Peppermint Oil: Clinical Uses in the Treatment of Gastrointestinal Diseases

Central JSM Gastroenterology and Hepatology

Research Article *Corresponding author David A. Johnson MD, MACG, FASGE, FACP 885 Peppermint Oil: Clinical Kempsville Road, Suite 114, Norfolk, VA 23502; Email: Submitted: 10 November 2014 Uses in the Treatment of Accepted: 13 January 2015 Published: 19 January 2015 Copyright Gastrointestinal Diseases © 2015 Johnson et al. Rouzbeh Shams1, Edward C. Oldfield2, Jennifer Copare3 and OPEN ACCESS David A. Johnson4* Keywords 1Department of Internal Medicine, Eastern Virginia Medical School, United States • Peppermint oil 2Department of Internal Medicine, Eastern Virginia Medical School, United States • Irritable bowel syndrome 3Department of Internal Medicine, Eastern Virginia Medical School, United States • Functional dyspepsia 4Department of Internal Medicine Gastroenterology, Division Eastern Virginia Medical • Spasmolytic School, United States

Abstract Peppermint oil has been used for centuries as a remedy for nausea, indigestion, and a host of other medical symptoms. Over the course of the past several years, studies have looked at the benefit of peppermint oil in Irritable Bowel Syndrome, functional dyspepsia and endoscopy and barium-induced spasm of the gastrointestinal tract. The benefit of peppermint oil is thought to be due to anti-spasmodic effects, as well as anti-inflammatory and anti-bacterial effects. Although more research may be beneficial, peppermint oil shows evidence justifying a more expanded using gastrointestinal disease management. This review focuses on the physiology and recent literature illustrating potential use of peppermint oil.

INTRODUCTION discomfort occurring at least 3 days a month in the last 3 months, Peppermint oil is derived from the peppermint plant, a associated[6]. Clinically, with IBS two is or defined more of: by improvement recurrent abdominal with defecation, pain or cross between water mint and spearmint, which is indigenous onset associated with a change in frequency of stool, onset to Europe and North America but now grown throughout the associated with a change in the form (appearance) of stool world. Chemically, peppermint oil is made up of primarily of menthol and the structurally similar compound menthone [1]. Although peppermint oil is most commonly associated with its increased[7]. The treatment rates of ofpsychiatric IBS can be conditions, quite complex namely given depression a poor understanding behind the exact etiology and an association with remedy for a variety of symptoms such as nausea, indigestion, focused on symptomatic control, there are also a number of using flavoring or fragrance, it has long been used as a home and headaches [1]. Since 1979, peppermint oil has been clinically complementaryand anxiety [8,9]. and With alternative pharmacologic medicine management treatments primarily being studied for symptomatic treatment of certain gastrointestinal practiced and reviewed for IBS. Peppermint oil is one of these conditions, including Irritable Bowel Syndrome (IBS), dyspepsia, treatment approaches to IBS currently gaining attention based and in preparation for endoscopic procedures [1,2]. Additionally, there is some promising data suggesting that peppermint oil may controlled trials. on its documented physiologic effects and efficacy in randomized Physiology be beneficial via anti-spasmotic, anti-inflammatory and antibacterial properties [3-5]. These properties, combined with a based on its documented effects as a spasmolytic agent. Early relatively minimal side effect profile make it a favorable treatment studiesThe onuse peppermint of peppermint oil using oil in electrophysiology the treatment of in IBS a guinea is largely pig option. This article will address the use of peppermint oil in peppermintirritable bowel oil insyndrome, relation to functional each, followed dyspepsia, by a discussion and endoscopy- of the induced spasm by first reviewing the pertinent physiology of available clinical data. amplitudesmodel showed while that also peppermint increasing oil the exerts rate of an current effect decay;on potential- in this manner,dependent peppermint calcium oil channels has a mechanism by decreasing of action the resembling peak current that IRRITABLE BOWEL SYNDROME Irritable Bowel Syndrome is a functional gastrointestinal eppermint oil is able to induce smooth of a dihydropyridine calcium channel antagonist [10]. By reducing the calcium influx, p illness affecting between 5-20% of the world’s population muscle relaxation within the gastrointestinal tract. In order to Cite this article: Shams R, Oldfield EC, Copare J, Johnson DA (2015) Peppermint Oil: Clinical Uses in the Treatment of Gastrointestinal Diseases. JSM Gas- troenterol Hepatol 3(1): 1036. Johnson et al. (2015) Email: Central achieve this effect, the peppermint oil must be formulated with ) and a delayed release enteric coating to ensure delivery to the lower PGE2 (Prostaglandin E2 4 4 GI tract and colon [11,12]. Additionally, inappropriate release arachidonic acid metabolism into LTB (leukotriene B ), which served as markers for the lipooxygenase and cyclooxygenase pathways, respectively [5]. 2 4 heartburn,of the peppermint the primary oil in adversethe upper effects GI tract of induces peppermint relaxation oil [12]. of Results showed that L-menthol significantly inhibited LTB (-64.4 the lower esophageal sphincter leading to resultant reflux and ± 10%), PGE (-56.6 ± 8%), and IL-1β (-64.2-7 ± 7%) production oil are available, the two formulations in particular which have atagent low [11]. doses Peppermint (therapeutic oil range has also of 10been g/ml) documented and in toa dose- have beenWhile predominately a number of entericused in coatedclinical formulationstrials are Colpermin of peppermint (McNeil antibacterialdependent manner, activity therebyin vitro against serving over as an22 anti-inflammatorydifferent bacteria Healthcare, Dublin, Ireland) and Mint oil (Cadigroup, Rome, the way in which the peppermint oil is prepared. Colpermin uses toincluding inhibit gram-positivethe proliferation cocci of Helicobacter and rods and pylori, gram-negative Salmonella Italy) [13]. The main difference between these two products is enteritidis,bacteria [17-19]. Escherichia Additionally, coli 0157:H7, peppermint and both oil was methicillin shown sensitive and methicillin resistant Staphylococcus aureus in liquid 0.2mL of peppermint oil in an enteric coated capsule, whereas Mint oil uses 225mg of peppermint oil and 45mg of Natrasorb, a bacterial overgrowth (SIBO) and IBS, the antimicrobial activity particular tapioca starch that absorbs oils in solid powder [14]. ofcultures peppermint [20] Given oil in the the relationship small intestine between may small provide intestinal anther There are no currently available studies comparing the efficacy mechanism for symptomatic improvement in IBS [21] of delivery for the two formulations. The dose of peppermint oil inhowever, outcomes is essentiallyto be attributed equivalent to the (0.2mLlevel of =dosing 200mg) used between in the Clinical Trials variousthe two trials,products. and notAs a to result, the choice one would of formulation. expect any differences In 1979, Rees et al originally documented the use of

