Seizures associated with low-dose tramadol for chronic pain treatment

Abstract

The management of cancer pain still poses a major challenge for clinicians. Tramadol is a centrally acting synthetic opioid analgesic. Its well-known side effects include nausea, vomiting, and dizziness; seizures are a rare side effect. Some reports have found that tramadol triggers seizure activity at high doses, whereas a few preclinical studies have found that this seizure activity is not dose-related. We herein present a case involving a patient with laryngeal cancer who developed seizures while on low-dose oral tramadol.

INTRODUCTION

Management of cancer pain is very important considering the rapidly increasing number of patients with cancer. The revised recommendations regarding analgesic treatment published by the World Health Organization must be followed to achieve successful pain management.

Tramadol hydrochloride is a synthetic, centrally acting, opiate-like analgesic that is used to treat acute and chronic pain. Tramadol and its active metabolite O-desmethyltramadol bind the µ-receptors of opioids, thus inhibiting gamma-amino butyric acid. Tramadol inhibits the re-uptake of monoamines such as noradrenaline and serotonin via two mechanisms.[1] However, its opioid component causes side effects including vomiting, nausea, constipation, and somnolence, whereas its monoaminergic effects include dizziness, sweating, and xerostomia.[2] Selective cyclooxygenase-2 inhibitors decrease the side effects of opioid analgesics, such as tramadol and transdermal fentanyl patches, which can be used to reduce pain for up to 72 h.[3]

Seizures are a rare side effect of tramadol. Tramadol-related seizures are short, tonic-clonic seizures that, like other drug-related seizures, are self-limiting. This epileptogenic effect of tramadol occurs at both low and high doses.[4] We herein report the development of seizures after the use of low-dose tramadol in a patient with laryngeal cancer. We also present a short review of the relevant literature.

CASE REPORT

A 51-year-old man had been diagnosed with laryngeal cancer 1.5 years prior to presentation. He had undergone total laryngectomy and tracheostomy followed by 2 months of postoperative radiotherapy and chemotherapy. He presented to our pain clinic with severe head, neck, and shoulder pain that was unilateral, throbbing, cutting, and did not change with movement or rest.

Using a visual analog scale, the severity of his pain was assessed as 6/10. The patient regularly used paracetamol (Parol 500 mg tablet, Atabey Pharma, Turkey) at 2 g/day, piroxicam (Felden Flush 20 mg tablet, Cardinal Health, UK) at 20 mg/day, and ondansetron (Zofer 4 mg tablet, Adeka Pharma, Turkey) at 4 mg/day. He consumed a liquid diet. His Eastern Cooperative Oncology Group performance scale score was 3 (reduced ability to care for himself and bedridden >50% of the time). This disrupted the patient's sleep habits and affected his daily life.

The patient was treated with oral tramadol drops in divided doses equal to 75 mg per day. Two days later, he returned to the clinic. His wife reported that 10 min after taking the drug, he began shaking, lost consciousness for approximately 1 min, and was diaphoretic. The patient was hospitalized and monitored. Although the oral tramadol was stopped, he had two short generalized tonic-clonic seizures while hospitalized that day. Cranial computed tomography and electroencephalography findings were normal and neurological metastasis findings were not determined. No seizures occurred during his follow-up.

DISCUSSION

Tramadol is a synthetic opioid consisting of (+) and (−) enantiomers that contribute to the analgesic activity via different mechanisms. The (+) enantiomer of tramadol is an opioid µ-receptor agonist that also stimulates serotonin release and inhibits its re-uptake, whereas the (−) enantiomer inhibits norepinephrine re-uptake.[5] After a single oral dose, tramadol is rapidly and almost completely absorbed, but its bioavailability is only 68% because of first-pass elimination in the liver. The bioavailability of tramadol reaches 90–100% after multiple oral doses after saturation of the first-pass effect of the liver.

A preclinical study of rats found that tramadol is both a pro-convulsant and anti-convulsant.[6] Tramadol has anti-convulsant effects at normal analgesic doses, but when increased to medium–high doses, myoclonic activity and generalized convulsions occur due to the interaction of the two tramadol enantiomers.[6] Nevertheless, our patient had seizures while treated with the normal therapeutic dose (75 mg/day). The pro-convulsant effects of low-dose opioids are reportedly associated with opioid receptor affinity or variation in cerebral and intrinsic activity.[3,5,7,8]

There are many reports of seizures following tramadol overdoses,[9] including seizures associated with intravenous tramadol as a premedication,[10] seizures in drug abusers, and seizures in association with tramadol intoxication.[11] In all of these cases, high blood tramadol concentrations likely induced the seizure activity. However, the relationship between the tramadol dose and seizure activity is controversial. One study reported that high doses of tramadol triggered the seizure activity, suggesting that seizure activity is dependent on the dose.[12] However, other studies reported that the seizure activity was not associated with the dose of tramadol.[4,7] We believe that tramadol can induce seizures at low doses, as in our case. We found no reports of seizure activity with low-dose oral tramadol used in the treatment of chronic pain in cancer therapy. However, we did find a report of a 5-month-old patient with a teratoma who developed a seizure when using patient-controlled analgesia with intravenous tramadol.[13]

Tramadol oral drops, capsules, and intravenous forms are frequently used to treat both cancer and noncancer pain. We believe that it is important to monitor them for seizure activity and other side effects of prolonged tramadol use, especially in the treatment of cancer pain.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest