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Loperamide: A pharmacological review
Abstract and Figures
Loperamide is an antidiarrheal medication approved for the control of diarrhea symptoms and is available without a prescription. Loperamide works by a number of different mechanisms of action that decrease peristalsis and fluid secretion, resulting in longer gastrointestinal transit time and increased absorption of fluids and electrolytes from the gastrointestinal tract. It is a phenylpiperidine derivative with a chemical structure similar to opiate receptor agonists such as diphenoxylate and haloperidol. It was designed to maintain the antidiarrheal activity of these drugs, but minimize the negative aspects associated with their effects on the opiate receptor. Because of loperamides's low oral absorption and inability to cross the blood-brain barrier, it has minimal central nervous system effects. It also has a longer duration of action than diphenoxylate. However, it has no clinically significant analgesic activity and does not decrease the pain associated with some forms of irritable bowel syndrome and diarrhea. Loperamide is metabolized by the cytochrome P450 (CYP) system and is a substrate for the CYP3A4 isoenzyme. Concurrent administration with CYP3A4 inhibitors may elevate loperamide concentrations. Common adverse reactions to loperamide include cramps and nausea. Loperamide is an effective treatment for patients with painless diarrhea and is considered to be free of abuse potential.
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... Similar to loperamide, diphenoxylate inhibits intestinal motility by stimulating opioid receptors in the intestine. 20 Furthermore, the addition of atropine to diphenoxylate also inhibit intestinal peristalsis. 21 However, limited efficacy data support the use of diphenoxylateand atropine compared to loperamide for the treatment of CRT-induced diarrhea. ...
... Loperamide and diphenoxylate and atropine are generally associated with limited risks of drug-drug interactions. 20 Gawron and Bielefeldt, et al, utilized the U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System database (FAERS) to examine pancreatitis following treatment with eluxadoline and compared with other medications such as loperamide, diphenoxylate and atropine, oxycodone, and rifaximin. Their findings indicated that pancreatitis accounted for a small percentage of AEs reported for diphenoxylate and atropine (0.43%) compared to eluxadoline (16.4%) and rifaximin (0.96%). ...
Background: Chemoradiotherapy (CRT)-induced diarrhea poses significant challenges for cancer patients, impacting both quality of life and treatment efficacy. Current management strategies often involve symptomatic relief with medications such as lomotil and loperamide, but limited data exist on the efficacy of lomotil for management of CRT-induced diarrhea. This study aimed to evaluate the efficacy and safety of lomotil in managing acute CRT-induced diarrhea. Methods: A cross-sectional observational trial was conducted at 25 Indian healthcare centers having medical records of adult patients with cancer who had received lomotil for the treatment of CRT-induced diarrhea. Adult patients (aged ≥18 years) with confirmed diagnosis of cancer, who were experiencing CRT-induced diarrhea of grade II or grade III severity were included in this study. Demographic information and treatment history were collected. Moreover, data related to stool frequency, stool consistency, abdominal cramp, and occurrence of blood or mucus were collected at baseline, day 1, day 2, day 3, 2nd week, 3rd week, and 4th week. Results: A total of 177 patients were included in this study. Of these 30.51% underwent radiotherapy, while 26.55% received both chemotherapy and radiotherapy in combination. Post-lomotil treatment, diarrhea incidence declined significantly by week 4 [pre-treatment to week 4: 3.58 to 0.42; P<0.001]. The presence of blood or mucus decreased significantly from baseline to week 4 (0.25 to 0.05; p<0.01). The overall global assessment for improvement showed that a majority of the patients (80.79%) experienced improvement. Conclusions: Lomotil demonstrated efficacy in reducing CRT-induced diarrhea incidence and symptoms, with minimal adverse effects.
... Among pharmaceutical agents, loperamide, an opioid receptor agonist, plays a role in treating diarrhea [9]. Used for chronic diarrhea and short bowel syndrome, it reduces longitudinal and circular smooth muscle tone in the intestines, culminating in diminished colonic mass movement and suppressing the gastrocolic reflex, ultimately alleviating the symptoms of diarrhea [10,11]. ...