peppermint oil for the treatment of IBS by enrolling 18 patients of theThe melastatinactivity of peppermint subfamily of oil transient on calcium receptor channels potential may be more specifically related to the mediation ofTRPM8, a member with IBS (no identification of subtype provided)to receive either 0.2 mL of peppermint oil in gelatin capsules (Elanco LOK caps, Eli cold temperatures and also menthol, the main constituent of trial period [2] Despite showing no effect on stool frequency, (TRP) cation channel super family, which can be activated by symptomLilly and Co analysis Ltd/Indianapolis/USA) revealed a lower total or placebo and mean for daily a three-week symptom contractions of smooth muscle in a manner inversely proportional peppermint oil [15]. The activation of the TRPM8 channels induces the small number of participants. to the temperature and also through a mechanism involving the score, however, this did not achieve clinical significance due to activation of Rho-kinase; Rho-kinase inhibits myosin light change Nearly 20 years later, Pittler and Ernst published one of the channels(MLC) phosphatase, have been allowingfound in fordorsal phosphorylation root ganglia, ofvagal MLC afferent kinase first critical reviews and meta-analysis on peppermint oil in and subsequent smooth muscle contraction [16]. These TRPM8 IBS [22]. They identified eight randomized control trials, five is, however, some controversial evidence concerning the ability peppermintof which were oil compared placebo-controlled, with placebo double-blind in symptomatic trials. treatment Overall, ofneurons, menthol the to gastric induce fund a release us, colon, of intracellular and small calciumintestine stores [3]. There from the meta-analysis suggested a significantly positive effect of calcium release was potentiated at high temperatures, opposite of (P < 0.001), based on three studies with a positive effect and the TRPM8 channels, as one study found that menthol-induced two without any significant difference; however, the authors concluded that significant methodological flaws associated with fromthe cold the activation endoplasmic of TRPM8 reticulum [4]. Additionally and Golgi bodies, these researchers in contrast the majority of the studies excluded establishing a benefit of found that menthol-induced calcium release primarily originates acceptedpeppermint clinical oil beyond features a for reasonable the diagnosis doubt. of The IBS main(leaving reasons only for the methodological flaws were the lack of correctly using to the TRPM8 receptors which they found to be localized to the plasma membrane [4]. When combined with the knowledge 9% diagnosed using the correct criteria), short treatment course that there is significant species and region-related Despite this, variability there are of effects(6 of 8 [22]. trials were ≤ 1 month of treatment), and failure to use these channels, any direct effect of peppermint oil on this specific a wash-out period in crossover trials to account for carry-over TRPM8also function channel as cannot release be channels concluded on [3]. intracellular membranes a number of other channels in the TRP super family that can Subsequently, a number of randomized control trials have that may serve as the site of action for menthol [4]. Regardless demonstrated a beneficial effect of peppermint oil for IBS. Liu et oil, it appears evident that peppermint oil does, indeed, have a al randomized 110 patients with IBS to receive Colpermin (one physiologicalof the specific effectchannel on responsible gut motility for through the effects mediating of peppermint calcium minutescapsule containing before meals, 0.2mL for ofone peppermint month showing oil) (McNeil that symptomatic Healthcare, release and enhancing smooth muscle contraction. Dublin, Ireland) or placebo three to four times daily, 15-30 Apart from the spasmolytic effects, peppermint oil also has improvements with peppermint oil were significantly better than placebo ( p < 0.05) [23].Results indicated that of the 52 patients in frommild efficacy healthy as volunteers, both an anti-inflammatory Juergens et al were and ableanti-microbial to study the Colpermin group, 41 (79%) experienced decreased severity, agent. Using lipopolysaccharide (LPS)-stimulated monocytes 29 (56%) were pain free, 43 (83%) had reduced stool frequency, and 41 (79%) had decreased flatulence. In comparison, of the 49 the anti-inflammatory activity of L-menthol on the levels of in the placebo group, 21 (43%) patients noticed a decrease in JSM Gastroenterol Hepatol 3(1): 1035 (2015) 2/11 Johnson et al. (2015) Email: Central

