There are a number of issues leading to greater use of methotrexate (MTX) in pediatric patients. First, there is accumulating evidence of the efficacy of MTX in Crohn disease (CD) administered at various patient ages (1–9). Second, the use of thiopurines is associated with intolerance, nonresponsiveness, and loss of responsiveness (10) with relapse of CD. Finally, there are concerns about the use of purine analogues with the development of lymphoma either as sole therapy or in combination with anti-tumor necrosis factor-α antibody therapy (11–13). All of these have factored into the greater use of MTX in pediatric CD.
One of the troublesome and common adverse events that develop with the use of MTX is nausea, which also can include an anticipatory component (14,15). In a retrospective, multicenter study evaluating the efficacy of MTX in children with CD, Uhlen et al (2) reported 7 of 61 (11.5%) patients developed nausea, which led to MTX discontinuation in 3. There was a sense that folic acid started before the initiation of MTX was beneficial in nausea prevention. Antiemetics were reported to provide no benefit, although their details are not provided. Turner et al (3) reported their experience in another retrospective review of MTX in pediatric CD (3) with nausea affecting 10 of 56 (17.9%), all of whom were prescribed folic acid. Willot et al (9) observed nausea with or without vomiting in 23.5% of children receiving MTX with no difference as to whether concomitant folic acid was administered. In a prospective, randomized trial using MTX as CD maintenance therapy, nausea and/or vomiting was a complaint in 40% of those receiving parenteral MTX (6).
Although none of the above studies reported on the use of ondansetron as a premedication to prevent nausea, ondansetron was being prescribed as a premedication to some of the children with CD receiving MTX at our institution. Ondansetron is a 5-HT3 receptor antagonist that is used to treat nausea and vomiting associated with oncologic chemotherapy. A previous report noted its benefit for reducing nausea following MTX usage in rheumatoid arthritis (16), but there is a paucity of literature regarding its use with MTX therapy for CD. We conducted a retrospective cohort study of children receiving MTX therapy for CD with the hypothesis that premedication with ondansetron at the initiation of MTX would reduce the incidence of nausea.
PATIENTS AND METHODS
We conducted a chart review of all of the patients receiving MTX for pediatric CD at the Children's Hospital of Eastern Ontario (CHEO), Ottawa, Canada, to compare those receiving treatment and ondansetron (treatment group) to those not receiving ondansetron premedication before MTX injections (control group). Our center cares for approximately 200 patients with CD annually. All of the children younger than 18 years with CD treated at CHEO from 2001 to 2009 were identified using a comprehensive database. Diagnosis of CD was established by the usual clinical, radiological, endoscopic, and histological criteria (17). Three physicians were involved in treating the included patients; there were differing practices among physicians with regard to the use of ondansetron premedication, and as such it was the physician's discretion that determined whether patients received ondansetron at the initiation of MTX. Patients were excluded from analysis whether they had been administered MTX for 2 weeks or less (N = 4), but none of these patients had reports of nausea during the short time they were taking the MTX medication.
MTX was administered on a weekly basis via subcutaneous injection at a starting dose of 15 mg/m2 to a maximum dose of 25 mg in the hospital's medical day unit or at the office of their primary care provider. No patients were prescribed oral, intramuscular, or intravenous MTX. After several weeks of safe injections and depending on the age of the patient and willingness of the patient and parents, parents or patients were taught to self-inject MTX. Before initiation of MTX, children underwent testing that included a chest x-ray, Mantoux testing, various routine blood tests (complete blood count, aspartate transaminase, alanine aminotransferase, γ-glutamyl transferase, total and direct bilirubin), and hepatitis viral screening (hepatitis B, hepatitis C, and Epstein-Barr virus titers). Folic acid supplementation (2 mg given 3 times weekly) was initiated in all of the children before MTX injections because reports suggest that it reduces MTX-induced nausea (18). When prescribed, patients were instructed to take ondansetron by mouth 30 to 60 minutes before the MTX injection. With the exception of a single patient, all of the patients weighing more than 40 kg were initiated on 8 mg of ondansetron and most (17 of 23) children lower than 40 kg body weight were initiated on 4 mg ondansetron. The initial ondansetron dose was taken for 2 to 4 weeks; this dose was subsequently halved for an additional 2 to 4 weeks. Patients were generally reassessed 1 month after MTX initiation and then every 3 to 4 months thereafter. A standardized clinic form with a checklist ensured that all of the physicians routinely asked questions of compliance, tolerance, and adverse effects (including nausea). Telephone contact with nursing staff was available to patients and both clinic records and telephone logs were reviewed.
