Peppermint oil in irritable bowel syndrome.
In a literature search 16 clinical trials investigating 180-200 mg enteric-coated peppermint oil (PO) in irritable bowel syndrome (IBS) or recurrent abdominal pain in children (1 study) with 651 patients enrolled were identified. Nine out of 16 studies were randomized double blind cross over trials with (n = 5) or without (n = 4) run in and/or wash out periods, five had a randomized double blind parallel group design and two were open labeled studies. Placebo served in 12 and anticholinergics in three studies as comparator. Eight out of 12 placebo controlled studies show statistically significant effects in favor of PO. Average response rates in terms of "overall success" are 58% (range 39-79%) for PO and 29% (range 10-52%) for placebo. The three studies versus smooth muscle relaxants did not show differences between treatments hinting for equivalence of treatments. Adverse events reported were generally mild and transient, but very specific. PO caused the typical GI effects like heartburn and anal/perianal burning or discomfort sensations, whereas the anticholinergics caused dry mouth and blurred vision. Anticholinergics and 5HT3/4-ant/agonists do not offer superior improvement rates, placebo responses cover the range as in PO trials. Taking into account the currently available drug treatments for IBS PO (1-2 capsules t.i.d. over 2-4 weeks) may be the drug of first choice in IBS patients with non-serious constipation or diarrhea to alleviate general symptoms and to improve quality of life.
[c] 2005 Elsevier GmbH. All rights reserved.
Keywords: Peppermint oil; Irritable bowel syndrome; Clinical trials; Efficacy; Safety; Treatment alternatives
The lack of efficacious and safe medications for irritable bowel syndrome (IBS) warrants a review of the quite extensive peppermint oil (PO) clinical database in IBS, taking into account the significant prevalence of the disease and its enormous costs as well as the potential cost effectiveness of PO and its clinical safety.
The current definition of IBS (Rome II criteria) is listed below (Thompson et al., 1999).
At least 12 weeks, which need not to be consecutive, in the preceding 12 months of abdominal discomfort or pain that has two out of three features:
* relieved with defecation; and/or
* onset associated with a change in frequency of stool; and/or
* onset associated with a change in form (appearance) of stool.
Symptoms that cumulatively support the diagnosis of IBS:
* abnormal stool frequency (for research purposes 'abnormal' may be defined as greater than three bowel movements per day or less than three bowel movements per week),
* abnormal stool form (lumpy/hard or loose/watery stool),
* abnormal stool passage (straining, urgency, incomplete evacuation),
* passage of mucus,
* bloating or feeling of abdominal distension.
PO exerts an antispasmodic action via interference of menthol, the main component of PO, acting as a calcium antagonist (Hawthorn et al., 1988) and anti-flatulent effects of currently unexplained nature (WHO, 2002).
A total of 15 published studies as listed in Table 1 using PO in IBS were found in a literature search. A further study (Kline and Barbero, 1997) refers to recurrent abdominal pain in children. It was included due to the spasmogenic nature of the underlying symptomatology. In Table 1 key information for all studies is summarized.
Nine out of 16 studies were randomized double blind cross over trials with (n = 5) or without (n = 4) run in and/or wash out periods, five had a randomized double blind parallel group design and two were open labeled studies. A total of 651 patients were enrolled. A sex distribution for patients enrolled is available for half of all studies. In general, there is a prevalence of women, which is in line with current literature. Inclusion criteria appear to be adequate, mentioning in 15 out of 16 studies IBS or relevant symptoms, taking into account that some studies started in the 1980s before definition of the Rome criteria. Qualitative efficacy rating by either or both patient and physician included symptoms of IBS and overall success judgments. Mostly per protocol analyses were done. Treatment duration ranged from 2 to 11 weeks, in one open study it was 6 months. As comparators served placebo (n = 12 studies; 1 study compares placebo and an anticholinergic), smooth muscle relaxants (anticholinergics, n = 3 studies; 1 study compares placebo and an anticholinergic) and psychotherapy (n = 1 study; stress management program). Placebo was usually matching the active treatment or double dummy technique was used were needed (anticholinergics). Out of these 13 trials refer to investigations with enteric-coated PO and three to PO formulations without galenic specification, the latter being presumably also enteric coated. Treatments were administered 1-2 capsules t.i.d., each capsule containing between 182 and 200 mg of PO, treatment duration was usually 2-4 weeks. Compliance was monitored in four studies. It was approximately 60-75%.