these events were mild and transient. Intention to treat analysis severity of pain, 4 (8%) were pain free, 16 (32%) with reduced experience adverse events, most commonly heart burn; however stool frequency, and 11 (22%) with decreased flatulence. These findings were supported by the results of another randomized was also performed from this meta-analysis yielding a number double-blind placebo controlled trial of 90 patients with IBS needed to treat (NNT) of 3 for global improvement in symptoms using Colpermin (one capsule containing 0.2 mL of peppermint at 2 to 12 weeks and a NNT of 4 for improvement in abdominal oil) or placebo three times daily for 8 weeks; after 8 weeks of pain at 2 to 8 weeks [13]. The authors concluded that overall the therapy, 14 patients (42%) in the Further, Colpermin the severity group were of abdominal free from results of this meta-analysis support the short-term efficacy of abdominal pain or discomfort compared to only 6 (22%) in the identifypeppermint variations oil for in the response treatment between of IBS; these however, subtypes. the specific placebo group (p < 0.001) [24]. subtypes of IBS were not defined and further study is needed to pain was significant decreased and the quality of life significantly In a recent monograph on the management of IBS and increased in the Colpermin group compared to placebo. While chronic idiopathic constipation, the American College of the overall summary score for quality of life was not significant (p = 0.194), the significant improvements in quality of life after 8 oil is superior to placebo in improving IBS symptoms [27]. Gastroenterology Task Force concluded that that peppermint weeks of treatment were noted improvements in bodily pain (p = 0.035), general health (p = 0.046), social functioning (p = 0.046), Additionally peppermint oil carries no greater risk for adverse and role limitations due to emotional problems (p=0.028) [24]. A effects than placebo. The basis for the weak recommendation is a major limitation of this study, however, was nearly a 30% loss to lack of differentiation between the types of IBS patients recruited, follow-upIn an [24]. attempt to better control for potential confounders, risk of bias in many studies, and a significant heterogeneity in the Summarystudies showing a significant benefit. Cappello et al. also performed a randomized double blind placebo controlled trial assigning 57 patients with IBS to receive two tolerated treatment for symptomatic improvement in IBS. capsules twice daily, one hour before meals of either enteric- In summary, peppermint oil appears to be a safe and well- studycoated wereMint oil determined (Cadigroup, to Rome, have IBSItaly) by or the placebo Rome for II 4 criteria, weeks as a spasmolytic agent, altering smooth muscle contraction in however,with a follow-up the patients 4 weeks were after only treatment. included Participants if small intestinal in this thePeppermint GI tract. oil’sIn addition, main efficacy peppermint in IBS oilis throughhas also its been ability shown to act to bacterial overgrowth, lactose intolerance, and celiac disease had

have activity as an anti-inflammatory and anti-microbial agent been previously excluded [14]. Results indicated that at 4 weeks suggesting respective potential efficacy modulating cytokine of treatment 75% (18/24) of patients in the peppermint oil group inflammatory pathways and /or gut microbiome effects on showed >50% reduction in their baseline IBS symptoms (p < isdietary not available, exposures, clinicians intestinal should sensory consider afferents peppermint or intestinal oil as a 0.01) compared to 38% (10/26) in the placebo group (p < 0.05). 4 treatmentmotility. While option long-term for those data suffering on the fromefficacy IBS of do peppermint to its proven oil weeks after treatment, the reduction in IBS symptoms remained thesignificant results inof the this peppermint study support oil group the use at 54% of peppermint (13/24) (p

the ambiguity of its symptoms, limited understanding of significantly superior to placebo for global improvement of pathophysiologydiagnosis for both and cliniciansabsence of and a gold patients standard alike treatment. due to IBS symptoms (RR 2.23, 95% CI 1.78-2.81) and improvement Patients present with a variety of symptoms including epigastric in abdominal pain (RR 2.14, 95% CI 1.64-2.79) [13]. Of note, the patients in the peppermint oil group were more likely to JSM Gastroenterol Hepatol 3(1): 1035 (2015) 3/11 Johnson et al. (2015) Email: Central pain or discomfort, epigastric fullness, early satiety, post prandial nausea, belching and abdominal bloating [32]. According to the meal and peppermint oil combination versus test meal alone 0.64mL of peppermint oil [37]. Patients who ingested the test of the following: postprandial fullness, early satiety or epigastric burningRome III forcriteria, at least functional 3 months dyspepsia duration is anddefined in theas having absence two of [37].demonstrated Dalvi et al a alsosignificant found accelerationthat subjects in fed gastric a radio emptying labeled (Ptest < 0.0367) primarily occurring during the early phase (P < 0.0218) even developed new subdivisions for symptoms related to meals water) had an accelerated gastric emptying rate as compared to andorganic those disease unrelated causing to meals. the symptoms. Postprandial The distresscurrent criteriasyndrome have is meal in conjunction with peppermint oil (0.2mL in 25mL of