Ulva pertusa Kjellman (U. pertusa) is a seaweed indigenous to the intertidal zone of the Korean coastline. U. pertusa exhibits immune-enhancing and antitumor activities, and its effects on intestinal health have gained attention. However, the mechanisms underlying its beneficial effects on intestinal physiology remain elusive. Here, the effect of U. pertusa intake in ameliorating loperamide-induced constipation in male mice was evaluated. Additionally, cellular levels of proinflammatory cytokines, including nuclear factor-kB and interleukin-1β, were assessed to decipher the intricate interplay between inflammation and improvements in bowel movement. U. pertusa intake increased fecal weight and water content and improved the intestinal transit rate. Moreover, it reduced the levels of proinflammatory cytokines, possibly via short-chain fatty acids implicated in modulating intestinal motility and mucosal inflammation. These findings underscore the efficacy of U. pertusa in improving bowel motility and intestinal functionality, and its potential in ameliorating constipation.
... 114 A synthetic oral opioid Loperamide acts via several different mechanisms, including decreased fluid secretion and peristalsis, which lengthens the time that food travels through the gastrointestinal tract and increases the absorption of fluids and electrolytes. 115 The recommended standard dose of loperamide is initially 4 mg, followed by 2 mg per diarrhea episode and a maximum dose of 16 mg per day, which depends on the degree of diarrhea experienced by the patient. 116 Patients with grade 1-2 diarrhea should begin loperamide medication and remain on EGFR-TKIs at the same dosage. ...
Breast cancer has the highest incidence among female malignancies, significantly impacting women’s health. Recently, numerous HER2-targeted therapies have achieved excellent clinical outcomes. Currently, anti-HER2 drugs are divided into three main categories: monoclonal antibodies, small-molecule tyrosine kinase inhibitors, and antibody-coupled drugs (ADCs). The main toxic side effects of small molecule TKI-based therapy are diarrhea, hand-foot syndrome, rash, nausea, and vomiting. Diarrhea is a potential predictor of tumor response, affecting up to 95% of cancer patients treated with TKIs. Severe gastrointestinal toxicity can result in the need for dose reductions and treatment interruptions. This not only compromises the efficacy of TKIs but also deteriorates human nutrition and quality of life. The majority of individuals develop diarrhea within 7 days of starting treatment, with approximately 30% developing grade 3 or higher diarrhea within 2-3 days of starting treatment. The severity of diarrhea typically correlates with the dosage of most TKIs. Current prevention and management strategies are primarily empirical, focusing on symptom alleviation rather than addressing the toxicological mechanisms underlying TKI-induced diarrhea. Consequently, anti-diarrheal drugs are often less effective in managing this condition in cancer patients receiving TKIs. Moreover, our understanding of the toxicological mechanisms responsible for such diarrhea remains limited, underscoring the urgent need to identify these mechanisms in order to develop effective anti-diarrheal medications tailored to this specific context. This review aims to elucidate management approaches and mechanisms for diarrhea induced by TKIs during HER2-positive breast cance.
... Intravenous pain relievers are given for pain control from the moment of needle insertion up to patient discharge. Patients also receive hydric diet and loperamide for peristalsis reduction [11]. A minimum time of 6 h between each HDR brachytherapy fraction is respected (from the first to second treatment there are 18 h and from the second to the third there is one week). ...
CT angiography might be a suitable procedure to avoid arterial puncture in combined intracavitary and interstitial brachytherapy for cervical cancer curatively treated with combined chemoradiation and brachytherapy boost. Data in the literature about this technique are scarce. We introduced this method and collected brachytherapy data from patients treated in our department between May 2021 and April 2024. We analyzed the applicator subtype, needle insertion (planned versus implanted), implanted depth and the role of CT angiography in selecting needle trajectories and insertion depths. None of the patients managed through this protocol experienced atrial puncture and consequent hemorrhage. Needle positions were accurately selected with the aid of CT angiography with proper coverage of brachytherapy targets and avoidance of organs at risk. CT angiography is a promising method for guiding needle insertion during interstitial brachytherapy.