Assessment of efficacy
In 11 out of 16 studies there was a daily patient rating of a whole set or only selected symptoms (e.g. abdominal pain, distension, assessment of winds, stool frequency, urgency, bloating, stool quality, frequency of attacks, severity of attacks). The symptom catalogue essentially followed the "Rome" criteria. In two studies rating by patients ensued at regular intervals of 2 weeks, in two studies the interval is not given and in one study there was the physician rating at the end of each study week (open trial).
To make all these variations comparable the variable "overall success" (overall benefit, global improvement, overall assessment) was used (% of responders). This parameter is either rated by investigators/patients or could be calculated from the data available. Also, this variable is used in recent IBS drug study meta-analyses (Poynard et al., 1994; Pittler and Ernst, 1998) and review articles (Camilleri and Choi, 1997) to achieve data comparability.
In Table 2 all overall success data from the 16 studies reviewed are summarized. Placebo response is in the range from 10% to 52% (mean 29%) for all studies. The open studies (Fernandez, 1990, Shaw et al., 1991) mark the extremes of PO response, i.e. 18% or 93%. The double blind cross over trials with (n = 5) or without (n = 4) run in and/or wash out periods and the five randomized double blind parallel group design trials show PO efficacy in the range from 39% to 79% (mean 58%). Eight out of 12 placebo controlled studies show statistically significant effects in favor of PO. Where no response data versus placebo are recorded (n = 3 studies) statistical information reveals significance (n = 2) in favor of or a borderline effect of PO. The three double blind cross over studies versus smooth muscle relaxants did not show differences between treatments hinting for equivalence of treatments, although a placebo arm is missing with the exception of one trial (Carling et al., 1989).
There is reasonable evidence that enteric-coated PO. 180-200 mg t.i.d., given over 2-4 weeks, in IBS is efficacious as compared to placebo and the smooth muscle relaxants investigated.
Adverse events reported were generally mild and transient, but very specific. PO caused the typical GI effects like heartburn (n = 14) and anal/perianal burning or discomfort sensations (n = 26), whereas the anticholinergics caused dry mouth (n = 21) and blurred vision (n = 14). There is no dose or time dependent pattern for either active treatment. Tolerance in the children study was good.
A total of 71 patients dropped out. The vast majority (n = 58) due to events unrelated to study drugs (e.g. protocol violations, failure to report back). Other reasons were: n = 6 worsening of symptoms (PO or placebo), n = 2 nausea and vomiting (PO), n = 3 perianal burning (PO) and n = 2 peppermint taste and pyrosis.
Data analysis of PO clinical data in IBS reveals that in a sufficient number of studies with appropriate design the oil is safe and efficacious as a symptomatic remedy. Average response rates are 58% (range 39-79%) and 29% (range 10-52%) for placebo. This is in line with the data compiled by Camilleri and Choi (1997) quoting 73% (range 39-89%) for various active treatments and 41% (range 13-69%) placebo response. In a meta-analysis focusing on smooth muscle relaxants Poynard et al. (1994) calculate 62% for active treatment and 35% for placebo from 25 drug studies. Mertz (2003) quotes a 20 [right arrow] 50% response rate for placebo. The significant variability of response to any treatment in IBS may underline the multi-causal etiology of the disease.