® those not given peppermint oil [41]. , characterized by postprandial fullness and early satiety, whereas burning [33]. A combination herbal medication STW 5 (Iberoast epigastric pain syndrome is characterized by epigastric pain and Physiology Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany) is frequently utilized for treatment of functional dyspepsia. It is currently believed that functional dyspepsia is a Peppermint leaf extract constitutes one of nine extracts (bitter candy tuft, peppermint leaf, chamomile flower, liquorice root, several mechanisms [32]. Possible etiologies include infection angelica root, caraway fruit, milk thistle fruit, Melissa leaf and withbiopsychosocial Helicobacter disorder pylori, abnormalinvolving agastrointestinal complex interplay motility, of greater celandine herb) in STW 5. Schemann et al, evaluated region specific effect of various concentrations of STW-5(concentrations As such, several treatment options have been investigated, all doseranging dependently from 32 to decreased512μg/mL) muscle and its tone components in gastric on fundus the gastric (P < altered visceral sensation and psychosocial factors [32,34,35]. fundus, corpus and antrum of guinea pig stomach [43]. STW5 with mixed therapeutic response rates; these treatments include 0.05) and corpus (P < 0.05), while enhancing antral contractility H. pylori eradication (6-14%), prokinetics (18-45%), proton (P < 0.05); unfortunately when evaluated separately, peppermint pump inhibitors (7-10%), histamine-type-2-receptor antagonists leaf extract (concentrations ranging from 24 to 188μg/mL) (8-35%), tricyclic antidepressants (64-70%) and serotonin had inconsistent effects provoking both mixed contraction and reuptake inhibitors (no better than placebo) [33]. Complicating relaxation responses in the proximal stomach. In the distal matters more, symptoms are non-specific and often do not reflect contraction amplitude was observed in a portion of antral muscle stripsstomach, but, anon-statistically these results were significant not sustained enhancement or concentration in muscle Complementarythe underlying and pathophysiology, Alternative Medicine making (CAM) treatment modalities selection has occurred,difficult and as patientscostly [31]. perceive Over recentthese treatments years, a shift as morein attention “natural” to and generally safer. [1] Peppermint oil containing formulations dependent. This may signify that the effect of STW 5 on gastric motility is likely the result of synergism between extracts [43]. are,Clinical perhaps, Trials the most extensively studied CAM. In a double-blind, placebo-controlled multicenter trial, May et al investigated a fixed combination of peppermint oil (90mg) and caraway oil (50mg)(Enteroplant, Dr Willmar Several studies have shown benefit of peppermint oil on the Schwabe GmbH, Karlsruhe, Germany)administered three times daily versus placebo in 45 patients diagnosed with non-ulcer gastricunderlying emptying pathophysiology have been of suggested functional as dyspepsiathe predominating [36-41]. both pain intensity and prognosis and severity of the disorder Impaired gastric relaxation, antral hypo-motility and abnormal asdyspepsia assessed [45]. by the After Clinical 4 weeks Global of Impressions treatment, Scale improvement (CGI) were in aetiology spasmolytic to patients to gastrointestinal suffering from muscle dysmotility-like through an antagonistic dyspepsia the peppermint oil/caraway oil group as compared to placebo [42,43]. In vitro studies have shown peppermint oil to function as significantly improved (P< 0.015 and P< 0.008, respectively) in mg of peppermint oil caused complete inhibition of gallbladder effect on calcium channels [10]. Goerg et al demonstrated that 90 peppermint[45]. In a followoil/caraway up double-blind, oil combination placebo-controlled administered at a trialby lower dosingthe same frequency investigators, (twice daily) the therapeutic versus placebo efficacy was ofevaluated the same in emptying (P < 0.04) and prolongation of small intestinal transit time as compared to placebo (a non-enteric-coated capsule containing 0.4mL of 0.9% NaCl) (85 minutes vs 65 minutes, 96 patients with functional dyspepsia after 28 days of treatment. respectively) (P< 0.004) [38]. Mizuno et al proved peppermint At the conclusion of the study, there was a statistically significant oil (PO) to have a significant spasmolytic effect in the esophagus difference in reduction of pain intensity (40% vs 22%) (P < (PO vs control: 0.35 ± 0.04 vs 0.65 ± 0.04 , P < 0.001), lower 0.0003), sensation of pressure, heaviness and fullness (44% vs stomach (PO vs control: 1.20 ± 0.05 vs 1.42 ± 0.11, P < 0.001) 22%) (P < 0.0005) and global improvement as assessed by CGI and duodenal bulb (PO vs control: 0.96 ± 0.05 vs 1.47 ± 0.05, P (67% vs 21%) (P < 0.00005) [46]. < 0.001) in patients orally administered peppermint oil (10mL In a prospective, randomized, double-blind multicenter trial of 3.2 % Peppermint oil solution) versus control (12ml of water) conducted by Freise et al, the equivalence and efficacy of two prior to a barium suspension undergoing a double-contrast fixed mixed preparations of peppermint oil and caraway oil in Inamori et al evaluated the early effects of peppermint oil barium meal examination [44]. 223 patients with non-ulcer dyspepsia was evaluated. Patients C breath test were treated with either enteric coated capsules (270mg (BreathID system, Oridion Medical, Jerusalem13- Israel) after peppermint oil and 150mg caraway oil: test formulation) or an onadministration gastric emptying of a test with meal continuous alone and real-time in combination with enteric soluble formulation (108mg peppermint oil and 60mg caraway oil: reference formulation) over 4 weeks. A statistically JSM Gastroenterol Hepatol 3(1): 1035 (2015) 4/11 Johnson et al. (2015) Email: Central

