Part 14 (1/2)

Summary 163.

Other a.n.a.lgesics 160.

Key references 163.

Pregnant women experience a variety of aches and pains and most do not require a.n.a.lgesic therapy. Headaches or pain secondary to dental procedures are common during pregnancy. Many nonnarcotic a.n.a.lgesics are commercially available (many of them over-the-counter medications) and fortunately, with few exceptions, can be utilized safely for the treatment of minor pain during pregnancy.

Limited data are available on the pharmac.o.kinetics of a.n.a.lgesics during pregnancy, and the findings are not entirely consistent. For example, acetaminophen has a decreased half-life and increased clearance in one study, but it is unchanged in another at about the same gestational age (Table 8.1). The pharmac.o.kinetics of meperidine in pregnancy are unchanged compared to nonpregnant controls, and the same is true of the kinetics of meptazinol. In contrast, morphine has a decreased half-life and increased clearance, implying the need for increased frequency or dose regimen to maintain adequate a.n.a.lgesia. Indomethacin has a decreased half-life, C , and C , which also implies dose or frequency regimen adjust-max SS.

ment. In contrast, sodium salicylate has an increased half-life during late pregnancy. Low-dose aspirin does not appear to significantly affect umbilical artery circulation (Owen et al et al., 1993; Veille et al et al., 1993). Notably, the half-life for aspirin increases during pregnancy, implying that a dose decrease in amount and/or frequency may be needed (Table 8.1).

NONSTEROIDAL ANTIINFLAMMATORY AGENTS.

Most of the agents in this group are relatively new a.n.a.lgesics and all are prostaglandin synthetase inhibitors. Some of the commonly used agents in this cla.s.s are listed in Box 8.1. Phenylbutazone and indomethacin are two of the 'oldest' agents in this group.

Box 8.1 Nonsteroidal antiinflammatory agents Phenylbutazone Diflunisal Indomethacin Ketorulac Ibuprofen Piroxicam Fenoprofen Diclofenac Meclofenamate Rofec.o.xib Naproxen Celec.o.xib Tolmentin Etodolac Sulindac 150.

a.n.a.lgesics during pregnancy Table 8.1 Pharmac.o.kinetics a.n.a.lgesic agents during pregnancy: pregnant compared with nonpregnant Agent Pharmac.o.kinetics a.n.a.lgesic agents during pregnancy: pregnant compared with nonpregnant Agent n EGA.

Route AUC.

V.

C.

C.

t Cl PPB.

Control Authors d max SS.

1/2.

(weeks) groupa Acetaminophen 8.3rd trimester PO.

Yes (1) Miners et al. (1986) Acetaminophen 6.36.PO.

Yes (2) Rayburn et al. (1986) Indomethacin 5.3638 IV.

Yes (1) Traeger et al. (1973) Meperidine 18.Term IV.

Yes (1) Kuhnert et al. (1980) Meptazinol 5.3638 IV.

Yes (1) Murray et al. (1989) Morphine 13.Term IM, IV.

Yes (1) Gerdin et al. (1990) Sodium salicylate 20.40.IV.

No Noeschel et al. (1972) Source: Little BB. Obstet Gynecol 1999; 93 93: 858.

EGA, estimated gestational age; AUC, area under the curve; V , volume of distribution; C , peak plasma concentration; C , steady-state concentration; t , half-life; Cl, d max SS.

1/2.

clearance; PPB, plasma protein binding; PO, by mouth; denotes a decrease during pregnancy compared with nonpregnant values; denotes an increase during pregnancy compared with nonpregnant values; = denotes no difference between pregnant and nonpregnant values; IV, intravenous, IM, intramuscular.

aControl groups: 1, nonpregnant women; 2, same individuals studied postpartum; 3, historic adult controls (s.e.x not given); 4, adult male controls; 5, adult male and female controls combined.

Nonsteroidal antiinflammatory agents 151.

Nonnarcotic a.n.a.lgesics SALICYLATES (ASPIRIN).

Aspirin has been used for a variety of therapeutic reasons, but is used primarily as an a.n.a.lgesic, antipyretic, or antiinflammatory agent. Salicylates have been used clinically use for over 100 years and are one of the most commonly used nonnarcotic a.n.a.lgesics.

