Opiate withdrawal in utero increases neonatal morbidity in the rat.

Long-term oral administration of the long-acting opiate 1-alpha-acetylmethadol (LAAM) to female rats beginning on the day of conception interfered with the dams' ability to carry litters to term. When treatment was initiated 3 weeks prior to mating this effect was not observed. Daily administration of the opiate antagonist naloxone from day 14 of gestation through term, to precipitate withdrawal in utero, resulted in increased stillbirths, decreased pup weight and size, and weight loss 24 hours after birth. These data question the validity of animal experiments which purport to be models for methadone maintenance programs but in which treatment is started immediately prior to or soon after conception. They also suggest that withdrawal in utero may be responsible for many of the adverse effects of opiates on human and animal development.

Pharmacologic management of cancer pain in rural Minnesota.

Use of analgesic medications for cancer pain was assessed in six Minnesota communities. In our survey, cancer patients were treated primarily by family practice physicians. Approximately 70% were given one or more analgesics; 84% received a nonsteroidal antiinflammatory drug and 73% received an opioid. Most patients given an antiinflammatory drug received less than the maximal recommended dose for the drug. The most common opioid for cancer pain was oral morphine. Approximately 40% of the patients treated with opioids took the drug only when needed; the remainder took the drug around-the-clock, with or without additional opioids for breakthrough pain. Only 14% of patients who received analgesics received a coanalgesic and only 13% received a nonanalgesic adjuvant. The patterns of analgesic use in these communities corresponded well with accepted principles of cancer pain management: liberal use of opioids, use of oral morphine as the predominant agent, and avoidance of meperidine and opioid agonist/ antagonists.

Physician knowledge and attitudes about cancer pain management: a survey from the Minnesota cancer pain project.

The purposes of the study were to determine the knowledge and attitudes about cancer pain management (CPM) among practicing physicians in six Minnesota communities and to determine the physician-related barriers to optimal CPM. Eligible community physicians were surveyed by telephone. The study analyzed responses of 145 physicians (response rate, 87%). The majority of the physicians were primary care specialists (73%). Significant knowledge deficits were identified in nine of 14 CPM principles, but inappropriate attitudes were found in only two of nine CPM concepts. Medical specialty had the strongest influence on knowledge and attitudes, with primary care physicians having significantly better outcomes than surgeons or medical subspecialists. Effective education strategies must address knowledge deficits, attitudes, and motivations of the relevant peer group influencing physicians, as well as those of individual physicians. The Minnesota Cancer Pain Project is testing strategies to enhance CPM by physicians and improve patient outcomes.

Postnatal abstinence or acute toxicity can account for morbidity in developmental studies with opiates.

The incidence of neonatal morbidity and mortality in rats exposed to opiates in utero is generally high. To determine the extent to which neonatal opioid intoxication and/or withdrawal contribute to this effect, addicted pups from dams treated chronically with the long-acting opioid levo-alpha-acetylmethadol (LAAM) and appropriate controls were injected within 12 h of birth with saline, an opioid agonist (LAAM and metabolites) or an antagonist (naloxone). The incidence of neonatal mortality for pups born to dams maintained on a high dose of LAAM was 52%. A single injection of agonist on the first day of life reduced mortality in this group to 29% while a single injection of the antagonist increased mortality to 88%. In contrast, administration of the agonist to control pups and pups born to dams maintained on lower doses of LAAM resulted in increased mortality. Naloxone was apparently innocuous in non-dependent neonates. These data show that, despite LAAM's long duration of action in the mature rat, newborn rats experience withdrawal soon after drug exposure is terminated. These data also indicate that continued opioid exposure is a highly effective means of treating/preventing severe spontaneous withdrawal in the newborn.

Neonatal opiate withdrawal alters the reactivity of adult rats to the hot-plate.

