A patient with Tramadol dependence and predictable provoked epileptic seizures.

Tramadol is an atypical, centrally acting synthetic analgesic with propensity for provoked seizures as well as abuse potential. The index case of Tramadol dependence discussed in this case report developed multiple epileptic seizures with high doses of Tramadol, used as a sexual enhancer by him, and later he learned to prevent the seizures by self-medicating with Alprazolam. The authors further emphasize on the regulation of Tramadol prescription.

INTRODUCTION

Tramadol is an atypical, centrally acting synthetic analgesic used to treat moderate to severe pain. Its antinociceptive effects are mediated by a combination of μ-opioid agonist effects and norepinephrine and serotonin reuptake inhibition, and it can suppress opioid withdrawal.[1] However, various controlled studies and post-marketing surveillance studies have reported an extremely small number of patients developing Tramadol abuse/dependence, with the incidence rate of 6.9/1000 persons per year.[2] A majority of Tramadol abusers (97%) had a history of other substance abuse.[3] Tramadol has also been reported to cause seizures at therapeutic and toxic doses.[4] In one study, it was most frequently associated with provoked seizures.[5] These were frequently generalized tonic–clonic type. They occurred most frequently within 24 h of Tramadol intake and were commonly seen in younger subjects with prolonged exposures to Tramadol and concomitant use of alcohol.[4] We present the case of a young male presenting with Tramadol dependence with a history of predictable provoked epileptic seizures that he was preventing by self-medicating with benzodiazepines.

CASE REPORT

The patient was a 24-year-old high school educated, married male farmer by occupation, who initially started chewing tobacco at the age of 17 years in the company of his friends. He developed dependence in the form of tolerance, withdrawal, and craving over a period of 6-8 months. At the age of 18 years, he took 2-3 tablets of Tramadol (as a combination preparation of 37.5 mg with Paracetamol 375 mg) on the advice of some friends who used the same to allay fatigue after working in the fields. These were freely available without prescription at the neighborhood pharmacy. The patient found it beneficial to allay fatigue and felt elated after its use and started to take it on a regular basis. Over the next 6-8 months, he developed tolerance and had to take 5-6 tablets/day to derive the same benefit and he experienced a craving to consume these tablets and would often start his day with these tablets. He also started to experience symptoms, of that he claimed were non-specific such as headache and fatigue when he did not take the regular dose of these tablets. This would be relieved on taking the tablets. Over the next 4-6 months, he also started to consume Alprazolam at the dose of 1-2 mg/day, again on the advice of friends who claimed it would help him relax. This too was available freely locally. Over a period of 1 year, he developed dependence to Alprazolam as well. After about 3 years of regular use of Tramadol and Paracetamol combination tablets, he once consumed 15-16 tablets on advice of a friend who claimed it would enable him to sustain an erection for longer duration sexual intercourse. His usual dose was 7-8 tablets of Tramadol–Paracetamol and 2 mg/day of Alprazolam. After about 1h of intake, the patient had an episode of unresponsiveness characterized by tonic–clonic movement of both upper and lower limbs for about 1 min, associated with clenching of teeth and frothing from mouth, following which he remained confused for about half an hour. He was at home at this time and did not take any particular treatment for the same. Gradually, however, he started to notice that whenever he took a higher than usual dose of Tramadol–Paracetamol combination, he would feel jittery and uncomfortable and then he would have an epileptic seizure. This, however, he could prevent by taking a higher than normal dose of Alprazolam at the dose of about 3-4 mg, which he would take concurrently with Tramadol–Paracetamol. He also observed that he could sustain an erection and withhold ejaculation for longer than was usual for him during intercourse whenever he took this higher than usual dose of Tramadol–Paracetamol. Therefore, whenever he planned for having sex, he would use a higher than usual dose of Tramadol–Paracetamol and then prevent the expected seizure with a higher than usual dose of Alprazolam. Whenever he got this combination wrong, he would either be dissatisfied with his sexual experience or have a seizure. Eventually, he was persuaded by family members to seek treatment for his drug taking and seizures. He took treatment from some private de-addiction centers without much relief. His usual pattern was to take 7-8 tablets of Tramadol–Paracetamol in the morning and 3-4 tablets in evening, which he would increase to 13-15 tablets in case he had to perform sexual intercourse and 7-8 tablets of 0.5 mg of Alprazolam daily in two divided doses. On admission and on quitting from his usual drugs, he complained of premature ejaculation and headache. His withdrawal symptoms were largely non-specific and the typical opioid withdrawal symptoms were not observed. His ward stay was essentially uncomplicated and a non-contrast computed tomography (CT) scan of the head and electroencephalography (EEG) were reported normal.

DISCUSSION

As seen in the index case and discussed above, Tramadol seems to have some abuse potential that is now being recognized. This action is probably due to its action at the μ-opioid receptor. This is further borne out by the fact that in the patient, the pattern of use was similar to that seen with other opioids. Its use as a sexual enhancer is also in keeping with the supposition that it is recognized and used as an opioid analog by experienced users.[6] The withdrawal symptoms described and observed were non-specific, but this could be more a function of the potency of the drug at the opioid receptor and modulation of symptoms by the complex neuropharmacology of the drug. Another point of interest is the predictability of the seizures in the setting of a higher than usual intake of Tramadol–Paracetamol. This is in keeping with the definition of provoked seizure by International League against Epilepsy.[7] The pattern seen here was similar to that seen with seizures reported with abuse of combination preparations of Dextropropoxyphene and Paracetamol.[8] Paracetamol is not known to be associated with seizures, so it is probable that the seizures seen in the index patient were due to Tramadol and this may be an idiosyncratic susceptibility. Finally, the patient was able to self-medicate and prevent seizures with Alprazolam, which as a benzodiazepine has anti-epileptic effects.

CONCLUSION

The index case discussed here had multiple seizures with Tramadol in higher dose, which he was preventing by self-medicating with benzodiazepine. We would like to use this case report as a call to practitioners to be aware of the abuse and seizure potential of Tramadol, and to call for strict regulation on the sale of the same.