To determine the effect of a laxative alone and in combination with tegaserod in alleviating pain and improving stool frequency in adolescents with constipation predominant irritable bowel syndrome.
Forty-eight postpubertal adolescents of both sexes with constipation predominant irritable bowel syndrome, as defined by Rome II criteria, were randomly allocated to Group A (n = 27) for treatment with a laxative (polyethylene glycol 3350 oral solution) only or Group B (n = 21) for combination therapy with the laxative and tegaserod. Symptoms of abdominal pain (scale 0–10) and frequency of bowel movements were recorded daily in the pre-treatment phase and the post-treatment phase after a 7-day ‘washout’ period. Patients served as their own controls.
Treatment with the laxative alone (Group A) resulted in significant increase in frequency of bowel movements (P < 0.05), but not significant improvement in pain (P > 0.05). Treatment with the combination of the laxative and tegaserod (Group B) led to significant increase in the frequency of bowel movements and also significant reduction in pain (P < 0.05).
The laxative alone improved stooling but not pain in adolescents with constipation predominant irritable bowel syndrome. Addition of tegaserod resulted in alleviation of pain as well.
Irritable bowel syndrome (IBS) is a chronic condition characterized by abdominal pain, altered bowel function and visceral hypersensitivity. There are no diagnostic histological, biochemical or serological markers.1 Based on the kind of alteration in bowel function, IBS can be further classified as diarrhoea predominant, constipation predominant or a combination of both.2 IBS type symptoms have been reported to afflict 14% of all high school students and 6% of all middle school students.3 The treatment of IBS is challenging and mainly based on the symptom relief. In general practice, constipation predominant IBS is managed with a combination of stool softeners, laxatives, antispasmodics, diet changes and antidepressants.4–6 Recently, tegaserod has shown promise in alleviating the pain and improving the frequency and consistency of stools in adult patients with constipation predominant IBS in several double-blind, placebo-control trials.7–11 Similar data in adolescents and younger children are lacking. In this pilot study, we studied the effect of a laxative (polyethylene glycol 3350 solution, MiraLax, Braintree Laboratories Inc., Braintree, MA, USA) alone and in combination with tegaserod (Zelnorm, Novartis Pharmaceuticals Corp., East Hanover, NJ, USA) as two active treatment options in alleviating the constipation and pain symptoms in adolescents with constipation predominant IBS.
Postpubertal patients (13–18 years), of both sexes, presenting with history and symptoms suggestive of constipation predominant IBS were considered for inclusion in the study. For inclusion, all patients had to fulfil the diagnosis of constipation predominant IBS as per the Rome II criteria. The Rome II criteria for IBS delineate, ‘at least 12 weeks, which need not be consecutive, in the preceding 12 months, of abdominal discomfort or pain that is accompanied by at least two of the following three symptoms: the abdominal discomfort or pain is (a) relieved with defecation, (b) associated with a change in the frequency of defecation and/or (c) associated with a change in the form or appearance of the stool’.2 Further, for inclusion in our study, the patients had to be neurologically intact and developmentally appropriate for age and with no known underlying psychiatric illness. Patients with any other underlying illness, such as allergies, asthma, hyperactivity, migraine, urinary or fecal incontinence, etc. were excluded. Patients consuming any concomitant drugs were also excluded. The study was approved by the institutional review board.
A uniform workup was performed on all the patients being considered for inclusion in the study. All patients were evaluated with a thorough physical exam including rectal exam and laboratory workup. Constipation was confirmed by history and an abdominal X-ray showing excessive retained fecal material. Prior to inclusion, abdominal ultrasound and oesophagogastroduodenoscopy had to reveal no abnormality. Urinalysis and haematological evaluation of total and differential white blood counts, electrolytes, liver function tests, thyroid function tests and sedimentation rate had to be negative in all the patients considered for inclusion in the study. Inclusion criteria also required that evaluation of stool for reducing substances, occult blood and giardia antigen be negative as well.
After completion of the workup, and obtaining consent, all patients fulfilling the entry criteria were randomly allocated via a simple randomization table to one of the two active treatment groups: Group A for treatment with the laxative only or Group B for combination therapy with the laxative and tegaserod. Prior to initiation of the study treatment, all patients in the study underwent a ‘cleanout’ using two doses of milk of magnesia, 3 oz. each, given 1 h apart and simultaneously, bisacodyl (10 mg) suppositories were administered rectally, twice, also at a 1 h interval. This cleanout regimen was repeated if at least two loose stools were not produced. The cleanout was performed for achieving some homogeneity in all patients at the starting point of the study rather than having the patients to start the study treatments with varying degrees of retained fecal material. Upon ‘cleanout’, the specific study treatments were initiated. Both the groups were treated with the same laxative. The laxative solution was prepared by dissolving 17 g of the powder in eight fluid ounces of water and taken by mouth daily within a period of 5–10 min at 1–2 h before supper. Tegaserod was given as 6 mg tablets and one tablet was taken twice daily by mouth on an empty stomach. The same physician managed all the patients.