Case records were reviewed for patient characteristics (sex, age at diagnosis, and age at MTX initiation), CD phenotype based on the Montreal Classification of Crohn's Disease (19), activity of disease based on the Pediatric Crohn's Disease Activity Index (PCDAI) (20), length of illness before MTX initiation, MTX dose, concomitant medications, side effects, duration and response to MTX, and reason for MTX discontinuation (if any). Nausea that occurred subsequent to the MTX injection was recorded, as was the occurrence of anticipatory nausea (ie, nausea felt by patients before receiving their MTX injection). Nausea occurred in 10 patients before the MTX injections as a consequence of their disease; however, the present study focused on nausea that was consistently time related to the MTX injection.
The primary outcome of the present study was occurrence of nausea as reported by the patient and reported in the chart. Secondary outcomes included discontinuation of MTX because of nausea, overall duration of MTX use, and efficacy of ondansetron to treat anticipatory nausea.
Descriptive statistics were reported as proportions for categorical variables and medians with interquartile range (IQR) for non-normally distributed data, or means with standard deviation (SD) for normally distributed data. Comparisons between groups were conducted using the Wilcoxon rank sum test for continuous variables. Analysis of categorical outcomes was conducted with the Pearson χ 2 test or the Fisher exact test for small cell sizes. Duration of MTX use was compared between groups using the Kaplan-Meier survival analysis. All of the hypothesis tests were 2-sided and considered significant at P < 0.05. Analyses were conducted using SAS 9.2 for Windows (SAS Institute Inc, Cary, NC).
Approval was received from the center's research ethics board before commencement of the study.
There were 64 children with CD who received MTX between 2001 and 2009. Four patients (3 receiving MTX and ondansetron and 1 receiving MTX alone) received 2 or fewer doses of MTX and were excluded from the analysis (Fig. 1). Of the included patients, 50 received dual therapy with MTX and ondansetron, while 10 did not receive ondansetron with their MTX. Descriptive characteristics are demonstrated in Table 1. The cohort consisted of 57 of 64 (89%) patients who began MTX after failure or adverse events following azathioprine or 6-mercaptopurine (6-MP) therapy. Of the remaining patients, 7 of 64 (11%) patients began MTX as first-line medication for maintenance of remission.
The average dose of MTX was 14.1 mg/m2 (range 9.7–18.0 mg/m2), and all 60 patients reported taking their suggested folic acid supplementation. Concurrent medications at the start of MTX included corticosteroids (prednisone or budesonide) in 45 of 60 (75%) and infliximab in 7 of 60 (11.7%); 5 (8.3%) patients were receiving antibiotics for Crohn-related flares of disease, and 4 of 60 (6.7%) were receiving a 5-aminosalicylate product. No other medications were initiated at the time of MTX. A multivitamin/multimineral supplement was taken by 57 of 60 (95%) patients.
Among the included patients, 1 of 50 (2%) receiving ondansetron experienced nausea within 3 months of initiating MTX, compared with 6 of 10 (60%) not receiving ondansetron (P < 0.0001; number needed to treat: 2). The median duration of MTX treatment (to date of last follow-up visit) was 0.9 (IQR 0.4–1.8) years in the ondansetron treatment group compared with 1.2 (IQR 0.3–1.7) years in the control group (P = 0.76, Fig. 2). The average dose of MTX in all of the patients who developed nausea was 14.8 mg/m2, similar to the overall average dose. The solitary patient with nausea in the treatment group was a boy; 3 of 6 (50%) patients with nausea in the control group were boys. Of the 10 patients who did not receive ondansetron at the onset of MTX injections, 5 took alternate medications to prevent nausea (dimenhydramine ± ginger supplement). Three of these patients eventually were prescribed ondansetron before MTX injection and no further nausea was reported. There were no noted adverse effects of ondansetron.
Nausea later developed in 5 patients in the treatment group but had been subsequently weaned from ondansetron. The average time to this late-onset nausea was 8.2 months (range 6–12 months), and reinstitution of ondansetron helped to relieve nausea in 3 patients. Anticipatory nausea was later experienced at anywhere from 2 to 13 months following methotrexate injections without pre-MTX ondansetron by 3 of 50 (6%) of the ondansetron group, compared with 3 of 10 (30%) of controls (P = 0.05). Institution of ondansetron relieved this in 3 patients. Of the patients who had late-onset nausea after discontinuation of ondansetron, only 1 also developed anticipatory nausea.