... Furthermore, pelvic floor dysfunction and faecal incontinence are common and should be considered when treating patients with IBD.6.3.1 | DiarrhoeaFor chronic or intermittent diarrhoea, antidiarrheal therapy can be beneficial. Loperamide, diphenoxylate, and eluxadoline are opioidreceptor agonists that inhibit intestinal motility, allowing more time for fluid absorption.[140][141][142] Eluxadoline is only approved in the United States. ...
Background
Persistent gastrointestinal symptoms are prevalent in adult patients with inflammatory bowel disease (IBD), even when endoscopic remission is reached. These symptoms can have profound negative effects on the quality of life of affected patients and can be difficult to treat. They may be caused by IBD‐related complications or comorbid disorders, but they can also be explained by irritable bowel syndrome (IBS)‐like symptoms.
Aims
To provide a practical step‐by‐step guide to diagnose and treat persistent gastrointestinal symptoms in patients with IBD in remission via a personalised approach.
Methods
We scrutinised relevant literature on causes, diagnostics and treatment of persistent gastrointestinal symptoms (abdominal pain or discomfort, bloating, abdominal distension, diarrhoea, constipation and faecal incontinence) in patients with IBD in remission.
Results
A graphical practical guide for several steps in diagnosing, identifying potential triggers and adequate treatment of persistent gastrointestinal symptoms in IBD in remission is provided based on supporting literature. The first part of this review focuses on the diagnostic and treatment approaches for potential IBD‐related complications and comorbidities. The second part describes the approach to IBS‐like symptoms in IBD in remission.
Conclusions
Persistent gastrointestinal symptoms in IBD in remission can be traced back to potential pathophysiological mechanisms in individual patients and can be treated adequately. For both IBD‐related complications and comorbidities and IBS‐like symptoms in IBD in remission, pharmacological, dietary, lifestyle or psychological treatments can be effective. A systematic and personalised approach is required to reduce the burden for patients, healthcare systems, and society.
... The extracts meets some criteria that were similar with loperamide such as prevented the production of wet and formless feces also inhibited GIT propulsive act. It has been reported that as therapeutic effect of loperamide have antimotility and anti-secretory activities (Baker, 2007;Hovdenak, 1987). Although immobile period in FST represents major depression symptoms, but it can also be a form of apathy or avolition. ...
The study evaluated several pharmacological effects including antidepressant, antidiarrheal and thrombolytic activities of ethanol extract of Amomum aromaticum leaves (EEAA). Upon the assessment for qualitative phytochemical groups in the extract, several doses of EEAA (1000 - 4000 mg/kg) were studied to find acute oral toxicity in mouse for safe dose selection. Then EEAA was tested whether it demonstrates antidepressant activity in tail suspension test (TST) and forced swim test (FST). Antidiarrheal and clot lysis activities of EEAA were evaluated in castor oil-induced diarrhoea in mouse and In vitro clot lysis method, respectively. Oral administration of EEAA (1000 - 4000 mg/kg) showed no morality after 10 days, and no sign of acute toxicity observed within 24 hrs post-treatment. The qualitative phytochemical screening showed the presence of carbohydrate, alkaloid, flavonoid, tannin, saponin, and polyphenol groups in EEAA. The TST and FST resulted with significant improvement in mobility in mice treated with EEAA (400 mg/kg), where fluoxetine (20 mg/kg) was used as standard in both tests. EEAA treatment also showed a moderate dose-dependent anti-diarrheal effect. The 400 mg/kg oral dosing for 14 days decreased the rate of defecation by 52.8% compared to the control group. This study also demonstrated that EEAA possesses clot lysis activity. Hence, further intense investigations are suggested to identify specific potential active phytochemicals. Bangladesh Pharmaceutical Journal 27(1): 51-58, 2024 (January)
... Loperamide, a synthetic opioid that primarily affects intestinal opiate receptors to control diarrhea [87], has been studied for microscopic colitis in seven minor studies, five of which were retrospective cohorts. In these studies with 2 mg tablets (up to eight tablets daily), a meta-analysis showed that 62% of the patients responded to loperamide therapy (95% CI, 0.43-0.80; ...
