Diphenoxylate is a centrally active opioid drug of the phenylpiperidine series that is used as a combination drug with atropine for the treatment of diarrhea. Diphenoxylate is an opioid and acts by slowing intestinal contractions; the atropine is present to prevent drug abuse and overdose. It should not be given to children due to the risk that they will stop breathing and should not be used in people with Clostridioides difficile infection.
Medical use
Diphenoxylate is used to treat diarrhea in adults; it is only available as a combination drug with a subtherapeutic dose of atropine to prevent abuse.
Diphenoxylate has moderate binding affinity for the μ-opioid receptor in humans at 12.37 nM (Morphine 1.168).
History and chemistry
Diphenoxylate was first synthesized by Paul Janssen at Janssen Pharmaceutica in 1956 as part of a medicinal chemistry investigation of opioids.
Diphenoxylate is made by combining a precursor of normethadone with norpethidine. Loperamide (Imodium) and bezitramide are analogs.
Like loperamide, it has a methadone-like structure and a piperidine moiety.
Society and culture
Pricing
In 2017 Hikma Pharmaceuticals raised the price of its liquid formulation of generic diphenoxylate-atropine in the US by 430%, from $16 to $84.00.
Regulation
In the United States, drugs containing diphenoxylate combined with atropine salts are classified as Schedule V controlled substances. (Diphenoxylate by itself is a Schedule II controlled substance.)
It is on Schedule III of the Single Convention on Narcotic Drugs, only in forms that contain, according to the Yellow List: "not more than 2.5 milligrams of diphenoxylate calculated as base and a quantity of atropine sulfate equivalent to at least 1 per cent of the dose of diphenoxylate".
Research
Diphenoxylate and atropine have been studied in small trials as a treatment for fecal incontinence; it appears to be less efficacious and have more adverse effects when compared with loperamide or codeine.