Abstract
Background:
Many patients presenting with migraine also complain of constipation. The relationship between these two symptoms has not been explored yet in detail. This study, therefore, was carried out to investigate the effect of treatment of constipation with lactulose on the improvement of migraine headache in patients who referred to neurology clinics in Arak.
Materials and Methods:
A total of 50 patients with migraine were selected based on the Headache International Society (HIS) index and the Rome Foundation is an independent not for profit 501(c) 3 organization that provides support for activities designed to create scientific data and educational information to assist in the diagnosis and treatment of functional gastrointestinal disorders (FGIDs) (ROME III) scale so as to diagnose their migraine and constipation. The patients were randomly divided into an experimental group and a control group. A 15 cc daily of lactulose syrup was prescribed to the experimental group with the antimigraine drugs (10-mg nortriptyline and 10-mg propranonol daily). In contrast, only the standard treatment for migraine was prescribed for the control group. The severity of disability was assessed based on the severity of migraine-induced disability (MIDAS) questionnaire. Having collected the data, the data analysis was carried out using Statistical Package for the Social Sciences (SPSS) (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.) statistical t-tests, and repeated measures test.
Results:
The results of the independent sample t-test showed no significant difference between the control and intervention group’s main variables of the research before the intervention (P < 0.05). On the contrary, the results of the repeated measures test indicated that the mean scores ‑of the severity of disability and the severity of migraine pain between the measurement times were significantly different for the intervention and control groups, in a way that after one and/or two months of using lactulose syrup, the severity of disability and pain in the intervention group was lower than those of the control group (P < 0.001).
Conclusion:
Short-term follow-up of this study showed that lactulose syrup could remove the constipation with no significant side effects––can be used as an adjunct for the treatment of patients with migraine. However, future studies suggested for long-term consequences of constipation control.
Keywords: Constipation, headache, lactalosis, migraine
Introduction
Migraine is one of the most common types of headache around the world, including Iran, affecting about 12% of the general population.[1] The prevalence of the migraine in women is three times higher than that of men.[2] It is a debilitating, progressive, and chronic neurovascular dysfunction of the parenchymal brain that has important effects on people’s lives.[3] The most common problems and costs associated with headache are disability, suffering and loss of quality of life.[1] The molecular mechanism of migraine has not yet been completely identified. It is believed that oxidative stress plays a key role in the pathology of migraine.[4] Studies have shown that in patients with migraine, the level of antioxidants is reduced, whereas the overall level of oxidants and the oxidative stress index is increased.[4,5,6] On the contrary, many patients with headache also complain of constipation.[7] The relationship between these two symptoms has not been explored yet in detail. It is likely that constipation plays a key role in starting a headache, or that headache and constipation have a common pathophysiology.[8] Constipation and migraines have common symptoms among which are pain and discomfort, which can lead to poor quality of life. Studies have shown that the prevalence of constipation in patients with primary headaches is higher than that of the normal population. Therefore, there is a potential association between headache and constipation, which has been confirmed by some studies.[7,8] Yet, because of the very limited studies carried out in this area, it cannot unconditionally be stated that treatment of constipation can help improve migraine headaches. There are several drugs, such as magnesium, lactulose, polyethylene glycol, and sorbitol, to treat constipation. These are prescribed as the first-line drugs. However, bisacodyl and the senna compounds, are prescribed as the next-step drugs.[9] Among the available drugs, lactulose is a low-dose drug that is more commonly used than other drugs.[10] Therefore, due to the lack of studies in this field, this study was carried out to investigate the effect of treatment of constipation with lactulose on improving the symptoms of patients with migraine.