During the first contact visit, patients were asked to recall frequency of bowel movements and pain levels for the previous 3 weeks. This was recorded on a preformed standard data sheet. Patients were then instructed to keep a daily diary of abdominal pain and bowel movements and to call in symptom records twice weekly. The same person recorded all data. Symptom monitoring involved recording pain and number of bowel movements per day and per week. Pain was quantified using a standard pain rating scale from 0 to 10, zero being no pain and 10 being pain the worst possible pain. The middle of the scale around five indicated moderate pain. The pain scale also had drawings of faces of people depicting varying degrees of pain, to augment correct selection of pain level. Following the initial visit and throughout the duration of the subsequent workup (7–10 days), but prior to randomization or active treatment, all patients were asked to prospectively maintain similar pain and bowel movement records. This 7–10 day prospective data, collected during the workup period, were then combined with the 3 week retrospective data obtained at the first visit. Data from these two periods together formed the pre-treatment data. After initiation of the two specific treatments, daily records of pain level and frequency of stools were maintained for the post-treatment phase. All data from the cleanout phase (2–3 days) and from the initiation of specific study treatments to a period of 7 days after initiation of that treatment were discarded and that period was regarded as a ‘washout’ period. Following this, every patient kept a daily prospective record for the next 4 weeks while receiving one of the two specific study treatments and this formed the data of the post-treatment phase.
The outcome measures were: frequency of bowel movements per week and the level of pain. The group means were obtained by taking into account all the individual daily values in that group. Comparisons were made in two ways: (i) the group means were compared and (ii) the individual patients were used as their own controls for their respective pre- and post-treatment values. Comparisons were made using the anova with repeated measure and proportions were compared using the chi-squared test.
The sample size was calculated for measuring a 50% difference in the outcome variables at a power of 90% and 95% confidence. Previous data on frequency of bowel movements and pain level from the clinic records of 25 similar untreated patients were used as the reference value for s.d. The sample size was calculated to be 21 patients in each group. The decisions to opt for a 50% difference and 4 weeks duration of the study were based on the recommendations from a consensus report.12
A total of 78 patients were screened and 48 patients fulfilled all entry criteria and were enroled in the study. Twenty-seven patients were randomly assigned to Group A (laxative only) and twenty-one patients were assigned to Group B (laxative + tegaserod). Table 1 shows that upon enrollment, Groups A and B were similar in age, sex distribution, frequency of bowel movements and abdominal pain levels (P > 0.05). In the post-treatment phase, both groups experienced a significant increase in frequency of bowel movements when compared with their respective pre-treatment frequency (P < 0.05). Group A patients did not experience a significant reduction in pain following the treatment when compared with their overall or individual pre-treatment levels (P > 0.05). In contrast, Group B patients experienced a significant reduction in pain level when compared with their respective pre-treatment levels (P < 0.05). Table 2 shows data on the degree of change in pain in the two groups. Good pain reduction was defined as a reduction in pain by ≥3 points on the pain rating scale when compared with the pre-treatment values. No pain reduction was defined as no change or a change ≤2 points on the pain rating scale when compared with the pre-treatment levels. Good pain reduction was seen in 66.7% of patients in Group B, which was significantly more (P < 0.05) than 18.5% seen in Group A. There was no pain reduction in 59.3% of Group A and 23.8% in Group B (P < 0.05). Post-treatment worsening of pain was experienced by 22.2% of Group A, which was significantly more than 9.5% in Group B (P < 0.05). No obvious clinical side effects such as diarrhoea, dehydration, vomiting, rectal bleeding, weight loss or headache were observed during the treatment in any patient. None of the patients was given any additional medications. There were no dropouts or protocol deviations. Electrocardiograms performed in 10 patients in Group B before and 2 weeks after starting tegaserod did not show any change in the rate, rhythm or R-R or QTc intervals.
