Difenoxin (Motofen, R-15403) is an

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 use ...

drug used, often in combination 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 ...

, to treat diarrhea. It is the principal metabolite of

diphenoxylate 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 ...

. It was first approved in the US in 1978 and in 1980 in the former West Germany. Difenoxin crosses the blood brain barrier and induces some euphoria; it is often sold with or administered with atropine to reduce the potential for abuse and overdose.

Available forms

The abuse-deterring effects of atropine when used as an adulterant are reasonably effective in reducing the combination's potential for recreational use. It combines the mechanisms of

naloxone Naloxone, sold under the brand names Narcan (4 mg) and Kloxxado (8 mg) among others, is a medication used to reverse or reduce the effects of opioids. It is commonly used to counter decreased breathing in opioid overdose. Effects begin withi ...

and

paracetamol Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol. At a standard dose, paracetamol only slightly decreases body temperature; it is inferio ...

(the two more commonly used abuse-deterring agents) by increasing the likelihood of the overdose resulting in harmful and/or fatal sequelae (as does paracetamol), in addition to reliably producing unpleasant side-effects which "spoil" the opioid euphoria and discourage abusers from overdosing again following their initial experience (as does naloxone). This does not deter the use of single doses of difenoxin to potentiate another opiate, the anticholingeric activity of a single tablet is actually likely to increase the pleasurable effects of opioid use in a manner similar to combining one or more opioids with

orphenadrine Orphenadrine (sold under many brand names) is an anticholinergic drug of the ethanolamine antihistamine class; it is closely related to diphenhydramine. It is a muscle relaxant that is used to treat muscle pain and to help with motor control i ...

Side effects

At high doses there are strong CNS effects and the atropine at such high doses causes typical anticholinergic side effects, such as

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

dysphoria Dysphoria (; ) is a profound state of unease or dissatisfaction. It is the semantic opposite of euphoria. In a psychiatric context, dysphoria may accompany depression, anxiety, or agitation. In psychiatry Intense states of distress and uneas ...

, and

delirium Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances ...

. Excessive use or overdose causes constipation and can promote development of

megacolon Megacolon is an abnormal dilation of the colon (also called the large intestine). This leads to hypertrophy of the colon. The dilation is often accompanied by a paralysis of the peristaltic movements of the bowel. In more extreme cases, the feces ...

as well as classic symptoms of overdose including potentially lethal respiratory depression. In the 1990s its use in children was restricted in many countries due to the CNS side effects, which included anorexia, nausea and vomiting, headache, drowsiness, confusion, insomnia, dizziness, restlessness, euphoria and depression.

Mechanism of action

Difenoxin has a high peripheral/central actions ratio, working primarily on various

opioid receptors Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostati ...

in the intestines. Although it is capable of producing significant central effects at high doses, doses within the normal therapeutic range generally do not notably impair cognition or

proprioception Proprioception ( ), also referred to as kinaesthesia (or kinesthesia), is the sense of self-movement, force, and body position. It is sometimes described as the "sixth sense". Proprioception is mediated by proprioceptors, mechanosensory neurons ...

, resulting in therapeutic activity roughly equatable to that of loperamide (Imodium). Increased dosages result in more prominent central opioid effects (and anticholingeric effects when the formulation also contains a

tropane alkaloid Tropane alkaloids are a class of bicyclic .2.1alkaloids and secondary metabolites that contain a tropane ring in their chemical structure. Tropane alkaloids occur naturally in many members of the plant family Solanaceae. Certain tropane alkaloid ...

). It therefore offers limited advantages over more potent anti-diarrheal opioid options (ex.

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies ('' Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. T ...

) when treating intractable cases of diarrhea which fail to respond to normal or moderately increased difenoxin doses, and may in fact be harmful in such circumstances if the formulation used also contains atropine or

hyoscyamine Hyoscyamine (also known as daturine or duboisine) is a naturally occurring tropane alkaloid and plant toxin. It is a secondary metabolite found in certain plants of the family Solanaceae, including henbane, mandrake, angel's trumpets, jims ...

Legal status

Difenoxin is a Schedule I drug by itself in the US; the combination with atropine is in the less-restrictive category Schedule IV on account of the adulterant (the practice of making opioids more easily available by including an abuse-deterring adulterating agent is standard practice in the United States). Pure difenoxin, in Schedule I, has a quota of 50 grammes, and an ACSCN of 9168. The combination of difenoxin and atropine, in Schedule IV, has the DEA ACSCN of 9167 and being in Schedule IV is not assigned an aggregate annual manufacturing quota.

References

{{Opioidergics Synthetic opioids Nitriles 4-Phenylpiperidines Antidiarrhoeals Mu-opioid receptor agonists