No patient discontinued MTX because of nausea. Patients taking ondansetron were as likely to discontinue MTX as controls, with 26 of 50 (52%) of the ondansetron-taking group discontinuing MTX compared with 6 of 10 (60%) controls (P = 0.74). Discontinuation of MTX therapy occurred after a mean of 9.7 months, with the most common reason being loss of effect in maintaining CD in remission. For those taking ondansetron, 25 of 26 discontinued because of loss of effect; 1 patient discontinued because she was also taking infliximab and elected not to continue both medications. Among the patients not taking ondansetron, 5 discontinued the MTX because of CD relapse and 1 patient had a flare of his concurrent rheumatoid arthritis and thus began receiving a biologic agent.
Four patients chose not to continue MTX after 1 to 2 doses; none of these patients were experiencing nausea at the time of the discontinuation of MTX. The reasons for this are as follows: CD symptoms became too severe to wait for a beneficial effect from MTX, leading to MTX discontinuation and initiation of a biologic agent (n = 2); patient electively decided to undergo an alternate maintenance therapy after further discussions without outside health personnel (n = 1); and patient who developed presumed MTX-induced pneumonitis (n = 1). This latter patient was an 11-year 8-month-old child and received MTX at a dose of 12.4 mg/m2. She reported shortness of breath and tachycardia around 3 hours after injection that later spontaneously resolved without specific treatment. Other adverse effects noted in those receiving MTX included elevated transaminases (n = 3) all of which resolved with MTX dose reduction, diarrhea (n = 1), brief abdominal pain (n = 1), vomiting with fever (n = 1), leukopenia (n = 1), and headache (n = 1). There were no cases of pancreatitis.
Thiopurines may fail to maintain a steroid-free CD remission or may cause adverse effects. MTX represents an alternative potential for maintenance treatment of steroid-dependent patients with CD (1–9). The majority of our patients began MTX after failure of or intolerance to thiopurines; however, nausea is reported in 12% to 40% of patients with CD taking MTX (2,3,6,9), and discontinuation of MTX treatment may be required should nausea control not be obtained.
The overall rate of nausea in our patient population was 17.2%. Although our use of 3 months to report initial nausea was arbitrary, this was chosen because this timing was at least 1 month after the discontinuation of ondansetron, and most patients who experienced nausea developed nausea within 1 month after MTX initiation. Our findings show that premedication with ondansetron can markedly reduce nausea in patients with CD being treated with MTX. These results are consistent with a study of adult patients with rheumatology that showed that ondansetron is effective in reducing the intensity and duration of nausea despite the use of metoclopramide (16).
In addition to preventing development of nausea, most of our patients (45/50, 90%) did not develop nausea following the discontinuation of ondansetron, showing that a proactive initiation of ondansetron may be an effective strategy to prevent post-MTX nausea. For those who do later develop nausea, reinstitution of ondansetron was an effective antinausea medication. Three patients in the control group were subsequently treated with ondansetron to control nausea, which may reflect an adherence to methotrexate and is potentially reflected in the similarity of the survival curves between the 2 groups (Fig. 2).
Nausea induced by MTX typically begins rapidly after commencement of MTX. Anticipatory nausea may develop as well. Anticipatory nausea appears to occur in approximately 29% of patients receiving chemotherapy (21). In pediatric patients with juvenile idiopathic arthritis, van der Meer et al (14) reported that the development of anticipatory nausea with MTX was common. Although most patients did not develop late anticipatory nausea, some of our patients did. Interestingly, some anticipatory nausea also responded to reinstitution of ondansetron before MTX injections. In oncology therapeutics, 5-HT3 receptor antagonists have been studied in anticipatory nausea. Comparable incidence and improvement rates were reported with ondansetron utilization (21–24). Identification of those who may need greater than an 8-week period of ondansetron would be helpful to delineate in future studies.
Medications such as corticosteroids or supplements such as folic acid may alleviate nausea. The use of folic acid has been shown to help with MTX-related nausea in rheumatoid arthritis (18). Uhlen et al (2) reported improvement of nausea with folic acid supplementation in 5 of 7 pediatric patients with CD receiving MTX, although others have found no such benefit (9). All of our patients received folic acid concurrently with MTX, yet reports of nausea were still present. If folic acid is indeed helpful in preventing nausea, then one may speculate that the prevalence of nausea could have been higher if folic acid had not been initiated. Even with concurrent administration of folic acid, however, ondansetron has a role in preventing such an adverse effect. Other potential limitations of our study are limited sample size, retrospective nature, and lack of placebo control. The placebo effect of ondansetron could have contributed to our findings; however, patients taking alternate medications for an antiemetic benefit still reported nausea, most of which was ameliorated after the initiation of ondansetron. As Figure 2 shows, patients who received ondansetron had an outcome similar to those who did not receive ondansetron with loss of benefit over time in this cohort. This loss of response of MTX in steroid-dependent, azathioprine-failure patients is similar to other reports of long-term outcome with MTX (9).
