Diphenoxylate is a centrally active

opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

of the

phenylpiperidine Phenylpiperidines are chemical compounds with a phenyl moiety (chemistry), moiety directly attached to piperidine. Of particular interest are a variety of chemical derivative, derivatives of 4-phenylpiperidine, which have pharmacology, pharmacolo ...

series that is used as a

combination drug A combination drug is a combination of two or more pharmaceutical drugs as active ingredients combined into a single dosage form, typically as a ''fixed-dose combination'', with each constituent standardized to specifications of a fixed dose. Fix ...

with

atropine Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically give ...

for the treatment of

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

. Diphenoxylate is an

and acts by slowing intestinal contractions; the atropine is present to prevent

drug abuse Substance misuse, also known as drug misuse or, in older vernacular, substance abuse, is the use of a drug in amounts or by methods that are harmful to the individual or others. It is a form of substance-related disorder, differing definitions ...

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

in adults; it is only available as a

with a subtherapeutic dose of

to prevent abuse. It should not be used in children due to the risk of

respiratory depression Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapni ...

. It does not appear harmful to a fetus but the risks have not been fully explored. It should not be taken with other central

depressant Depressants, also known as central nervous system depressants, or colloquially known as "downers", are drugs that lower neurotransmission levels, decrease the electrical activity of brain cells, or reduce arousal or stimulation in various ...

s like alcohol, as they can increase its risks. It should not be used for people with diarrhea caused by an infection, for example with ''Clostridioides difficile'' infection, since the slowing of peristalsis can prevent clearing of the infectious organism.

Adverse effects

The drug label (in some jurisdictions) has warnings with regard to the risk of

anticholinergic toxicity Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous system by sel ...

and

opioid overdose An opioid overdose is toxicity due to excessive consumption of opioids, such as morphine, codeine, heroin, fentanyl, tramadol, and methadone. This preventable pathology can be fatal if it leads to respiratory depression, a lethal conditio ...

, the risk of dehydration and electrolyte imbalance that people with severe diarrhea always run, and

toxic megacolon Toxic megacolon is an acute form of colonic distension. It is characterized by a very dilated Colon (anatomy), colon (megacolon), accompanied by abdominal distension (bloating), and sometimes fever, abdominal pain, or Shock (circulatory), shock. ...

in people with

ulcerative colitis Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary sympto ...

. Other adverse effects include numbness in the hands and feet, euphoria, depression, lethargy, confusion, drowsiness, dizziness, restlessness, headache, hallucinations, edema, hives, swollen gums, itchiness, vomiting, nausea, loss of appetite, and stomach pain.

Pharmacology

Diphenoxylate is rapidly metabolized to

difenoxin Difenoxin (Motofen, R-15403) is an opioid drug used, often in combination with atropine, to treat diarrhea. It is the principal metabolite of diphenoxylate. It was first approved in the US in 1978 and in 1980 in the former West Germany. Dife ...

; it is eliminated mostly in feces but also in urine. Like other

s, diphenoxylate acts by slowing intestinal contractions, allowing the body to consolidate intestinal contents and prolong transit time, thus allowing the intestines to draw moisture out of them at a normal or higher rate and therefore stop the formation of loose and liquid stools; the atropine is an

anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system. These agents inhibit the parasympatheti ...

and is present to prevent

and overdose.

History and chemistry

Diphenoxylate was first synthesized by

Paul Janssen Paul Adriaan Jan, Baron Janssen (12 September 1926 – 11 November 2003) was a Belgian physician. He was the founder of Janssen Pharmaceutica, a pharmaceutical company with over 20,000 employeesPaul Lewi, Obituary of Dr Paul Janssen (1926–20 ...

Janssen Pharmaceutica Johnson & Johnson Innovative Medicine (formerly Janssen Pharmaceuticals) is a Belgian pharmaceutical company headquartered in Beerse, Belgium, and wholly owned by Johnson & Johnson. It was founded in 1953 by Paul Janssen. In 1961, Janssen Ph ...

in 1956 as part of a medicinal chemistry investigation of opioids. Diphenoxylate is made by combining a precursor of normethadone with

norpethidine Norpethidine (normeperidine, pethidine intermediate B) is a 4-phenylpiperidine derivative that is both a precursor to, and the toxic metabolite of, pethidine (meperidine). It is scheduled by UN Single Convention on Narcotic Drugs. It is a Sch ...

Loperamide Loperamide, sold under the brand name Imodium, among others,Drugs.co Page accessed 4 September 2015 is a medication of the opioid receptor agonist class used to decrease the frequency of diarrhea. It is often used for this purpose in irritable ...

(Imodium) and

bezitramide Bezitramide is an opioid analgesic. Bezitramide itself is a prodrug which is readily hydrolyzed in the gastrointestinal tract to its active metabolite, despropionyl-bezitramide. Bezitramide was discovered at Janssen Pharmaceutica in 1961. It is ...

are analogs. Like loperamide, it has a

methadone Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid used medically to treat chronic pain and opioid use disorder. Prescribed for daily use, the medicine relieves cravings and opioid withdrawal sym ...

-like structure and a

piperidine Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless liquid with an odor de ...

moiety.

Society and culture

Pricing

In 2017

Hikma Pharmaceuticals Hikma Pharmaceuticals plc is a British multinational pharmaceutical company with headquarters in London, UK that manufactures non-branded generic and in-licensed pharmaceutical products. It was founded by Samih Darwazah in Amman, Jordan in ...

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

salts are classified as Schedule V controlled substances. For label updates se
FDA index page for NDA 012462
/ref> (Diphenoxlate by itself is a Schedule II controlled substance.) It is on Schedule III of the

Single Convention on Narcotic Drugs The Single Convention on Narcotic Drugs, 1961 (Single Convention, 1961 Convention, or C61) is an international treaty that controls activities (cultivation, production, supply, trade, transport) involving specific narcotic drugs and lays down a ...

, 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 Fecal incontinence (FI), or in some forms, encopresis, is a lack of control over defecation, leading to involuntary loss of bowel contents—including flatus (gas), liquid stool elements and mucus, or solid feces. FI is a sign or a symptom ...

; it appears to be less efficacious and have more adverse effects when compared with loperamide or codeine.

References

{{Opioidergics Synthetic opioids Antidiarrhoeals Nitriles 4-Phenylpiperidines Mu-opioid receptor agonists Janssen Pharmaceutica Belgian inventions