declinesignificant in epigastric improvement pain intensity in pain (measured frequency on was a visual observed analog in find the most relief from peppermint oil treatment through its the test formulation (P < 0.04), while a statistically significant spasmolytic properties, which facilitate both gastric relaxation and gastric emptying. Additionally, peppermint oil has anti- scale ranging from 0- no pain to 10- extremely strong pain) was emetic benefits. While future studies are undoubtedly needed to observed in both groups (P < 0.001) [47]. oilevaluate in the the treatment long-term of functionalefficacy and dyspepsia, side effects as of current peppermint evidence oil, physicians should be strongly encouraged to utilize peppermint In a randomized controlled double-blind study, the therapeutic equivalence of a fixed combination preparation supportsENDOSCOPY-INDUCED its short-term efficacy SPASM and overall tolerability. (Enteroplant) of peppermint oil (180mg peppermint oil and 100mg caraway oil, 1 capsule twice daily) versus the prokinetic Esophageal and colonic spasms during endoscopic Aagent comparable cisapride reduction(10mg, 1 tablet in mean three pain times score daily) (peppermint in 120 patients oil/ procedures are a common and challenging aspect of endoscopy. with functional dyspepsia over a 4-week period was evaluated. Many endoscopists use a variety of medications to help reduce caraway oil combination: 4.62 vs cisapride: 4.60, P < 0.021), these spasms, to improve visualization and to minimize (assessedfrequency byof painthe Dyspeptic (peppermint Discomfort oil/caraway Score oil and combination: CGI) was seen4.65 butylbromide (delivered oral, sublingual, or intramuscular) or vs cisapride: 4.16, P < 0.0034), and other dyspeptic symptoms patient discomfort. Antispasmodic drugs such as hyoscine-N of the gut lumen; however these agents are associated with ® in both test groups (P value not listed) [48]. ) in the glucagon (delivered intravenously) are used to obtain relaxation

Several studies support the use of STW-5 (Iberogast asmany anticholingeric serious side disturbances effects. Hyoscine-N in urinary, butylbromide salivary and has ocular been oftreatment Iberogast of® functional dyspepsia. In a recent meta-analysis, linked to cardiovascular events and cardiac arrhythmias as well data was pooled from 3 RCTs observing the safety and efficacy as well as gastrointestinal symptoms including acute nausea and (138 patients) vs® placebo (135 patients) in patients systems. Glucagon also imposes the risk of delayed hypoglycemia, with functional dyspepsia [49]. In all 3 trials, patients were given infused/sprayed peppermint oil may be a safe and effective 20predominating drops (1 mL) baseline of Iberogast symptom. vs placebo At the conclusion over a 4-week of the period. study, alternativevomiting [35,50]. to these New drugs. evidence suggests that oral or topically theThe Iberogastmajority of® grouppatients reported (124) reported their most acid bothersome regurgitation symptom as their Physiology addition, difference in patients reporting their most bothersome Recent studies have shown the effectiveness of peppermint as “mild” or “absent” as compared to placebo (P < 0.01). In symptom as “severe” and “very severe” at the termination of oil in reducing smooth muscle contraction and providing ® group the study® was also significant between the Iberogast Iberogast thisrelaxation phenomenon of the is gastrointestinal thought to be tract secondary during to colonoscopy, the menthol (7%)for the and following placebo symptoms: (26%) (P abdominal < 0.001). Incramps, patients epigastric treated pain, with ERCP, and barium enema examinations. The physiology behind nausea, acid, treatment regurgitation, was significantly retrosternal related troubles to and the vomiting outcome oil,action its use against has been the subject smooth to muscle more clinical calcium investigations. channels [53-57]. correlation was found for in appetence, fullness, retching or early Furthermore, due to the low adverse effect profile of peppermint (P < 0.001). Of the remaining symptoms assessed, no significant Clinical Trials satiety [49]. evaluatedPeppermint in a trialoil may assigning also have patients benefit to in receive treating peppermint nausea as In a randomized double-blind, double-dummy, controlled a predominating symptom of functional dyspepsia. This was study by Hiki et al, the antispasmodic effects of 16 ml intra- luminally administered peppermint oil (Miyazawa Medical oil inhalation or placebo for post-operative nausea in patients upperCo., Tokyo, endoscopy Japan) were ,compared evaluated to intramuscularly [39]. Peppermint administered oil had a undergoing major gynecological surgery [50]. The peppermint hyoscine-N-butyl bromide (20 mg) in 100 patients undergoing oil group had a nausea rate of 66% compared to 100% in the incontrol woman group, post however cesarean this section finding treated was non-significant with peppermint (P value oil decreasesignificant in increase the closing in the ratio opening (percent ratio change (percent in the change diameter in aromatherapynot listed) [50,51]. (POA) Lane as compared et al also to reported an inhaled reduced inert placebo nausea the pyloric ring before and after treatment) and a significant In addition, the time required for the disappearance of gastric antrumbetween contraction the maximally rings and in patients minimally treated opened with pyloric peppermint ring). and standard antiemetic therapy (SAT), as assessed at 2 minutes (POA vs placebo: P <0.000, POA vs SAT: P< 0.001) and 5 minutes In contrast to the patients receiving peppermint oil, those who post treatment (POA vs placebo: P < 0.000, POA vs SAT: P < oil versus hyoscine-N-butylbromide was reduced (p < 0.0001). Summary0.003) [52]. effects including dry eyes, urinary retention and blurry vision received hyoscine-N-butylbromide experienced a variety of side Peppermint oil appears to be a viable treatment option for [39]. patients suffering from functional dyspepsia, a disorder plagued care. Patients with dysmotility predominating symptoms may Hiki and colleagues conducted another study to determine by disabling symptoms and lack luster results with standard the effective dose and safety of L-menthol (Nihon Pharmaceutical Co., Tokyo, Japan) during endoscopy by looking directly at gastric JSM Gastroenterol Hepatol 3(1): 1035 (2015) 5/11 Johnson et al. (2015) Email: Central