Materials and Methods
The study was a single-blind study conducted on patients with migraine suffering at least six months from the disease, having at least three headaches per month. This article is the result of a research project approved by ethics committee of Arak University of Medical Sciences (Approval no. IR.ARAKMU.REC.1394.283), which is also registered at Iranian Clinical Trials System with the number IRCT2016040322030. After obtaining a license from the university research council by the researchers, the patients were referred to the clinics of Arak University of Medical Sciences so as to their migraine being diagnosed by a neurologist and based on the HIS index.[1] Patients with migraine who were also complaining of constipation were interviewed by a trained researcher (nursing student) based on the Rome III scale to examine their incidence of constipation.[8] The Rome III criteria classification system, also known as the only standardized symptom-based diagnostic criteria for functional gastrointestinal disorders (FGIDs), was used for recognizing the constipation.[11,12] Patients with migraine who simultaneously suffered from constipation, those who signed the informed consent form, and those who were satisfied to participate in our study were divided into an experimental group and a control group. In the experimental group, lactulose syrup (15 cc daily) and antimigraine drugs (10–25mg nortriptyline and 20–40mg propranonol daily) were prescribed.[1] In the control group, only the standard treatment for migraine (10–25mg nortriptyline and 20–40mg propranonol daily) was prescribed. When the constipation of the patient was not treated with this dose, the dose of the drug was increased to 30 cc daily.[9]
The inclusion criteria of the study included the following: a history of migraines for six months, the number of headaches at least three times a month, being aged 15–50 years, nonuse of prophylaxis medication, and lack of self-medication for the treatment of constipation. The exclusion criteria of the study included the following: reluctance to continue the study, discontinuation of antimigraine drugs and lactulose, and the use of arbitrary drugs for the treatment of constipation. In addition, patients who had other psychiatric comorbidities and diagnosed with other gastrointestinal disorders were excluded from the study. Participants in this study were evaluated in terms of the severity of disability and the severity of pain three times on the onset of the study and one and two months after the administration of the drugs. The severity of disability was assessed based on the severity of migraine-induced disability (MIDAS) questionnaire. The questionnaire comprises five questions that indicate the number of days that a person has not participated in social, family, and recreational activities during the past three months, or has not had a satisfactory performance because of migraine.[13] Moreover, the severity of pain was assessed by Visual Analog Scale (VAS). This scale is a valid tool for assessing the severity of pain in which the numbers from 0 to 3 are defined as mild, 4 to 7 as average pain, and 8 to 10 as severe pain.[1,3,7] Participants in the study received informed consent form approved by Arak Medical University Ethics Committee, and the patients were assured that their participation in the study would be completely voluntary and they could be excluded from the study at any time they were unwilling to participate in the study as well as the fact that their failure to collaborate would not bring about any disruption to their treatment. On the contrary, questionnaires were nameless and the participants were assured that the information obtained would be published anonymously without mentioning their addresses. In the same vein, to observe the ethics, only those patients who tended to use the lactulose syrup were included in the intervention group, and other patients were included in the control group. After data collection, statistical analyses were performed by using Statistical Package for the Social Sciences software version 16, analysis of variance (ANOVA), chi-squared test, t-test, and repeated-measures ANOVA test at the significant level of 0.05.
Results
A total of 50 patients with migraine were selected for this study. The participants were divided into two groups: intervention and control. The independent t-test showed that the average age in the two groups was not significantly different (P = 0.78). The average age was 41.86 ± 72.2 in the control group and 40.72 ± 83.8 in the intervention group. The ANOVA and chi-squared tests showed that no significant difference was found between demographic characteristics of the two groups (P < 0.05). Most of the participants in this study (76%) were women. Also, most of the participants were married, holding a diploma, and were housewives.
The independent t-test showed that the severity of disability was not significant between the two groups at the beginning of the intervention, whereas it was significant after one and two months from the onset of the intervention. In addition, the repeated measures test indicated that the severity of disability among the three measurements was significant for both the control and intervention groups (P = 0.001) [Table 1].
Table 1.
The severity of migraine disability in the control and intervention groups
| Duration of intervention | Control group |
Intervention group |
The significance level | ||
|---|---|---|---|---|---|
| Mean | Standard deviation | Mean | Standard deviation | ||
| Before the intervention | 47.12 | 13.55 | 49.96 | 16.67 | |
| 30 days after the intervention | 42.12 | 13.34 | 29.12 | 13.84 | 0.001* |
| 60 days after the intervention | 38.84 | 11.91 | 16.64 | 8.80 | 0.001* |
| The significance level | 0.001** | 0.001** | |||
*Independent t-test
**Repeated-measures test
The independent t-test showed that although the mean of pain intensity was not significant between the two groups at the onset of intervention (P < 0.05), it was significant after one and two months from the beginning of the intervention (P = 0.001). Likewise, a repeated-measurement test showed that the pain intensity was significant among the three measurements for both the control and intervention groups (P = 0.001) [Table 2].
