tramadol

TRAMADOL

Fetal Risk Summary

Tramadol is a synthetic, centrally acting, analgesic analogue of codeine that has the potential to cause physical dependence similar to, but much less, than that produced by opiates. Because of its low addiction potential, tramadol is not classified as a controlled substance. The drug is available only as an oral tablet in the United States but has been used both parenterally and rectally in other countries.

Oral doses up to 50 mg/kg in male rats and 75 mg/kg in female rats had no effects on fertility (1). Reproductive studies, conducted with tramadol in mice (120 mg/kg), rats (25 mg/kg or higher), and rabbits (75 mg/kg or higher), showed embryotoxic and fetotoxic effects at maternally toxic doses, 3–15 times the maximum human dose or higher, but no fetal toxicity was observed with lower doses that were not maternally toxic (1). No teratogenic effects were observed with any of the doses. The observed toxicity consisted of decreased fetal weights, skeletal ossification, and increased supernumerary ribs. Transient delays in developmental or behavioral parameters were seen in rat pups.

Shepard described a reproductive study using oral and SC tramadol in mice, at doses up to 120 mg/kg, and in rats, at doses up to 60 mg/kg, that observed no teratogenic effects (2). Schardein also cited the same study (3).

Tramadol has a molecular weight of approximately 300 and crosses the placenta to the fetus. In 40 women given 100 mg of tramadol during labor, the mean ratio of drug concentrations in the umbilical cord and maternal serum was 0.83 (4).

Several studies outside of the United States, some of which were reviewed in 1993 (5) and 1997 publications (4), have compared the use of tramadol with meperidine or morphine for labor analgesia (6,7,8,9,10,11 and 12). In five of these studies (6,7,8,9 and 10), the use of tramadol was associated with less neonatal respiratory depression than meperidine, but no difference was observed in two studies in comparison with meperidine or morphine (11,12). In one of these latter studies, no differences in maternal response, adverse effects, or newborn condition were observed between tramadol, meperidine, and morphine (11). In the other study, tramadol and meperidine were combined with triflupromazine, a phenothiazine tranquilizer added in an attempt to reduce the emetic effects of the analgesics, and compared with tramadol alone (12). No decrease or difference between the three groups in the incidence and severity of the side effects was observed.

The effects of tramadol and meperidine, 100 mg IV for each drug, were compared in laboring patients in a study conducted in Thailand (9). A second or third dose of 50 mg IV was given at 30-minute intervals if requested. A significant increase in the incidence of neonatal respiratory depression was observed in the offspring of the meperidine group, if delivery occurred 2–4 hours after the last dose. The respiratory depressant effects of meperidine are known to be time- and dose-related, increasing markedly after 60 minutes (see Meperidine).

A study from Singapore found that 100 mg IM of tramadol was equivalent in analgesic effect to 75 mg IM of meperidine for the control of labor pain (10). Meperidine was associated with a significantly higher frequency of adverse effects (nausea, vomiting, fatigue, drowsiness, and dizziness) in the mothers and a significantly lower respiratory rate in the newborns. However, the injection-delivery interval in the patients was 7–8 hours.

In a 1997 case report, a male infant developed withdrawal symptoms between 24 and 48 hours after birth (13). Symptoms consisted of trembling, tachypnea, tachycardia, hypertonic muscle tone, signs of tetany when touched, and a single mild convulsion. The mother admitted to taking tramadol 300 mg/day for 4 years. The infant was treated with diazepam and/or phenobarbital for 13 days until the symptoms had fully resolved. No long-term follow-up of the infant was reported. The authors concluded that the estimated elimination half-life of 36 hours was consistent with the course of the withdrawal syndrome (13).

Only the one report above has described the use of tramadol early in human gestation and an assessment of the risk, if any, that the drug presents to the embryo and fetus cannot be determined. Based on that case, neonatal withdrawal is a potential complication after continuous use in the mother. Because dose-related embryo and fetal toxicity have been observed in animals, use of tramadol during early human gestation should probably be avoided until additional data are available. Moreover, the delays in development and behavior observed in newborn rats appear to lessen any clinically significant advantage the drug may have over traditional narcotic analgesics.

Breast Feeding Summary

Both tramadol and its pharmacologic active metabolite are excreted into human milk (1). After a single 100-mg IV dose, the cumulative amounts of the parent drug and metabolite excreted into milk within 16 hours were 100 and 27 µg, respectively (1). The recommended dose of tramadol is 50–100 mg every 4–6 hours up to a maximum of 400 mg/day. Moreover, the mean absolute bioavailability of a 100-mg oral dose is 75%. Thus, ingestion of the recommended dose may produce drug amounts in breast milk that could exceed those reported above. The effects of this exposure on a nursing infant are unknown.

References

1. Product information. Ultram. McNeil Pharmaceutical, 1997.
2. Yamamoto H, Kuchii M, Hayano T, Nishino H. A study on teratogenicity of both CG-315 and morphine in mice and rats. Oyo Yakuri 1972;6:1055–69. As cited in Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: Johns Hopkins University Press, 1995:420.
3. Yamamoto H, Kuchii M, Hayano T, Nishino H. Teratogenicity of the new central analgesic 1-(m-methoxyphenyl)-2-(dimethylaminomethyl)cyclohexanol hydrochloride (Cg-315) in mice and rats. Oyo Yakuri 1972;6:1055–69. As cited in Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York: Marcel Dekker, 1993:133.
4. Lewis KS, Han NH. Tramadol: a new centrally acting analgesic. Am J Health-Syst Pharm 1997;54:643–52.
5. Lee CR, McTavish D, Sorkin EM. Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 1993;46:313–40.
6. Husslein P, Kubista E, Egarter C. Obstetrical analgesia with tramadol—results of a prospective randomized comparative study with pethidine. Z Geburtshilfe Perinatol 1987;191:234–7.
7. Bitsch M, Emmrich J, Hary J, Lippach G, Rindt W. Obstetrical analgesia with tramadol. Fortschr Med 1980;98:632–4.
8. Bredow V. Use of tramadol versus pethidine versus denaverine suppositories in labor—a contribution to noninvasive therapy of labor pain. Zentralbl Gynakol 1992;114:551–4.
9. Suvonnakote T, Thitadilok W, Atisook R. Pain relief during labour. J Med Assoc Thailand 1986;69:575–80.
10. Viegas OAC, Khaw B, Ratnam SS. Tramadol in labour pain in primiparous patients. A prospective comparative clinical trial. Eur J Obstet Gynecol Reprod Biol 1993;49:131–5.
11. Prasertsawat PO, Herabutya Y, Chaturachinda K. Obstetric analgesia: comparison between tramadol, morphine, and pethidine. Curr Ther Res Clin Exp 1986;40:1022–8.
12. Kainz C, Joura E, Obwegeser R, Plockinger B, Gruber W. Effectiveness and tolerance of tramadol with or without an antiemetic and pethidine in obstetric analgesia. Z Geburtshilfe Perinatol 1992;196:78–82.
13. Meyer FP, Rimasch H, Blaha B, Banditt P. Tramadol withdrawal in a neonate. Eur J Clin Pharmacol 1997;53:159–60.
    
    

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