Prenatal exposure of rats to 0.2 mg LAAM/kg/day but not to 0.05 mg LAAM/kg/day resulted in faster hot-plate escape latencies in 6 mo old offspring. No differences in tail-flick latencies were observed at 7 mo of age in offspring exposed to either dose of LAAM prenatally. Subsequent testing of littermates at 16 mo of age revealed that the greater sensitivity to the hot-plate observed in rats prenatally exposed to LAAM is apparently a result of neonatal withdrawal rather than a primary consequence of the drug. The data are discussed in relation to possible effects of drug or withdrawal on central nervous system development.

Cumulation of active metabolites of levo-alpha-acetylmethadol in the rat fetus and neonate.

Levo-alpha-acetylmethadol (LAAM, 0.2 or 2.0 mg/kg/day) was orally administered to female Sprague-Dawley rats for one month prior to and throughout pregnancy. The rats were killed on the 18th day of gestation along with a group of 18-day pregnant females given a single oral 2.0 mg/kg dose of LAAM 24 hours earlier. Although cumulation of LAAM or its active metabolites was not seen in plasma or brain of pregnant rats given drug chronically, significant cumulation was observed in whole fetus and in fetal brain. In addition, a 2-3 fold elevation in the concentrations, and an even greater elevation of total content, was noted in the newborn pup. These data suggest that opiate intoxication soon after birth may be a factor responsible for the increased morbidity and mortality of rat pups prenatally exposed to LAAM.

Separation of hepatic N-demethylase-inducing and opioid dependence-producing doses of levo-alpha-acetylmethadol in the pregnant rat.

A 2.0 mg per kg oral dose of 1-alpha-acetylmethadol (LAAM) administered daily to female rats prior to mating and throughout pregnancy increased ethylmorphine N-demethylase activity in liver microsomes of the dams measured 24 h after parturition. This dose of LAAM decreased maternal weight gain during gestation and increased postnatal mortality. However, 0.05 mg LAAM per kg was sufficient to produce dependence in the dams without affecting hepatic drug metabolism, gestational weight gain or neonatal mortality. The data indicate that it is not necessary to use doses of LAAM which can affect drug metabolizing enzymes in dams and increase pup mortality to maintain opioid-type physical dependence.

Outcome of pregnancy in rats chronically exposed to 1-alpha-acetylmethadol (LAAM).

Repeated oral administration of 0.2, 0.5 or 2.0 mg of LAAM per kg to mature female rats for 21 days resulted in diminished weight gain and was sufficient to induce opiate dependence. Chronic oral administration of 0.2 and 2.0 mg/kg/day to female rats before mating and throughout gestation gave rise to a population of pups which were shown to be dependent at birth by precipitated weight loss after a s.c. injection of 2.5 mg of naloxone per kg. Among the litters born to dams maintained on the 2.0 mg/kg/day dose of LAAM, there was a high incidence of stillbirths and infanticide by biological mothers or by surrogate mothers to which they were transferred within a few hours of birth. Surviving pups from this group lost weight during the next 24 hr and weighed less than controls at the time of weaning (21 days). In contrast, pups born to dams maintained on the low dose of LAAM were not cannibalized and weighed the same as or more than controls from birth until weaning. Although this group had a higher incidence of mortality during the 1st week after fostering, mortality was significantly less than for the higher dose group.

Neonatal undernutrition alters responsiveness to morphine in mature rats: a possible source of epiphenomena in developmental drug studies.

We studied the effect of neonatal undernutrition and its attendant stresses on the behavior and thermoregulation of adult rats in the absence and presence of morphine. Undernutrition was accomplished by fostering half the pups in each litter to a nonpregnant, nonlactating female rat every other day for the first 6 days of life. As a control, the remaining pups were fostered to lactating rats. Significant alterations in body and brain weight and in brain DNA, RNA and protein were noted in undernourished rats at 10 and 21 days of age. At 6 months of age, no difference was observed in unconditioned exploratory behavior or in the acquisition and performance of a conditioned autoshaped lever touch response. Differential sensitivity to morphine was observed in nourished and undernourished rats performing the autoshaped response at asymptotic levels. At 1 year of age, undernourished rats displayed lower rectal temperatures than controls and showed an altered thermic response to morphine. These data demonstrate that poor nutritional status and other nondrug factors may be responsible for the altered thermoregulation and opiate sensitivity observed in rodents perinatally addicted to opioids, effects generally regarded as specific consequences of early opiate exposure.