Microscopic colitis, a diagnosis under the umbrella term of inflammatory bowel disease, is a prevalent cause of watery diarrhea, often with symptoms of urgency and bloating, typically observed in older adults aged ≥ 60 years. Its incidence has been reported to exceed those of ulcerative colitis and Crohn’s disease in some geographical areas. Although nonpathognomonic endoscopic abnormalities, including changes of the vascular mucosal pattern; mucosal erythema; edema; nodularity; or mucosal defects, e.g., “cat scratches” have been reported, a colonoscopy is typically macroscopically normal. As reliable biomarkers are unavailable, colonoscopy using random biopsies from various parts of the colon is compulsory. Based on the histological examination under a microscope, the disease is divided into collagenous (with a thickened subepithelial collagenous band) and lymphocytic (with intraepithelial lymphocytosis) colitis, although incomplete forms exist. In routine clinical settings, the disease has a high risk of being misdiagnosed as irritable bowel syndrome or even overlooked. Therefore, healthcare providers should be familiar with clinical features and rational management strategies. A 6–8-week oral budesonide treatment course (9 mg/day) is considered the first-line therapy, but patients often experience relapse when discontinued, or might become intolerant, dependent, or even fail to respond. Consequently, other therapeutic options (e.g., bismuth subsalicylate, biologics, loperamide, bile acid sequestrants, and thiopurines) recommended by available guidelines may be prescribed. Herein, clinically meaningful data is provided based on the latest evidence that may aid in reaching a diagnosis and establishing rational therapy in geriatric care to control symptoms and enhance the quality of life for those affected.
... As a result of stimulation of these receptors the level of cyclic 3 ,5 adenosine monophosphate (cAMP) decreases, Ca 2+ channels are inhibited, and K + channels are opened. The consequence of these changes is inhibition of acetylcholine and prostaglandins release from enteric nerves, as well as inhibition of the nerve impulse as a result of membrane hyperpolarization, a decrease in peristalsis and an increase in intestinal transit time [27,28]. Pregnant women may suffer from constipation as a result of an increase in progesterone levels, a decrease in motilin levels, and an increase in the amount of water absorbed from the intestine. ...
Easy access to over-the-counter (OTC) drugs makes it possible to procure active substances that normally used in therapeutic doses do not raise health problems. The use of high doses of OTC drugs containing codeine, loperamide, pseudoephedrine, diphenhydramine or dimenhydrinate, as well as the use of benzidamine systemically raises concerns regarding the increase in units sold. These drugs are used for recreational or euphorizing purposes, including by young women of childbearing age, psychoactive substance users representing a risk group in terms of the possibility of an unplanned pregnancy. Abusive consumption of OTC products during pregnancy is harmful, with consequences for both fetal and late development that can occur in the infant. This literature review presents the risks (teratogenicity, fetal toxicity, neonatal abstinence syndrome, etc.) associated with the use of potentially psychoactive OTC drugs to emphasize the importance of re-evaluating OTC classification and dispensing.
The management of the irritable bowel syndrome (IBS) remains unsatisfactory. For abdominal pain, antispasmodics are, at best, of only modest efficacy. Tricyclic antidepressants in low dose are useful (with the number needed to treat being three), but side effects and patient concerns regarding use of a centrally acting agent for depression remain limitations. Selective serotonin reuptake inhibitors are of uncertain efficacy in IBS. Opioid agonists, especially loperamide, are useful for diarrhea but not for pain in IBS; rebound constipation also remains a problem. Bile salt sequestering agents are not of established value in IBS but seem to be useful clinically in a small group of IBS patients with diarrhea. Aloestron, a 5HT(3) antagonist, should be reserved, if available, for women with severe diarrhea predominant IBS who have failed to respond to conventional therapy, and started at a low dose. Fiber and bulking agents may help constipation in some trials, but the evidence that they are efficacious in IBS is equivocal; they are frequently prescribed as first-line drugs for IBS regardless of the primary bowel disturbance but often increase bloating, gas, and pain. Laxatives are not of established value in IBS but are often taken by patients with constipation predominant IBS. Tegaserod, a partial 5HT(4) agonist, is now available in the United States and other countries for use in women with IBS whose primary bowel symptom is constipation; its efficacy in men and in those with alternating bowel habits is unknown. Probiotics are of uncertain efficacy. Chinese herbal medicine data are insufficient. Other new drugs in development include the cholecystokinin antagonists and novel visceral analgesics. Both current and potential therapies for IBS are reviewed in this article.