It is interesting to note that also with recently developed more targeted drugs like tegaserod (Mertz, 2003), alosetron (SCRIP, 2000) or cilansetron (Pink Sheet, 2004) versus placebo response rates cover the same range (52/42%, 41/29%, 60/45%). Only cilansetron appears to be effective in both sexes. In 2000 (FDA Talk Paper, 2000) alosetron was withdrawn from the US market because of ischemic colitis. In 2002, the drug was re-launched for women with serious IBS under a restricted distribution program (Pink Sheet, 2004). Also for tegaserod, in an FDA Talk Paper (2004) new risk information was announced referring to serious diarrhea, ischemic colitis and other forms of intestinal ischemia. The drug is only approved for short-term treatment of women. Also cilansetron, a new chemical in this group may have comparable risks (Pink Sheet, 2004).
In a recent meta-analysis assessing the global improvement of IBS by PO Pittler and Ernst (1998) identified eight randomized placebo controlled trials. Five studies were eligible for a meta-analysis and calculation shows a beneficial effect of the oil (p < 0.001). This is in line with the results of this review. The discussion touches a number of significant issues (e.g. inclusion criteria, carry over effects) and it is stated that definitive conclusions concerning efficacy cannot be inferred.
A critical view has to be made on: (1) The authors missed four randomized trials versus placebo (Evans, 1982; Weiss and Kolbl, 1988; Liu et al., 1997; Kline and Barbero, 1997 [children]), irrespective of their eligibility for meta-analysis. (2) No wash out period in cross over trials is addressed as a serious concern (carry over effect). It is stated that only the study by Schneider and Otten (1990) had an appropriate wash out period. But also the eligible double blind cross over studies by Dew et al. (1984) and Rees (1979) must have had variable wash out periods because the authors explicitly write that "each treatment began when active symptoms developed". (3) Whether the study by Shaw et al. (1991) does not corroborate the positive findings of other studies remains an open question because 6 months psychotherapy are compared to drug treatment in an open design. There is only 18% drug and 72% psychotherapy response. The drug rate is at the very low end of placebo response, and it may be speculated that drug patients aggravated their symptoms.
The data presented in this review depict the current knowledge of PO in IBS, providing evidence that the oil, administered orally in an enteric coated form, is a safe, efficacious and cost-effective symptomatic short term treatment in reducing global symptoms and pain due to its spasmolytic and antiflatulent effect. The adverse event pattern of PO is distinct from that of anticholinergics and 5HT3/4-ant/agonists with a low frequency and mild symptoms, which in general do not require any intervention, thus resulting in a positive benefit/risk ratio. Taking into account the currently available drug treatments for IBS PO may be the drug of first choice in IBS patients with non-serious constipation or diarrhea to alleviate the general symptoms and to improve quality of life, e.g. pain or bloating. Anticholinergics and 5HT3/4-ant/agonists do not offer increased improvement rates, but the latter appear to be useful under tight medical supervision in patients with serious constipation or diarrhea.
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H.-G. Grigoleit*, P. Grigoleit
Johann-Sebastian-Bach-Str.27, 65193 Wiesbaden, Germany
Received 13 September 2004; accepted 26 October 2004
*Corresponding author. Tel.: +49611 520509; fax: +49611 5990443.
E-mail addresses: Dr.Grigoleit@t-online.de (H.-G. Grigoleit), Dr.Grigoleit@t-online.de (P. Grigoleit).