was also studied by Asao et al. Four hundred and nine patients peristalsis using video-recorded endoscopic figures [53]. This Peppermint oil’s effectiveness in reducing colonic spasm phase II, multicenter, double-blinded study enrolled one hundred thirty-one patients who were randomly assigned to receive a received a 200 ml solution containing 8 ml of peppermint oil, 20ml solution with three different concentrations of L-menthol 1 L of water and 0.2 ml of Tween 80 (Polysorbate 80, synthetic or placebo (0.0% n=34, 0.4% n=32, 0.8% n=35, and 1.6% n=30). substance used to stabilize aqueous formulations of medications Patients were extensively monitored starting 3 minutes before, for parenteral administration-Wako Pure Chemical Industries during and at least 30 minutes after completion of the procedure. Ltd, Osaka, Japan).Thirty six patients were selected into a control beforeThe primary the completion outcome of was endoscopy. to achieve Results absence of the of studyperistalsis showed 75 togroup, the accessoryreceiving achannel 200 ml ofsolution the colonoscope. that contained Patient only positioning water and to 105 seconds after administration of the solution and again wasTween changed 80. The insolution order was distribute administered the solution via hand throughout pump attached the dose dependent suppression of peristalsis (P<0.001). Patients who received higher dosages (0.8% P=0.015 and 1.6% P=0.009) colon. Improvement in spasm was seen in 88.5% of treated group had significantly higher suppression of peristalsis compared to compared to 33.3% in the control group (p<0.0001) [56]. placebo group. There was no difference in rate of adverse events Peppermint oil has also been investigated for its efficacy between all four groups [53]. (DCBE). Another study done by Asao compared peppermint as a spasmolytic during a double-contrast barium® (Boehringer enema endoscopicA similar retrogradestudy conducted cholangio by Yamamoto pancreatography et al looked (ERCP) at the use of peppermint oil (Miyazawa Medical, Tokyo, Japan) during oil to intramuscular injection of 20mg Buscopan to site of administration and peppermint oil concentration. Ingelheim Limited Consumer Healthcare), a commonly used Groups[54]. Forty 1 and patients 3 received were the divided solution into only four around groups, the accordingduodenal Buscopanspasmolytic® [57]. Patients (n=383) were divided into four groups: peppermint in barium (n=91), peppermint in tube (n=90), antrum of the stomach, and around the duodenal papilla. All (n=105), or no treatment (n=97). The peppermint papilla, as compared to group 2 and 4, which received it at the oil solution was prepared by mixing 8ml of peppermint oil with 0.2 ml of Tween 80 (Wako Pure Chemical Industries Ltd, four groups received 20ml of peppermint oil solution; groups 1 forOsaka, respected Japan) groups.and 100 All ml patients water. Thirty were evaluated milliliters for of peppermintpresence of archivesand 2 received and selected lower concentrations16 patients who of underwent1.6% compared ERCP to with 3.2% 1 solution was mixed with barium or was placed in the enema tube mgreceived of intravenously by groups administered3 and 4. Authors glucagon used aspreviously historical recordedcontrols. ERCP was successfully performed with peppermint oil alone in inspasm tube, on peppermint spot films. The in percent barium, of Buscopan patients ®without, and no any treatment spasm in the entire colon was 41.8, 37.8, 38.1 and 13.4 for the peppermint No difference was noted on motility reduction between the receiving peppermint in barium versus in tube. Compared to 91.4% of patients, and it was equally effective amongst all groups. Buscopangroups respectively.®, peppermint There oil had was the no same difference spasmolytic between effect patients in the transverse and descending colon. Furthermore, peppermint oil groups (P=0.327). Two patients, each in groups 1 and 4 required ® in the caecum additional glucagon or hyoscine-N-butylbromide. Serious complications related to peppermint oil did not occur [54]. showed to be significantly superior to Buscopan Summaryand the ascending colon (p<0.005) [57]. peppermintAnother oil non-randomized to Hyoscine butyl prospective bromide (Buscopan study done© by ImagawaNippon BoehringerIngelheim, and colleagues [55], Hyogo, compared Japan) the and efficacy glucagon of Gastrointestinal spasms related to endoscopic procedures (Glucagon G Novo© 20 mg; pose the challenge of patient discomfort and reduced