In acute diarrhoea, loperamide provides more rapid control of symptoms than diphenoxylate when given in a flexible dosage according to unformed bowel movements, and in single dose studies 4mg loperamide has a much longer duration of effect than 5mg diphenoxylate. Loperamide is probably superior to diphenoxylate in providing symptomatic control of chronic diarrhoea such as that associated with chronic inflammatory bowel disease or following gastrointestinal surgery, It has been used for up to 3 years in such conditions without evidence of tolerance. The possibility of once daily dosage of loperamide in chronic diarrhoea is an advantage. Side-effects have not proved a problem. In man, loperamide has a significant constipating effect in healthy volunteers, with a similar onset but longer duration of activity than diphenoxylate. Central opiate activity, as demonstrated by pupillary diameter measurements with or without challenge by the narcotic antagonist naloxone, does not occur at normal therapeutic oral doses. In a single dose study in acute diarrhoea, 4mg loperamide had a much longer duration of effect than 5mg diphenoxylate or 400mg clioquinol plus 40mg phanquone. In studies in acute and chronic diarrhoea involving a flexible dosage according to unformed bowel movements, loperamide 2mg per dose has controlled diarrhoea at a lower dose level (i.e. total number of doses or average daily doses) than diphenoxylate 2.5mg per dose. It seems that a larger initial and subsequent dosage of diphenoxylate is needed to provide equivalent control of diarrhoea. Thus, in 1 study which compared loperamide 2mg per dose with diphenoxylate 5mg per dose in chronic diarrhoea, the number of doses required for control did not differ, although diarrhoea was better controlled by loperamide in terms of reduced stool frequency and improved stool consistency. In acute diarrhoea, a larger initial dose ( 10mg instead of 5mg) and subsequent larger fixed dosage (5mg every 6 hours instead of 2.5mg as needed) of diphenoxylate achieved similar control as the standard flexible dose schedule of loperamide (4mg initially then 2mg after each loose bowel movement).
Irritable bowel syndrome (IBS) is the most common disorder diagnosed by gastroenterologists and one of the more common ones encountered in general practice. The overall prevalence rate is similar (approximately 10%) in most industrialized countries; the illness has a large economic impact on health care use and indirect costs, chiefly through absenteeism. IBS is a biopsychosocial disorder in which 3 major mechanisms interact: psychosocial factors, altered motility, and/or heightened sensory function of the intestine. Subtle inflammatory changes suggest a role for inflammation, especially after infectious enteritis, but this has not yet resulted in changes in the approach to patient treatment. Treatment of patients is based on positive diagnosis of the symptom complex, limited exclusion of underlying organic disease, and institution of a therapeutic trial. If patient symptoms are intractable, further investigations are needed to exclude specific motility or other disorders. Symptoms fluctuate over time; treatment is often restricted to times when patients experience symptoms. Symptomatic treatment includes supplementing fiber to achieve a total intake of up to 30 g in those with constipation, those taking loperamide or other opioids for diarrhea, and those taking low-dose antidepressants or infrequently using antispasmodics for pain. Older conventional therapies do not address pain in IBS. Behavioral psychotherapy and hypnotherapy are also being evaluated. Novel approaches include alosetron; a 5-HT3 antagonist, tegaserod, a partial 5-HT4 agonist, κ-opioid agonists, and neurokinin antagonists to address the remaining challenging symptoms of pain, constipation, and bloating. Understanding the brain-gut axis is key to the eventual development of effective therapies for IBS.
