Diphenoxylate is a centrally active

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid us ...

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...

of the

phenylpiperidine Phenylpiperidines are chemical compounds with a phenyl moiety directly attached to piperidine. There are a variety of pharmacological effects associated with phenylpiperidines including morphine-like activity or other central nervous system effects. ...

series that is used as a

combination drug A combination drug or a fixed-dose combination (FDC) is a medicine that includes two or more active ingredients combined in a single dosage form. Terms like "combination drug" or "combination drug product" can be common shorthand for a FDC prod ...

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 given i ...

for the treatment of

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...

. Diphenoxylate is an

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

drug abuse Substance abuse, also known as drug abuse, is the use of a drug in amounts or by methods which are harmful to the individual or others. It is a form of substance-related disorder. Differing definitions of drug abuse are used in public health, ...

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 ''Clostridium 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 (hypercapnia ...

. 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 A depressant, or central depressant, is a drug that lowers neurotransmission levels, which is to depress or reduce arousal or stimulation, in various areas of the brain. Depressants are also colloquially referred to as downers as they lower the ...

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 ''Clostridium 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 neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous system ...

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 condition that ca ...

, 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 (megacolon), accompanied by abdominal distension (bloating), and sometimes fever, abdominal pain, or shock. Toxic megacolon is usually a complica ...

in people with

ulcerative colitis Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and a ...

. 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. Difeno ...

; 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 neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous system ...

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 employees which is now a subsidiary of Johnson & Johnson. Ea ...

Janssen Pharmaceutica Janssen Pharmaceuticals is a pharmaceutical company headquartered in Beerse, Belgium, and wholly-owned by Johnson & Johnson. It was founded in 1953 by Paul Janssen. In 1961, Janssen Pharmaceuticals was purchased by New Jersey-based American ...

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 Sched ...

Loperamide Loperamide, sold under the brand name Imodium, among others,Drugs.co Page accessed September 4, 2015 is a medication used to decrease the frequency of diarrhea. It is often used for this purpose in inflammatory bowel disease and short bowel syn ...

(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 m ...

are analogs. Like loperamide, it has a

methadone Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid agonist used for chronic pain and also for opioid dependence. It is used to treat chronic pain, and it is also used to treat addiction to heroin ...

-like structure and a

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

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 1 ...

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) of specific narcotic drugs and lays down a syst ...

, 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, both liquid stool elements and mucus, or solid feces. When this loss includes flatus (gas), it is referred ...

; 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