1 mg; Novo Nordisk Pharma, Tokyo, Japan) during esophagogastroduodenoscopy (EGD). The visualization of anatomy. Contrary to peppermint oil, currently peppermint oil was prepared by mixing peppermint oil (Yoshida used anti-spasmodic agents are accompanied by a number of side pharmaceutical, Tokyo, Japan) with distilled water and catalyst suggesteffects. The it may aforementioned be a more favorablestudies show alternative promise to in thethe efficacy current of peppermint oil in reduction of endoscopy-related spasm and outcomesorbitan monostearateof this study was(Wako to comparePure Chemical antispasmodic Industries, scores Osaka, in japan), a 20ml solution with 1.6% peppermint oil. The primary roletreatment of peppermint options oil used. in endoscopy. Further investigations, including cost- elderly (≥70 years old) or non-elderly (<70 years old) patients. effective analyses, may be beneficial in determining the precise INFLAMMATORY BOWEL DISEASE Antispasmodic score (1-5, where 5 represent no spasms) was defined by the degree of spasm of the antrum and difficulty of biopsy. A total of 8,269 EGDs were performed with 1,893 patients received peppermint oil, 6,063 received Hyoscine butyl bromide searchThere of PubMed is limited using data the search available terms concerning “peppermint the oil” use and of (HB) and 157 patient received glucagon. No significant difference peppermint oil in inflammatory bowel disease (IBD). A literature was observed in the non-elderly group between peppermint oil addressing the topic; however, a Google search for these same and HB groups (mean score ± standard deviation: 4.025 ± 0.925 “inflammatory bowel disease” returns no articles specifically vs. 4.063 ± 0.887, P=0.23). Among the elderly patients, the scores between peppermint oil (n = 1,294, 4.073 ± 0.917) and HB (n = topics [58] returns a large number of patient testimonials for 1,480, 4.064 ± 0.921, P = 0.83) groups were similar, which was peppermint oil on various IBD support forums. This section will significantly better than the glucagon group (n = 69, 3.797 ± seek to explain two possible pathways through which peppermint 0.933, P < 0.05) [55]. oil may exert a beneficial effect in IBD. JSM Gastroenterol Hepatol 3(1): 1035 (2015) 6/11 Johnson et al. (2015) Email: Central

Table 1: Review of Clinical Studies for Functional Dyspepsia. Study Design/Objective Patients Medication Outcomes Freise et al.47 ulcer dyspepsia Prospective, randomized, 223 patients with non- mgTest caraway formula oil) (270mg in enteric Over 4 weeks: preparationsdouble-blind multicenterof peppermint trial oil to and coatedpeppermint capsules oil and 150 improvement in pain frequency carawaycompare oilthe efficacy of two mixed Test formulation showed a significant Reference formula Both(p<0.04) groups showed decline in

oil)(108mg as enteric peppermint soluble formulationoil and 60 mg caraway epigastric pain intensity (p<0.001) Goerg et al.38 Ultrasonic determination of 12 healthy volunteers vs. Peppermint oil: gallbladder emptying and vs. assessment of orocecal transit time placebo90mg peppermint oil using lactulose H2 breath test 50mg caraway oil 2)1) prolongedinhibited gall-bladder small intestinal emptying transit compared to placebo (p<0.04) Inamori et al.37 study assessing the effect of volunteers accelerationtime compared in gastricto placebo emptying (p =0.004) peppermintRandomized, oil two-way on gastric crossover emptying 10 healthy male 0.64mL peppermint oil Peppermint oil caused a significant using 13C breath test (p<0.0367) Madisch et al.36 Comparable reduction seen in both controlled trial comparing groups for (enteroplant vs cisapride): EnteroplantRandomized, versus double-blind cisapride for 60 Enteroplant carawayEnteroplant oil, 1(90mg capsule vs functional dyspepsia 58 Cisapride twicepeppermint daily) oil and 50mg 1) Mean pain score (4.62 vs 4.60, p<0.021) three times daily) 2)3) FrequencyOther dyspeptic of pain symptoms (4.65 4.16, (p value Cisapride (10mg, 1 tablet notp<0.0034) listed) May et al.45 19 Enteroplant Enteroplant Enteroplant group showed multicenter trial in patients with improvement in both pain intensity Double-blind, placebo controlled Enteroplant to placebo 20 placebo Three times daily for 4 [assessed by CGI – Clinical Global non-ulcer dyspepsia comparing weeks Impressions(p<0.015) and Scale] severity (p<0.008) May et al.46 Enteroplant Enteroplant group showed multicenter trial in patients with improvement in both pain intensity Double-blind, placebo controlled 48 Enteroplant vs Enteroplant to placebo 48 placebo Twice daily for 4 weeks vs non-ulcer dyspepsia comparing (40% 22%, p<0.0003) and global improvement assessed by CGI (67% et al.44 Random recruitment of patients 21%, p<0.00005) participants vs. spasmolytic effect in: Mizuno 250 randomly selected 12ml10mL water peppermint oil Peppermint oil had significantvs administeredundergoing double-contrast peppermint oil controls (3.2%) vs barium meal examination (DCBM) 215 sex and age matched 1) Esophagus (0.35 0.65, p<0.001) 2) Lower stomach (1.20vs 1.42, p<0.001) 3) Duodenal bulb (0.96 1.47, p<0.001) As mentioned earlier, the physiologic mechanism of differen peppermint oil in the treatment of IBS is largely related to ces, a number of similarities exist between the TRPV1 channel and other members of the TRP family, including TRPM8, its activity on calcium channels, more specifically the TRPM8 channel,which shares there a isligand limited binding data site to suggestwith 36% a rolesimilarity for peppermint of amino- channel. Within this same TRP family, the transient receptor oilacid in identity this pathway; [62]. Given however, the well-characterized given the contrasting role ofmechanisms the TRPV1 potential vanilloid type 1 (TRPV1) has been shown to be frominvolved animal in regulationstudies using of neurogenicmice with chemically inflammation induced within colitis, the similarity in their structure, it is plausible that alterations in whichcolon [59].showed Evidence both macroscopic suggesting and a role microscopic of TRPV1 improvements in IBD comes activationof action betweenor inhibition the TRPM8of one of and these TRPV1 channels channels could and alter some the activity of the other channel through as of yet undiscovered pathways. in inflammation when treated with the TRPV1 antagonist, capsazepine [60]. The TRPV1 channel appears to act in opposite Another potential role of peppermint oil in the treatment of to the TRPM8 channel, as it is activated by a number of stimuli IBD pertains to the antimicrobial activity of peppermint oil and including capsaicin, lipoxygenase products, leukotriene B4, high complicated and a number of potential pathways have been oftemperatures these ligands (>43C), is not acidicfully understood pH (<5.3), intracellular[61]. Despite redox these states,major its effect on the gut microbiota. The etiology of IBD is extremely and electrostatic charge; however, the exact mechanism of action identified. Most recently, increasing evidence suggests that JSM Gastroenterol Hepatol 3(1): 1035 (2015) 7/11 Johnson et al. (2015) Email: Central