Aspirin is one of the drugs most used by pregnant women (Corby, 1978; Sibai and Amon, 1988; Streissguth et al et al., 1987). In one prospective study of 1529 pregnant women in 1974 and 1975 (Streissguth et al et al., 1987), almost 50 percent of the women reported taking aspirin, and about 3 percent took it daily. Salicylates are prostaglandin synthetase inhibitors, and act primarily via inactivation of the enzyme cyclo-oxygenase (c.o.x) (Sibai et al et al., 1989), and are well known for inhibiting c.o.x-1 and c.o.x-2 enzymes. Suppression of c.o.x-1 inhibits production of protective esophageal and gastric mucosa, increasing the risk for gastrointestinal bleeds and a.s.sociated complications.

Suppression of c.o.x-1 also inhibits synthesis of vasoactive prostaglandins (prostacyclin and thromboxane A ). Prostacyclin, a potent vasodilator, also inhibits platelet aggrega-2 tion, while thromboxane A , a potent vasoconstrictor, stimulates platelet aggregation 2 (Bhagwat et al et al., 1985; Ellis et al et al., 1976). Prostaglandin E and prostaglandin F are also 2 inhibited. In usual human therapeutic doses, aspirin results in 'nonselective inhibition of prostaglandin synthetase in various tissues' (Sibai and Amon, 1988), thus suppressing c.o.x-2. Suppression of c.o.x-2 has an a.n.a.lgesic effect by blocking prostaglandins a.s.sociated with inflammation.

High or normal doses (>325 mg) block production of prostacyclin and thromboxane, and low-dose aspirin (6083 mg) results in selective block of thromboxane production, and favors the prostacyclin (vasodilation) pathway (Beaufils et al et al., 1985; Masotti et al et al., 1979; Schiff et al et al., 1989; Sibai et al et al., 1989; Spitz et al et al., 1988; Wallenberg, 1995; Wallenberg et al et al., 1986). This provides the basis for the use of low-dose aspirin to fore-stall or prevent pregnancy-induced hypertension (Gant and Gilstrap, 1990) (see Special considerations). Importantly, low-dose aspirin does not completely inhibit thromboxane and does not completely 'spare' prostacyclin. One group of investigators found that 81 mg of aspirin inhibited thromboxane by 75 percent, but also inhibited prostacyclin by approximately 20 percent (Spitz et al et al., 1988).

There have been several large studies regarding the effect of aspirin on preeclampsia (Hauth et al et al., 1993; Sibai et al et al., 1993), as well as a meta-a.n.a.lysis, Collaborative Low-Dose Aspirin Study in Pregnancy (CLASP, 1994). These results indicate that low-dose aspirin does decrease the incidence of preeclampsia (Hauth and Cunningham, 1995).

Review of four large controlled trials that included over 13 000 pregnant women led to the conclusion that daily low-dose aspirin significantly reduced the risk of preeclampsia (Wallenberg, 1995). In a follow-up study, compared to untreated women, aspirin-treated women had: (1) a greater than twofold longitudinal reduction in serum thromboxane B2 levels; (2) a significantly decreased frequency of preeclampsia; and (3) fewer premature and growth-stunted newborns (Hauth et al et al., 1995a).

Aspirin readily crosses the placenta and results in physiologically significant fetal levels (Levy et al et al., 1975; Palminsano and Ca.s.sudy, 1969; Turner and Collins, 1975). Aspirin has been reported to be teratogenic in various laboratory animals when given at several times the human adult dose (Wilson et al et al., 1977), and there have been anecdotal case 152 152 a.n.a.lgesics during pregnancy reports of congenital anomalies in humans (Agapitos et al et al., 1986). However, the risk of congenital anomalies in infants of mothers exposed to aspirin in the first 16 weeks of pregnancy was not increased when compared to unexposed infants (Slone et al et al., 1976).

The major malformation rate in a large national study in the USA was 6.7 percent for heavy aspirin use, 6.8 percent for intermediate use, and 6.3 percent for women who did not use aspirin (Heinonen et al et al., 1977). Among 144 pregnant women who were 'heavy aspirin' users, the frequency of major birth defects in offspring was 4.2 percent not significantly different from that in the general population (3.55 percent; Turner and Collins, 1975). Similarly, among 62 women who used aspirin in the first trimester, the rate was not significantly higher than that expected in the general population (Aselton et et al al., 1985).