Table 2.
The severity of migraine pain in the control and intervention groups
| Duration of intervention | Control group |
Intervention group |
The significance level | ||
|---|---|---|---|---|---|
| Mean | Standard deviation | Mean | Standard deviation | ||
| Before the intervention | 8.25 | 1.44 | 8.16 | 2.19 | 0.70* |
| 30 days after the intervention | 7.64 | 1.22 | 5.92 | 2.37 | 0.001* |
| 60 days after the intervention | 7.40 | 1.22 | 3.44 | 1.44 | 0.001* |
| The significance level | 0.001** | 0.001** | |||
*Independent t-test
**Repeated-measures test
Although the mean score of the severity of constipation was not found to be significant between the intervention and control groups at the beginning of the study (P < 0.05), it was found to be significant for the intervention group in the first and second months after the intervention (P = 0.001) and it was not found to be significant for the control group (P = 0.70) [Table 3].
Table 3.
The severity of constipation (score) in the control and intervention groups
| Duration of intervention | Control group |
Intervention group |
The significance level | ||
|---|---|---|---|---|---|
| Mean | Standard deviation | Mean | Standard deviation | ||
| Before the intervention | 10.64 | 0.7 | 10.88 | 0.71 | |
| 30 days after the intervention | 10.6 | 0.50 | 7.48 | 1.16 | 0.001* |
| 60 days after the intervention | 10.52 | 0.50 | 6.44 | 0.65 | 0.001* |
| The significance level | 0.70** | 0.001** | |||
*Independent t-test
**Repeated-measures test
Discussion
The results of this study indicated that the mean score of the MIDAS and the mean pain score based on VAS, measured at three times, showed a decrease and such a difference was statistically significant. Similarly, the mean score of the severity of pain and the severity of disability in the intervention group were less than those of the control group in the first and second months after treatment, and the difference was also statistically significant. Hence, constipation can help improve migraine and can reduce the severity of pain and disability caused by the disease. The results of this study are in agreement with some studies in the field. Inaloo et al.,[7] examining the relationship between headache and constipation in 12-to-14-year-old children, found a strong correlation between constipation and headache that can be due to such accompanying conditions as stress and anxiety, which is consistent with the results of this study. In a study by Park et al.[8] to investigate the relationship between constipation and headache, the results showed that the treatment of constipation led to relief of headache in all the participants and that reduced constipation was accompanied by a significant reduction in the severity of headache, which also confirms the findings of this study. In another study by Gupta, migraine was reported to cause constipation and to reduce the peristaltic movements of the intestine. They also found that the removal of constipation in the patients led to a reduction in their migraine attacks, which also confirms the findings of this study.[14] Therefore, the likelihood that there may be a relationship between the initial headache and constipation will become stronger. In addition, Park et al.[8] believe that constipation plays an important role in causing headaches, and that constipation and headache may also have a common pathophysiology. Among the common cases of pathophysiology between these two diseases, one can refer to serotonin (5-hydroxytryptamine), which plays a key role in both diseases and is increased in the gastrointestinal mucosa of the patients with constipation and is decreased in patients with migraine.[3,15] By the same token, the prevalence of mental disorders, including depression, in patients with both diseases is higher than those of the normal population.[16,17,18] Moreover, constipation is associated with stress, dehydration, low-fluid intake, and loss of appetite. These factors may also cause headaches. On the contrary, Valsalva maneuver, which occurs in patients with constipation for their intestinal excision, can also lead to headaches.[19] Furthermore, severe vascular sensitivity as well as DNA sequencing and mitochondrial disorders are also among other pathophysiological similarities of these two diseases, which can be valid for justifying the relationship between these two diseases.[20,21,22] In a study of Machnes-Maayan et al.,[23] a significant relationship was reported between headache and abdominal pain in pediatric patients. If abdominal pain is treated, the severity of headache––especially migraine––is also reduced. People with irritable bowel syndrome (IBS) are usually diagnosed with constipation or diarrhea. Cole et al.[24] reported that people with IBS have a 40%–80% higher risk of migraine than others. Cole et al.[23] and Machnes-Maayan et al.[24] reported that the pathophysiology of migraine and constipation are similar in some cases. Some studies have also shown that the level of antioxidants is reduced in patients with migraine.[4] Constipation is therefore likely to reduce the absorption of antioxidants and help cause or exacerbate headaches. Hence, it is expected that the treatment duration of these groups of patients can be decreased through eliminating the migraine-induced constipation.