|Group A: laxative alone (n = 27)||Group B: laxative + tegaserod (n = 21)|
|Mean age (year)||15.37||15.10|
|Mean duration of symptoms prior to diagnosis (month)||6.93 (±2.27)||7.38 (±2.27)|
|Mean frequency of bowel movements/week||2.07 (±0.62)||2.19 (±0.51)|
|Mean pain level||7.0 (±1.86)||7.43 (±1.63)|
|Mean frequency of bowel movements/week||5.04 (±1.51)**||6.57 (±1.66)*|
|Mean pain level||6.15 (±2.38)||4.29 (±2.31)*|
|Group A: laxative alone (n = 27)||Group B: laxative + tegaserod (n = 21)|
|Number of patients with good pain reduction*||5 (18.5)||14 (66.7)***|
|Number of patients with no pain reduction**||16 (59.3)||5 (23.8)***|
|Number of patients with increased pain||6 (22.2)||2 (9.5)***|
Based on the findings of our study, treatment with the laxative alone resulted in increased frequency of bowel movements, but not significant improvement in pain in adolescents with constipation predominant IBS. The addition of tegaserod to the laxative led not only to increased frequency of bowel movements, but also a significant reduction in pain as well.
Some features of our study design need to be explained. The treatments were allocated randomly. It would have been difficult to double blind both the laxative and tegaserod. Crushing the tegaserod tablet and putting it inside a capsule would alter its pharmacokinetics so it was not carried out. Our purpose was indeed to find out whether alleviation of constipation with a laxative will alleviate the pain as well in our patients with constipation predominant IBS and whether there is really a need to consider additional interventions. There is no such published data. We compared two active treatment groups: laxative alone and laxative with tegaserod and we used patients as their own controls in a pre-treatment vs. post-treatment model. All the patients were indeed constipated and therefore received a laxative as we chose not to deny any patient an effective treatment for constipation. Also, there is no specific approved medicine for treating constipation predominant IBS in this population.
The diagnosis of IBS is being made with increasing frequency in adolescent populations. In one recent Russian population study, the prevalence of IBS among 14–17 year olds was reported to be 24% in females and 14% in males.13 In the US, estimates by Hyams et al. show that up to 17% of the adolescent population experience symptoms typical of IBS.3 The treatment of IBS is aimed at symptom relief. Present strategies to alleviate constipation include dietary fibre, stimulant laxatives, osmotic laxatives and stool softeners. Pain relief strategies include antispasmodics, antidepressants and anxiolytics. Among the antidepressants used for IBS, a review of randomized placebo-controlled studies using tri-cyclic antidepressants concluded that this class was effective in alleviating the pain.14 Among the selective serotonin reuptake inhibitors, paroxetine was found to improve symptoms for patients with severe IBS,15 but fluoxetine was determined not to decrease abdominal pain or alter rectal sensitivity in IBS patients.16 Recently, tegaserod, a partial agonist of 5HT4 receptor, has shown promise in adult patients with constipation predominant IBS for relief of abdominal pain, bloating as well as constipation.5, 7–11 It is reported to be well tolerated and safe in short- and long-term studies.7–11, 17 There is no reported experience on the use of tegaserod in the paediatric population.
We assessed frequency of bowel movements, an objective measure and pain. The expression and perception of pain is subjective, but this subjectiveness is likely to be evenly distributed in both groups as well as in the pre- and post-treatment phases especially as the treatments were randomly assigned. There may be an individual patient-to-patient variation in pain perception that may make comparisons of group means less reliable. The data were also analysed using patients as their own controls in the pre- and post-treatment phases, which would possibly negate the individual patient-to-patient variation in pain perception. As an effective marker of laxative efficacy, there was indeed a significant improvement in stooling with the use of the laxative; however, there was no alleviation of pain. In fact 22% of patients experienced an increase in the pain level with the use of laxative alone. The addition of tegaserod to the effective laxative led not only to improvement in stooling, but also to reduction in pain as well.
We did not use a placebo in the control group and therefore it could be argued that the effects of tegaserod in the study group may likely reflect a ‘placebo effect’. The patients receiving laxative and tegaserod were not aware of the patients receiving laxative alone so they could not possibly have a placebo effect; moreover, they served as their own controls. The fact that with the use of laxative alone, despite increase in frequency of stooling there was no relief of pain, is in itself a significant finding that has never been previously reported in the paediatric population. This should suggest that one should consider specific modalities for pain management in patients with constipation predominant IBS and target treatment beyond simply increasing bowel frequency. Tegaserod seems to be a potential candidate for pain relief in paediatric patients with constipation predominant IBS and warrants further larger scale evaluation.
No external financial support was received for this study.