pubmed.ncbi.nlm.nih.gov

Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy - PubMed

Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy

H Potschka et al. Br J Pharmacol. 2000 Sep.

Abstract

1. The centrally acting analgesic tramadol has recently been reported to cause seizures at re-commended dosages in patients, whereas animal experiments had indicated that seizures only occur in high, toxic doses. Tramadol has a dual mechanism of action that includes weak agonistic effects at the mu-opioid receptor as well as inhibition of monoamine (serotonin, norepinephrine) re-uptake. Its major (M1) metabolite mono-O:-desmethyltramadol, which is rapidly formed in vivo, has a markedly higher affinity for mu receptors and may thus contribute to the effects of the parent compound. Furthermore, the pharmacological effects of tramadol appear to be related to the different, but complementary and interactive pharmacologies of its enantiomers. In the present study, we evaluated (+/-)-tramadol, its enantiomers, and its M1 metabolite ((+)-enantiomer) in the amygdala kindling model of epilepsy in rats. Adverse effects determined in kindled rats were compared to those in nonkindled rats. 2. At doses within the analgesic range, (+/-)-tramadol and its enantiomers induced anticonvulsant effects in kindled rats. However, at only slightly higher doses seizures occurred. With (+/-)-tramadol, generalized seizures were observed at 30 mg kg(-1) in most kindled but not in nonkindled rats. The (-)-enantiomer induced myoclonic seizures at 30 mg kg(-1) in most kindled but not in nonkindled rats, although myoclonic seizure activity was observed in some nonkindled rats at 10 or 20 mg kg(-1). Seizures were also observed after the (+)-enantiomer and the (+)-enantiomer of the M1 metabolite, but experiments with higher doses of these compounds were limited by marked respiratory depression. 3. The data demonstrate that kindling enhances the susceptibility of rats to convulsant adverse effects of tramadol and its enantiomers, indicating that a preexisting lowered seizure threshold increases the risk of tramadol-induced seizures.

PubMed Disclaimer

Figures

Figure 1
Figure 1

Stereochemistry of tramadol and metabolic activation to the M1-metabolite O-desmethyltramadol.

Figure 2
Figure 2

Effect of (±)-tramadol on afterdischarge threshold (ADT) and seizure severity (SS), seizure duration (SD), and afterdischarge duration (ADD) recorded at ADT in fully kindled rats. Doses in mg kg−1 i.p. are indicated below each bar. Data from predrug control trials are shown as open bars. Data are means±s.e.mean of groups of nine rats per dose. Significance of difference between a drug trial and the individual predrug control experiment in the same group of rats is indicated by asterisk (P<0.05).

Figure 3
Figure 3

Effect of (−)-tramadol on afterdischarge threshold (ADT) and seizure severity (SS), seizure duration (SD), and afterdischarge duration (ADD) recorded at ADT in fully kindled rats. Doses in mg kg−1 i.p. are indicated below each bar. Data from predrug control trials are shown as open bars. Data are means±s.e.mean of groups of 7–9 rats per dose. Significance of difference between a drug trial and the individual predrug control experiment in the same group of rats is indicated by asterisk (P<0.05).

Figure 4
Figure 4

Effect of (+)-tramadol on afterdischarge threshold (ADT) and seizure severity (SS), seizure duration (SD), and afterdischarge duration (ADD) recorded at ADT in fully kindled rats. Doses in mg kg−1 i.p. are indicated below each bar. Data from predrug control trials are shown as open bars. Data are means±s.e.mean of groups of 7–8 rats per dose. Significance of difference between a drug trial and the individual predrug control experiment in the same group of rats is indicated by asterisk (P<0.05).

Figure 5
Figure 5

Effect of (+)-desmethyltramadol, i.e., the active M1 metabolite of tramadol on afterdischarge threshold (ADT) and seizure severity (SS), seizure duration (SD), and afterdischarge duration (ADD) recorded at ADT in fully kindled rats. Doses in mg kg−1 i.p. are indicated below each bar. Data from predrug control trials are shown as open bars. Data are means±s.e.mean of groups of 8–9 rats per dose. Significance of difference between a drug trial and the individual predrug control experiment in the same group of rats is indicated by asterisk (P<0.05).

Similar articles

Cited by

References

    1. ALBERTSON T.E., JOY R.M., STARK L.G. Modification of kindled amygdaloid seizures by opiate agonists and antagonists. J. Pharmacol. Exp. Ther. 1984;228:620–627. - PubMed
    1. ALLDREDGE B.K. Seizure risk associated with psychotropic drugs: clinical and pharmacokinetic considerations. Neurology. 1999;53 Suppl. 2:S68–S75. - PubMed
    1. BAMIGBADE T.A., LANGFORD R.M. Tramadol hydrochloride: an overview of current use. Hosp. Med. 1998;59:373–376. - PubMed
    1. BOWDLE T.A. Adverse effects of opioid agonists and agonists-antagonists in anaesthesia. Drug Saf. 1998;19:173–189. - PubMed
    1. BRODIE M.J. Drug interactions in epilepsy. Epilepsia. 1992;33 Suppl. 1:S13–S22. - PubMed

Publication types

MeSH terms

Substances