hur vanligt är det med kramper som biverkningar till Tramadol?

Fråga: Frågeställaren har en fråga kring Tramadol tabletter. Hur vanligt är det att man får kramp till följd av Tramadol?

Svar: SAMMANFATTNING

The incidence of seizures under tramadol therapy is reported to be less than 1%. The threshold dose for seizures may be as low as 100 mg although most seizures occur in younger adults abusing tramadol at doses greater than 1000 mg. The risk is increased with concomitant intake of SSRIs, tricyclic antidepressants, tricyclic compounds, MAOIs, neuroleptics, opioids, and other drugs that lower the seizure threshold, as well as in patients with a history of epilepsy and in patients with a recognized risk for seizures.

Interethnic differences in variant CYP2D6 allele frequencies may explain why subjects from certain populations may be more susceptible to adverse events than other population.

The higher frequency of seizures among Iranian patients observed by the questioner may be partially explained by the higher CYP2D6*10 allele frequency and the consequent reduced tramadol metabolic capacity among the Iranian population compared to other populations.

SVAR
The question concerning the association between tramadol and seizures has been recently evaluated by the Region Västerbotten drug information center ELINOR (1).

The incidence of seizures under tramadol therapy is reported to be less than 1% in clinical trials or postmarketing experience (2-3) and described as rare (dvs =1/10 000, <1/1 000) in the Tramadol SPC (4). The risk is increased with concomitant intake of SSRIs, tricyclic antidepressants, tricyclic compounds, MAOIs, neuroleptics, opioids, and other drugs that lower the seizure threshold, as well as in patients with a history of epilepsy and in patients with a recognized risk for seizures (such as with head trauma, metabolic disorders, or drug and alcohol withdrawal) (2-3).

Although tramadol triggered seizures have been reported with doses as low as 75mg (5), a recent published review (6) reported that the threshold seizurogenic tramadol doses range from 100 to 500 mg, while other suggest an even higher range (500 to 1000 mg, 7). Emerging data suggests that most seizures occur in younger adults abusing tramadol at doses greater than 1000 mg (6). A case- control study showed that the risk of seizure was highest for people aged 25 to 54 years (8).

The metabolism of tramadol to the active metabolite o-desmethyltramadol is catalyzed by the hepatic enzyme CYP2D6, the activity of which varies widely between individuals and it is highly polymorphic (6, 9). The seizure risk appears to be greater in combination with CYP2D6 inhibitors (6).

A prospective multicenter registry survey, with participating sites in the United States, Canada, Israel, and Thailand, evaluating the effects of a single dose of tramadol in 80 patients (10), found that tramadol induced seizures are more likely in Asian patients. The authors hypothesized that this may be due to altered CYP2D6 metabolism. The frequency of the CYP2D6*10 allele, that causes reduced enzyme function, is rather high in Asian populations and may be present in 40%–50% of individuals, while its frequency among Caucasians is only 1-2% (10-11). This allele causes slower drug metabolism and has been associated with prolonged mean serum half-life of tramadol in CYP2D6*10 homozygous individuals compared with subjects carrying one (heterozygous) or no variant allele. Tramadol is known to cause serotonin and norepinephrine reuptake inhibition. Murray et al. (10) suggested that its prolonged presence may in part explain the increased seizure frequency in the Asian population due to increase risk from serotonergic toxicity.

A recent published study on 300 Iranian subjects of different ethnicities showed that approximately 24% of the studied population was homozygous for the CYP2D6*10 allele, a condition that may cause susceptibility to adverse or poor drug responses l (12). The CYP2D6*10 allele was found to have a frequency of 31,9% in the Iranian population, much higher than the frequency among Caucasians (12).

1. https://vardgivare.skane.se/contentassets/4a6d46b0be074ff296d0d7b7d3599006/tramadol-risk-for-kramper-mediacin-2019-13.pdf
2. MICROMEDEX Healthcare Series, Thomson MICROMEDEX, Greenwood Village, Colorado [hämtat 2020-07-14].
3. https://www.uptodate.com/contents/search, sökning gjord 2020-07-14
4. Produktresumé. www.fass.se, sökning gjord 2020-07-14
5. Beyaz SG. Sonbahar T, Bayar F, Erdem AF. Seizures associated with low-dose tramadol for chronic pain treatment. Anesth Essays Res. 2016 May-Aug;10(2): 376-8.
6. Hassamal S, Miotto K, Dale W, Danovitch I. Tramadol: Understanding the Risk of Serotonin Syndrome and Seizures. Am J Med. 2018;131(11): 1382.e1-1382.e6.
7. Talaie H, Panahandeh R, Fayaznouri M, Asadi Z, Abdollahi M. Dose-independent occurrence of seizure with tramadol. J Med Toxicol. 2009 Jun; 5(2):63-7.
8. Gardner JS, Blough D, Drinkard CR, et al.Tramadol and seizures: a surveillance study in a managed care population. Pharmacotherapy. 2000 Dec;20(12):1423-31.
9. Stamer UM, Musshoff F, Kobilay M, et al. Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther. 2007; 82:41–47.
10. Murray BP, Carpenter JE, Dunkley CA, et al. Seizures in tramadol overdoses reported in the ToxIC registry: predisposing factors and the role of naloxone. Clin Toxicol (Phila). 2019;57(8):692-696.
11. Ingelman-Sundberg, M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 5, 6–13 (2005).
12. Bagheri A, Kamalidehghan B, Haghshenas M, et al. Prevalence of the CYP2D6*10 (C100T), *4 (G1846A), and *14 (G1758A) alleles among Iranians of different ethnicities. Drug Des Devel Ther. 2015;9:2627-2634.