Congenital behavioral effects in mature rats prenatally exposed to levo-alpha-acetylmethadol (LAAM).

Male and female rats exposed prenatally to LAAM (0.2 mg/kg maternal body weight per day, PO) or water were tested for congenital effects on their performance of various unconditioned and conditioned behaviors. No differences were found in neuromuscular development or in exploratory activity. Although they acquired and performed an autoshaped lever-touch response like controls, the LAAM rats responding under this paradigm were less affected by dextroamphetamine than were controls, suggesting an alteration in catecholamine neurotransmission in these subjects. Furthermore, when required to respond on a progressive fixed-ratio (FR) procedure, in which the response requirement for reinforcement was doubled each day from FR1 to a maximum of FR128, LAAM rats made more responses at the higher ratios than did controls. Although these data suggest that LAAM may be a behavioral of functional teratogen, the possibility that early postnatal toxicity or withdrawal are responsible for these findings is discussed.

Prenatal levo-alpha-acetylmethadol (LAAM) and/or naloxone: effects on brain chemistry and postweaning behavior.

Female rats were treated daily with water or 0.2 mg LAAM/kg (PO) beginning 3 weeks before mating and continuing until parturition, after which addicted neonates were allowed to withdraw spontaneously. Beginning on the 14th day of gestation half of the animals in each group were injected (SC) 4 and 2 hours earlier with naloxone (Nx, 1 or 5 mg/kg) and the others with saline. Treatment with LAAM retarded maternal weight gain prior to mating but not during gestation. Evidence of dependence in the LAAM treated dams was manifest as a transient but robust weight loss following each dose of Nx. Offspring exposed to LAAM whose mothers were injected with Nx demonstrated significant perinatal mortality but survivors showed no evidence of growth retardation or biochemical and behavioral dysfunction. Pups exposed only to LAAM and withdrawn after birth showed some evidence of congenital effects. These include (1) lower 21 day postnatal body weights, (2) lower 1 and 3 day postnatal brain weights, (3) lower 19 day fetal brain protein concentrations, (4) lower 1 day postnatal brain DNA, RNA and protein content, and (5) lower levels of unconditioned exploratory activity at 1 1/2 and 10 months of age. The effects on growth and brain weight and biochemical parameters were transient, since control values were attained by 21 or 45 days of age. The absence of these effects in subjects exposed to both LAAM and Nx is interpreted as a screening effect of in utero withdrawal, with only the most resistant subjects surviving to be tested, the result of less severe spontaneous withdrawal because of displacement of cumulated LAAM metabolites by Nx or habituation to postnatal withdrawal stress by precipitated in utero withdrawal.

A method for determining cumulative behavioral toxicity after chronic oral administration of l-alpha-acetylmethadol to female rats.

A behavioral method is described in which fixed-ratio 15 (FR 15) responding for food is measured before and after daily oral administration of l-alpha-acetylmethadol (LAAM) by schedule-induced polydipsia. We hypothesized that if the interval between doses of drug was too great, and the subjects experienced episodes of withdrawal between doses, this would be manifest as diminished responding before drug which improved following drug administration. On the other hand, if the doses of drug given were too high or spaced too closely, any decrement in responding seen prior to drug would worsen following drug administration. Using this method we have shown that daily oral administration of 0.5-2.0 mg LAAM/kg to female rats resulted in apparent cumulative toxicity in 6 of 10 subjects tested in the above manner. Further behavioral testing revealed that those subjects not showing signs of toxicity were both dependent upon LAAM and cross-tolerant to the behavioral suppressant action of morphine.