In castor oil challenged rats, low doses of loperamide inhibit diarrhea and normalize intestinal propulsion. Unlike other opioids, loperamide is devoid of central opiate-like effects, including blockade of intestinal propulsion, up to the highest subtoxic oral dose. Nevertheless, the antidiarrheal action of loperamide can be considered to be -opiate receptor mediated, only a fewin vitro effects at rather high concentrations being not naloxone-reversible. There is little evidence that interactions with intestinal opiate receptors directly change epithelial cell function. When secretory stimuli increase mucosal tension, however, loperamide may reverse the elevated hydrostatic tissue pressure that opposes normal absorption. This antisecretory effect at the mucosal level is accompanied by motor effects when loperamide reaches the myenteric -opiate receptors. At therapeutic doses for the treatment of acute diarrhea, it is likely that the mucosal effect prevails.
Loperamide, a butyramide derivative is a new agent for use in symptomatic control of acute non-specific diarrhoea and chronic diarrhoea. Unlike diphenoxylate or codeine, loperamide does not appear to exert opiate activity in man at normal therapeutic doses. In acute diarrhoea, loperamide provides more rapid control of symptoms than diphenoxylate when given in a flexible dosage according to unformed bowel movements, and in single dose studies 4mg loperamide has a much longer duration of effect than 5mg diphenoxylate. Loperamide is probably superior to diphenoxylate in providing symptomatic control of chronic diarrhoea such as that associated with chronic inflammatory bowel disease or following gastrointestinal surgery. It has been used for up to 3 years in such conditions without evidence of tolerance. The possibility of once daily dosage of loperamide in chronic diarrhoea is an advantage. Side-effects have not proved a problem.
This crossover, double-blind study investigated the effects of single oral doses of the prodrug loperamide oxide, which is reduced gradually to loperamide in the intestine, and loperamide on jejunal motor activity in 12 fasting healthy men. Five minutes after a phase III of the migrating motor complex (MMC), 2 mg loperamide oxide, 4 mg loperamide oxide, 4 mg loperamide, or placebo were administered. Thereafter, motor activity 10-30 cm abroad the ligament of Treitz was recorded with five catheter orifices at 3-cm intervals over 4 hr. Number of contractions and area under curve increased significantly with 4 mg loperamide and 4 mg loperamide oxide, the increases with loperamide oxide occurring more gradually. Placebo and 2 mg loperamide oxide had no discernible effects. With both 4 mg loperamide and 4 mg loperamide oxide, phase I of the MMC was slightly prolonged and phase II and the time from drug administration to the onset of the first phase III slightly shortened. The percentage of aborally propagated contractions in phase II increased with all active treatments, whereas the occurrence of phases III was not altered.
Loperamide is a safe and effective antidiarrheal for the treatment of acute diarrhea. Efficacy data suggest that loperamide is more effective than the prescription drug diphenoxylate and an over-the-counter bismuth subsalicylate preparation. Loperamide is a safe drug, with few adverse reactions reported worldwide. It also lacks significant abuse potential. Loperamide may prove to be the antidiarrheal agent of choice when compared with currently available nonprescription treatments for acute diarrhea.
Tritium labelled loperamide was administered in a dose of 2.0 mg to 3 normal men, and of 1.25 mg/kg to rats. Urine and feces were collected up to 8 days for the men, and up to 4 days for the rats. Blood samples were taken at regular intervals in the men; groups of rats were killed at different times after drug administration in order to examine blood, organs and tissues. In one rat the bile was drained for 48 hr. The radioactive content of each sample was measured and the fractions due to loperamide, metabolites and volatile radioactivity were determined by the inverse isotope dilution technique and lyophilization. The fate of orally administered loperamide 3H appeared to be similar in rats and in man. Only 5 to 10% of the drug and its metabolites was recovered from the urine, the bulk being excreted with the feces. Plasma and tissue levels were low at all times. The existence of an enterohepatic shunt was shown, but uptake of the drug into the general circulation was low.