128 Diphenoxylate
usual, but a case report tells of someone who used dozens of tablets every
day for years. Under medical supervision the individual gradually reduced
and finally stopped dosage over a two-week period; dependence was only
slight, with mild flulike symptoms. A case is also reported of a drug addict
using diphenoxylate-atropine tablets to hold off withdrawal symptoms when
the person’s abused drug was unavailable. Medical personnel have adminis-
tered the diphenoxylate-atropine combination in order to wean addicts off
methadonemaintenance. When the combination was used in that context,
recipients showed no signs of tolerance or addiction to it, an intriguing finding
because that population of recipients would be particularly susceptible to such
effects. Diphenoxylate has also been used to help addicts withdraw from
heroin.
Drug interactions.The drug may interact dangerously with monoamine
oxidase inhibitors (MAOIs, a component of some antidepressants and other
medication). Tranquilizers,alcohol, or barbiturates should not be mixed with
diphenoxylate.
Cancer.Diphenoxylate’s potential for causing cancer is unknown, although
animal experiments with the drug have found no tendency for the disease to
appear.
Pregnancy.Fertility of female rats was impaired when they were dosed
daily throughout a three-litter cycle at 50 times the recommended human
level. Litter sizes declined when the females daily received 10 times the human
dose. Tests on rats, mice, and rabbits revealed no birth defects, but results
were not conclusive. A small survey of human medical records found “no
strong associations” between the drug and various congenital malformations,
and associations are only an indication that further investigation is needed,
not that a problem exists. Diphenoxylate’s effect on milk of nursing mothers
is uncertain, but the atropine component in a diphenoxylate combination
product does pass into the milk.
Additional information.Although difenoxin (CAS RN 28782-42-5) is avail-
able as a pharmaceutical preparation, body chemistry also produces this sub-
stance from a dose of diphenoxylate. By itself, difenoxin is a Schedule I
substance illegal to possess under any circumstance (DEA no. 9168), officially
classified as having no medical value. When combined with enough atropine
sulfate, however, difenoxin is a Schedule IV prescription drug known as Lys-
pafen and Motofen.
Difenoxin acts much like diphenoxylate and is used to treat diarrhea. Dan-
gers are similar to diphenoxylate’s. A two-year experiment gave daily doses
of difenoxin and atropine to rats and produced no evidence that the combi-
nation causes cancer.
In rat experimentation the difenoxin-atropine combination (Pregnancy Cat-
egory C) had only a weak impact on fertility, and no birth defects were at-
tributed to the combination after being administered to rats and rabbits at
levels that were dozens of times the amount recommended for humans. Preg-
nant rats, however, did have longer labor and more stillbirths, and a higher
percentage of their offspring died as newborns. The difenoxin-atropine com-
bination is not recommended for pregnant women or nursing mothers.
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