Naltrexone

Name: NALTREXONE
Class: Narcotic Antagonist
Risk Factor: CM

Fetal Risk Summary

Naltrexone is an opioid antagonist that is used in the treatment of alcohol dependence and to block the effects of exogenously administered opioids. The agent is a synthetic congener of oxymorphone and is also related to another opioid antagonist, naloxone.
In fertility studies, a significant increase in pseudopregnancy and a decrease in the pregnancy rate after mating was observed in rats administered 100 mg/kg/day orally (16 times the recommended human therapeutic dose based on body surface area [RHTD]) (1). No adverse effects on male rat fertility were seen at this dose. A significant increase in early fetal loss was observed in rats and rabbits at 5 and 18 times the RHTD, respectively (1). No evidence of teratogenicity was found in either species at doses up to 32 and 65 times the RHTD, respectively, administered during organogenesis. Because rats do not form appreciable amounts of the major metabolite found in humans (6-b-naltrexol), the potential reproductive toxicity of the metabolite is unknown (1).
An animal study published in 1984 evaluated the reproductive effects of naltrexone in rats and rabbits (2). In rats, prolonged administration of naltrexone at doses that did not affect body weight produced excitatory signs in both sexes, increased production of seminal plugs in males, and decreases in estrus cycling and fertility in females. No adverse effect on mating activity was observed, but there was an increase in pseudopregnancy in those receiving 100 mg/kg/day. Fertility was also reduced (i.e., fewer females became pregnant) when both sexes received this dose. No evidence of teratogenicity or embryo toxicity was noted in either pregnant rats or rabbits (2).
When administered to rats near term (20 days' gestation), naltrexone crossed the placenta and was measured in all fetal tissues (3). Apparently, the human placental transfer of naltrexone has not been studied, but the relatively low molecular weight of the drug (about 378) indicates that transfer to the fetus should be expected.
In an experiment with stressed (noise and light at unpredictable frequency) pregnant rats, a continuous infusion of naltrexone (10 mg/kg/day) was administered by implanted minipumps from day 17 of gestation (4). Compared to controls receiving an infusion of vehicle only, naltrexone prevented the reduction in anogenital distance in male pups and restored the growth rate in both sexes. Other adverse fetal effects of prenatal stress were also prevented by naltrexone, leading the authors to conclude that some of the morphologic and behavioral changes induced by prenatal stress may result from excess opioid activity (4).
The effects of daily injections of naltrexone (50 mg/kg) administered to rats throughout gestation on fetal growth were described in a 1997 publication (5). Compared to controls given daily injections of saline, naltrexone-exposed pups had greater body weights, crown-rump lengths, and organ and skeletal muscle weights. Naltrexone had no effect on the length of gestation, course of pregnancy, litter size, or viability of the mother or offspring (5). The effects on growth were attributed to the blocking of endogenous opioids.
Decreased sensitivity to morphine has been observed in rat offspring exposed in utero to naltrexone (6,7). The appreciation of pain was not affected. However, insensitivity was not observed to butorphanol (7). These results raise the possibility that, later in life, morphine would provide less effective analgesia in human offspring who were exposed during gestation to naltrexone.
Other rat studies have also demonstrated that naltrexone can modify behavior of both the mother and the offspring (8,9 and 10). Naltrexone was administered at parturition to ewes lambing for the first time (8). Compared to controls, naltrexone significantly delayed the onset of maternal behavior (licking and bleating) toward the newborn. The drug facilitated sexual behavior in adult male rats who had been exposed in utero (9). Another study found that naltrexone exposure throughout gestation modified postnatal behavioral development of rat offspring (10). The investigators concluded that blocking the endogenous opioid systems during embryogenesis altered the somatic, physical, and behavioral development after birth. Of interest, a 1998 study found that naltrexone was present in the brains and hearts of newborn rats after maternal administration during gestation, but it was not present on postnatal days 2 and 10 (11). The investigators concluded that the somatic and neurobiological acceleration observed in previous studies was not due to opioid receptor blockade during the postnatal period (11).
Two 1993 reports, from the same research group, described the use of naltrexone (25–150 mg/day for 4–100 weeks) in 138 women with various grades of hypothalamic or hyperandrogenic ovarian failure (12,13). A total of 24 pregnancies in 22 women were achieved. Naltrexone was discontinued as soon as pregnancy had been diagnosed. Four pregnancies ended in an early spontaneous abortion, six women had delivered (no data provided on newborn condition), eight pregnancies were ongoing, and no information was given for six cases. A 1995 study of women with functional hypothalamic amenorrhea, however, found that even after priming with exogenous estradiol and progesterone or pulsatile gonadotropin-releasing hormone, the continued use of naltrexone alone did not maintain gonadotropin secretion and eventual ovulation (14).
Continuous naltrexone (50 mg/day), either alone or with intermittent clomiphene, has been used successfully in women with clomiphene resistant normogonadotrophic anovulation (15). In this study, 19 of 22 women achieved ovulation and 12 singleton pregnancies were documented. Naltrexone was discontinued when pregnancy was diagnosed. The outcomes of the pregnancies included two spontaneous abortions and eight ongoing pregnancies (15).
Except for the reports above in which the naltrexone was discontinued very early in gestation, no other References describing the use of the agent during human pregnancy have been located. Although naltrexone did not produce gross structural abnormalities in any of the animal studies, it did alter some opioid receptors in the brain that appeared to have long-lasting consequences. This potential for behavioral alteration in humans cannot be assessed because of the lack of data, but concern is warranted.