Table 1. Summary of study information Study drug(s) Study no./Ref. Design Peppermint oil 1 Rees (1979) db, co, wash out One to two period capsules t.i.d. (b) 2 Evans et al. (1982) db, co, randomized, One to two wash out? capsules t.i.d. (d) 3 Dew et al. (1984) db, co, wash out One to two period capsules t.i.d. (b) 4 Nash et al. (1986) db, co, no wash out, Two capsules randomized t.i.d. (a) 5 Munst et al. (1987) db, co, wash out, One capsule double dummy, t.i.d. (a) randomized 6 Weiss and Kolbl (1988) db, pg, randomized One capsule t.i.d. (a) 7 Lawson et al. (1988) db, co, no wash out One capsule t.i.d. (b) 8 Lech et al. (1988) db, pg, randomized One capsule t.i.d. (d) 9 Wildgrube (1988) Matched pairs, db pg, Capsules (c) randomized 10 Carling et al. (1989) db, 3 way co, wash out One to two capsules t.i.d. (a) and matching placebo 11 Schneider and Otten (1990) db, co, wash out, One capsule randomized t.i.d. (a) 12 Fernandez (1990) Open One capsule t.i.d. (b) 13 Ambross (1990) db, co, randomized Not specified (d) 14 Shaw et al. (1991) Open, pg, randomized One capsule t.i.d. (a) 15 Liu et al. (1997) db, pg, randomized One capsule t.i.d. or q.i.d. (a) 16 Kline and Barbero (1997) db, pg, randomized One to two capsules t.i.d. (a) Study drug(s) Treatment Patients Study no./Ref. Comparator(s) weeks enrolled 1 Rees (1979) Placebo 1-2 3/ 18 capsules t.i.d. treatment 2 Evans et al. (1982) Placebo 2/ 20 treatment 3 Dew et al. (1984) Placebo 1-2 2/ 29 capsules t.i.d. treatment 4 Nash et al. (1986) Pacebo 2 2/ 41 capsules t.i.d. treatment 5 Munst et al. (1987) Matching 3/ 16 mebeverine treatment 135 mg 1 tablet t.i.d. 6 Weiss and Kolbl (1988) Placebo, 1 3 60 capsule t.i.d. 7 Lawson et al. (1988) Placebo, 1 4 25 capsule t.i.d. 8 Lech et al. (1988) Placebo, 1 4 47 capsule t.i.d. 9 Wildgrube (1988) Matching placebo 2 40 capsules 10 Carling et al. (1989) Hyoscyamine 0.2 2/ 40 mg and matching treatment placebo, 1-2 tablets t.i.d. 11 Schneider and Otten (1990) Placebo 1 capsule 6/ 60 t.i.d. treatment 12 Fernandez (1990) 4 50 13 Ambross (1990) Alverine citrate 11/ 18 treatment 14 Shaw et al. (1991) Stress management 24 35 program, median 6 psychotherapy sessions of each 40 min/patient 15 Liu et al. (1997) Placebo 1 capsule 4 110 t.i.d. or q.i.d. 16 Kline and Barbero (1997) Placebo 1-2 2 42 capsules t.i.d. db = double blind, co = cross over, pg = parallel groups. (a) Colpermin[R]. (b) Enteric-coated PO capsule. (c) Mentacur[R]. (d) Unspecified PO formulation. Table 2. Summary of "overall success" data for peppermint (PO) oil in IBS Study Overall success (%) Overall success no. peppermint oil Comparator comparator (%) 1 50 Placebo 13 2 No numerical data Placebo No numerical data 3 41 Placebo 10 4 39 Placebo 52 5 No numerical data Mebeverine No numerical data 6 74 Placebo 17 7 Placebo 8 68 Placebo 26 9 No numerical data Placebo No numerical data 10 57 Placebo 37 Hyoscyamine 38 11 57 Placebo 39 12 93 13 No numerical data Alverine No numerical data 14 18 Stress 72 management program 15 79 Placebo 32 16 70 Placebo 43 Study no. Comments 1 p < 0.01 2 Overall success in favor of PO (p < 0.025) 3 p < 0.001 4 n.s. 5 Except for "fullness" no difference between treatments 6 p < 0.001 7 Increase in stool frequency (p < 0.05), formulation problem 8 p < 0.02 9 All symptoms improved in favour of peppermint oil (p < 0.05) 10 Symptom score before/after PO p < 0.01; placebo and hyoscyamine p>0.05 11 Difference n.s. p = 0.08 12 Open study 13 No difference between treatments 14 Strongly in favour of psychotherapy after 6 months 15 Overall success calculated from mean improvement values of symptoms, single symptoms all p < 0.05 16 Children/recurrent abdominal pain, p < 0.002
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|Author:||Grigoleit, H.-G.; Grigoleit, P.|
|Publication:||Phytomedicine: International Journal of Phytotherapy & Phytopharmacology|
|Date:||Aug 1, 2005|
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