondansetron.⁶ Metoclopramide may lower the seizure threshold in patients with epilepsy.⁷  Therefore, if it is necessary for tramadol to be administered with or immediately after these medicines, the lowest effective doses of tramadol should be used.  Tramadol should be avoided in all patients who have epilepsy or are susceptible to seizures unless there are compelling circumstances.¹

Competing interests (author): none declared.

TRAMADOL DOSING GUIDELINES¹ *

The dose of tramadol should be titrated to the severity of the pain and the clinical response of the individual patient, after taking into account patient-specific factors such as renal function, concomitant medicines and co-morbidities such as seizures.

Oral tramadol - immediate release capsules, oral drops, and sustained release tablets
The total daily dose should not exceed 400mg.

Injectable tramadol
Single doses should not exceed 100mg.
For post-operative pain, the total daily dose must not exceed 600mg.
For less severe pain, the maximum daily dose is 400mg.

Renal insufficiency(see Note below)
Tramadol is not recommended in patients with severe renal impairment (creatinine clearance <10 mL/min).
In patients with a creatinine clearance of less than 30 mL/min, the dosage frequency of tramadol (injection, oral drops, and immediate release capsules) should be changed to 12-hourly, and to once every 24 hours for tramadol sustained release tablets.

Note: Clinical evidence is that the thresholds for classifying renal impairment are too generous⁸ and, consequently, dose adjustments may be warranted when creatinine clearance is less than 60 mL/min.⁹

* for adults and adolescents over the age of 12 years

References

1. CSL Biotherapies (NZ) Limited. Tramal (tramadol) data sheet. July 2007. www.medsafe.govt.nz/profs/Datasheet/t/TramalcapSRtabinjoraldrops.htm
2. ADRAC. Serotonin syndrome. ADRAC Bulletin 2004;23(1). www.tga.gov.au/adr/aadrb/aadr0402.htm
3. Pfizer New Zealand Ltd. RA Morph (morphine hydrochloride) data sheet. 31 May 2005. www.medsafe.govt.nz/profs/Datasheet/r/ramorphsol.htm
4. Hospira NZ Limited. Pethidine injection data sheet. 8 March 2012. www.medsafe.govt.nz/profs/Datasheet/d/dbPethidineinj.pdf
5. AFT Pharmaceuticals Ltd. Nausicalm (cyclizine hydrochloride) tablets data sheet. 22 March 2007. www.medsafe.govt.nz/profs/Datasheet/n/Nausicalmtab.htm
6. Arrow Pharmaceuticals (NZ) Ltd. Ondanaccord (ondansetron) injection data sheet. 21 August 2012. www.medsafe.govt.nz/profs/Datasheet/o/ondanaccordinj.pdf
7. AstraZeneca Limited. Metoclopramide injection data sheet. 30 October 2003. www.medsafe.govt.nz/profs/Datasheet/m/Metoclopramideinj.htm
8. Levey AS, Eckardt K-U, Tsukamoto Y, et al. Definition and classification of chronic kidney disease: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney International 2005;67:2089-2100.
9. Personal communication, 29 August 2007. Clinical pharmacologist, Wellington.