Breast Feeding Summary

No reports describing the use of naltrexone during human lactation have been located. Naltrexone and its metabolite, 6-b-naltrexol, are excreted into the milk of lactating rats (1). Because the molecular weight (about 378) is low enough, excretion into human breast milk should be expected. The effects of this exposure on a nursing infant are unknown, but there appears to be the potential for altering opioid receptors in the brain. In addition, based on studies in adults, baseline levels of some hormones of hypothalamic, pituitary, adrenal, and gonadal origin may also be altered (1).

References

1. Product information. Revia. DuPont Pharma, 2000.
2. Christian MS. Reproductive toxicity and teratology evaluations of naltrexone. J Clin Psychiatry 1984;45:7–10.
3. Zagon IS, Hurst WJ, McLaughlin PJ. Transplacental transfer of naltrexone in rats. Life Sciences 1997;61:1261–7.
4. Keshet GI, Weinstock M. Maternal naltrexone prevents morphological and behavioral alterations induced in rats by prenatal stress. Pharmacol Biochem Behav 1995;50:413–9.
5. McLaughlin PJ, Tobias SW, Lang CM, Zagon IS. Chronic exposure to the opioid antagonist naltrexone during pregnancy: maternal and offspring effects. Physiol Behav 1997;62:501–8.
6. Harry GJ, Rosecrans JA. Behavioral effects of perinatal naltrexone exposure: a preliminary investigation. Pharmacol Biochem Behav 1979;11(Suppl):19–22.
7. Zagon IS, Tobias SW, Hytrek SD, McLaughlin PJ. Opioid receptor blockade throughout prenatal life confers long-term insensitivity to morphine and alters µ opioid receptors. Pharmacol Biochem Behav 1998;59:201–7.
8. Caba M, Poindron P, Krehbiel D, Levy F, Romeyer A, Venier G. Naltrexone delays the onset of maternal behavior in primiparous parturient ewes. Pharmacol Biochem Behav 1995;52:743–8.
9. Cohen E, Keshet G, Shavit Y, Weinstock M. Prenatal naltrexone facilitates male sexual behavior in the rat. Pharmacol Biochem Behav 1996;54:183–8.
10. McLaughlin PJ, Tobias SW, Lang CM, Zagon IS. Opioid receptor blockade during prenatal life modifies postnatal behavioral development. Pharmacol Biochem Behav 1997;58:1075–82.
11. Zagon IS, Hurst WJ, McLaughlin PJ. Naltrexone is not detected in preweaning rats following transplacental exposure: implications for growth modulation. Life Sciences 1998;62:221–8.
12. Wildt L, Leyendecker G, Sir-Petermann T, Waibel-Treber S. Treatment with naltrexone in hypothalamic ovarian failure: induction of ovulation and pregnancy. Hum Reprod 1993;8;350–8.
13. Wildt L, Sir-Petermann T, Leyendecker G, Waibel-Treber S, Rabenbauer B. Opiate antagonist treatment of ovarian failure. Hum Reprod 1993;8(Suppl 2):168–74.
14. Couzinet B, Young J, Brailly S, Chanson P, Schaison G. Even after priming with ovarian steroids or pulsatile gonadotropin-releasing hormone administration, naltrexone is unable to induce ovulation in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 1995;80:2102–7.
15. Roozenburg BJ, van Dessel HJHM, Evers JLH, Bots RSGM. Successful induction of ovulation in normogonadotrophic clomiphene resistant anovulatory women by combined naltrexone and clomiphene citrate treatment. Hum Reprod 1997;12:1720–2.

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