In summary, ondansetron helps to prevent the nausea that is typically associated with parenteral MTX treatment in CD. Although a strategy to treat MTX-induced nausea will provide benefit for some, a proactive preventive strategy may be more effective. Furthermore, avoidance of nausea can be anticipated to improve overall patient interest and compliance in using MTX when it is otherwise safe and effective in maintaining CD in remission. A larger prospective controlled study would help to support these observations.
1. Mack DR, Young R, Kaufman SS, et al. Methotrexate in patients with Crohn's disease after 6-mercaptopurine. J Pediatr
2. Uhlen S, Belbouah R, Narebski K, et al. Efficacy of methotrexate in pediatric Crohn's disease: a French multicenter study. Inflamm Bowel Dis
3. Turner D, Grossman AB, Rosh J, et al. Methotrexate following unsuccessful thiopurine therapy in pediatric Crohn's disease. Am J Gastroenterol
4. Ravikumara M, Hinsberger A, Spray CH. Role of methotrexate in the management of Crohn's disease. J Pediatr Gastroenterol Nutr
5. Weiss B, Lerner A, Shapiro R, et al. Methotrexate treatment in pediatric Crohn's disease patients intolerant or resistant to purine analogues. J Pediatr Gastroenterol Nutr
6. Faegan BG, Fedorak RN, Irvine EJ, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease: North American Crohn's Study Group Investigators. New Engl J Med
7. Faegan BG, Rochon J, Fedorak RN, et al. Methotrexate for treatment of Crohn's disease. New Engl J Med
8. Din S, Dahele A, Fennel J, et al. Use of methotrexate in refractory Crohn's disease: the Edinburgh experience. Inflamm Bowel Dis
9. Willot S, Noble A, Deslandres C. Methotrexate in the treatment of inflammatory bowel disease: an 8-year retrospective study in a Canadian pediatric IBD center. Inflamm Bowel Dis
. 2011 Feb 18 [Epub ahead of print].
10. Chebli JMF, Gaburri PD, De Souzza AFM, et al. Long-term results with azathioprine therapy in patients with corticosteroid-dependent Crohn's disease: open-label prospective study. J Gastroenterol Hepatol
11. Kandiel A, Fraser AG, Korelitz BI, et al. Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut
12. Beaugerie L, Brousse N, Bouvier AM, et al. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet
13. Rosh JR, Gross T, Mamula P, et al. Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn's disease: a cautionary tale? Inflamm Bowel Dis
14. van der Meer A, Wulffraat NM, Praken BJ, et al. Psychological side effects of MTX treatment in juvenile idiopathic arthritis: a pilot study. Clin Exp Rheumatol
15. Andrykowski MA, Redd WH, Hatfield AK. Development of anticipatory nausea: a prospective analysis. J Consult Clin Psychol
16. Blanco R, Gonzalez-Gay MA, Garcia-Porrua C, et al. Ondansetron prevents refractory and severe methotrexate-induced nausea in rheumatoid arthritis. Br J Rheumatol
17. Satsangi J, Silverberg MS, Vermeire S, et al. The Montreal Classification of Inflammatory Bowel disease: controversies, consensus and implications. Gut
18. Morgan SL, Baggott JE, Vaughan WH, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis: a double-blind, placebo-controlled trial. Ann Intern Med
19. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition; Colitis Foundation of America, Bousvaros A, Antonioli DA, et al. Differentiating ulcerative colitis from Crohn disease in children and young adults: report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn's and Colitis Foundation of America. J Pediatr Gastroenterol Nutr
20. Turner D, Griffiths AM, Walters TD, et al. Appraisal of the Pediatric Crohn's Disease Activity Index (PCDAI) on four prospectively collected datasets: recommended cutoff values and clinimetric properties. Am J Gastroenterol
21. Morrow GR, Roscoe JA, Kirshner JJ, et al. Anticipatory nausea and vomiting in the era of 5-HT3 antiemetics. Support Care Cancer
22. Aapro MS, Kirchner V, Terrey JP. The incidence of anticipatory nausea and vomiting after repeat cycle chemotherapy: the effect of granisetron. Br J Cancer
23. Fernández-Marcos A, Martin M, Sanchez JJ, et al. Acute and anticipatory emesis in breast cancer patients. Support Care Cancer
24. Roscoe JA, Morrow GR, Hickok JT, et al. Nausea and vomiting remain a significant clinical problem: trends over time in controlling chemotherapy-induced nausea and vomiting in 1413 patients treated in community clinical practices. J Pain Symptom Manage
Keywords:Copyright 2011 by ESPGHAN and NASPGHAN
Crohn disease; inflammatory bowel disease; methotrexate; nausea; pediatrics