Table 2:

Study Review of ClinicalDesign/Objective Studies for Endoscopy-Induced Patients Spasm. Medication Outcomes Asao et al Satisfactory spasmolytic effect was 56 of peppermint oil administration oil group duringProspective colonoscopy trial on the efficacy 409 patients in peppermint 200ml of solution (8ml 36 patients in control water)peppermint oil and 0.2mL patientsseen in 88.5% of peppermint oil group of Tween 80 per 1L of patients versus 33.3% of control Asao et al Peppermint solution Percent of patients with no spasm: 57 results from occult blood contractProspective barium trial enemaon the efficacy(DCBE) 383 DCBEs with positive of peppermint oil during double- groups: peppermint in (100ml water, 8mL no treatment (13.4%) testing assigned to 4 peppermint oil, 0.2mL peppermintBuscopan (38.1%) in barium solution peppermint in enema tube Tween 80) peppermint in enema tube (41,8%) barium solution (n=91), Buscopan 20mg Peppermint(37.8%) oil was equally (n=90), Buscopan (n=105), spasmolytic in transverse and or no treatment (n=97) descending colon, however, has stronger effect in cecum and

et al 39 Peppermint oil: ascending colon (p<0.005) upper endoscopy Hiki comparingRandomized peppermint double-blind, oil to 100 patients undergoing Peppermint oil (16mL ratio* double-dummy, controlled trial intra-luminal) 1) Significant increase in opening ratio^ hyoscine-N-butylbromide hyoscine-N-butylbromide 3)2) DecreasedSignificant timedecrease to disappearance in closing (20mg intramuscular) of gastric contraction rings

(p<0.0001) et al 131 patients underdoing 4) Decreased adverse effects 53 upper endoscopy Hiki Phase II, multicenter, double- 20 mL solution with: Significant dose dependent blind study for efficacy and 0% L-menthol (n=34) suppression of peristalsis (p<0.001) safety of L-menthol preparation 0.4% L-menthol (n=32) 0.8% L-menthol (n=35) Effect greatest for 0.8% (p=0.015) 1.6% L-menthol (n=30) Noand difference 1.6% (p=0.009) in adverse solutions events between groups Imagawa et al 55 enrollment of patients performed noted between PO and HB on undergoingNon-randomized upper prospective endoscopy 8,269 endoscopies 20ml 1.6% PO No significant difference wasvs

peppermint oil (PO) as an antispasmodic score (4.025 comparing the efficacy of 1,896 PO 4.063, p=0.23) butylbromide (HB), glucagon 6,603 HB PO and HB groups had similar antispasmodic to hyoscine-N- 157 GL Among the elderly (>70 years old) 156 NO vs (GL), and no antispasmodic (NO) antispasmodic scores (4.073 4.064, p=0.83), which were significantly better than the GL Yamamoto et al Peppermint oil equally reduced group (p<0.05) 54 enrollment of patients groups around duodenal papilla duodenal motility in all groups Non-randomized prospective 40 patients divided into 4 Group 1: 20ml 1.6% PO Duodenal movement none or mild anundergoing antispasmodic ERCP examining the around duodenal papilla efficacy of peppermint oil (PO) as andGroup stomach 2: 20mL antrum 1.6% PO Noin 69.2% serious complications related to peppermint oil were reported around duodenal papilla Group 3: 20mL 3.2% PO

around duodenal papilla andGroup stomach 4: 20ml antrum 3.2% PO

* opening ratio = percent change in pyloric ring before and after treatment ^ closing ratio = present change in diameter between the maximally and minimally opened pyloric ring JSM Gastroenterol Hepatol 3(1): 1035 (2015) 8/11 Johnson et al. (2015) Email: Central

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Cite this article Shams R, Oldfield EC, Copare J, Johnson DA (2015) Peppermint Oil: Clinical Uses in the Treatment of Gastrointestinal Diseases. JSM Gastroenterol Hepatol 3(1): 1036.

JSM Gastroenterol Hepatol 3(1): 1035 (2015) 11/11