Conclusion
Given the results of this study, which indicates the relationship between constipation and migraine, it is recommended that patients with migraine should be diagnosed with gastrointestinal dysfunctions, including constipation, and if constipation is diagnosed, all the necessary actions should be taken to treat the disease so as to increase the patients’ response to treatment and to relieve them from the pain and discomfort. As a result, the short-term follow-up of this study showed that lactulose syrup––being able to remove the constipation with no significant side effects––can be used as an adjunct for the treatment of patients with migraine. However, future studies suggested for long-term consequences of constipation control.
Ethical policy and institutional review board statement
This project was approved by the ethics committee of Arak University of Medical Sciences (Approval no. IR.ARAKMU.REC.1394.283).
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgements
We would like to thank the deputy director of technology at the Arak University of Medical Science, all the respected patients, and all those who were involved in the study for their support.
References
- 1.Ebrahimi-Monfared M, Sharafkhah M, Abdolrazaghnejad A, Mohammadbeigi A, Faraji F. Use of melatonin versus valproic acid in prophylaxis of migraine patients: a double-blind randomized clinical trial. Restor Neurol Neurosci. 2017;35:385–93. doi: 10.3233/RNN-160704. [DOI] [PubMed] [Google Scholar]
- 2.Aminoff MJ, Greenberg D, Simon RP. Clinical neurology. 9th ed. New York: McGraw-Hill Professional; 2015. [Google Scholar]
- 3.Mottaghi T, Khorvash F, Askari G, Iraj B, Ghiasvand R. Vitamin D and migraine: review of current evidence. J Isfahan Med Sch. 2013;31:32–40. [Google Scholar]
- 4.Alp R, Selek S, Alp SI, Taşkin A, Koçyiğit A. Oxidative and antioxidative balance in patients of migraine. Eur Rev Med Pharm Sci. 2010;14:877–82. [PubMed] [Google Scholar]
- 5.Teigen L, Boes CJ. An evidence-based review of oral magnesium supplementation in the preventive treatment of migraine. Cephalalgia. 2015;35:912–22. doi: 10.1177/0333102414564891. [DOI] [PubMed] [Google Scholar]
- 6.Ghasami K, Faraji F, Mohammadbeigi A. Treatment effect of iron tablets on women in productive age with iron deficiency anemia and vascular headaches. Pak J Med Sci. 2012;28:476–9. [Google Scholar]
- 7.Inaloo S, Dehghani SM, Hashemi SM, Heydari M, Heydari ST. Comorbidity of headache and functional constipation in children: a cross-sectional survey. Turk J Gastroenterol. 2014;25:508–11. doi: 10.5152/tjg.2014.6183. [DOI] [PubMed] [Google Scholar]
- 8.Park M-N, Choi M-G, You MSJ, You SJ. The relationship between primary headache and constipation in children and adolescents. Korean J Pediatr. 2015;58:60–3. doi: 10.3345/kjp.2015.58.2.60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Wald A. Constipation: advances in diagnosis and treatment. JAMA. 2016;315:185–91. doi: 10.1001/jama.2015.16994. [DOI] [PubMed] [Google Scholar]
- 10.Malekzadeh F, Ansari R, Malekzadeh R. Approach to chronic constipation. Govaresh. 2014;19:7–13. [Google Scholar]
- 11.Tack J, Müller-Lissner S, Stanghellini V, Boeckxstaens G, Kamm M, Simren M, et al. Diagnosis and treatment of chronic constipation––a European perspective. Neurogastroenterol Motil. 2011;23:697–710. doi: 10.1111/j.1365-2982.2011.01709.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Kellow JE. Introduction: a practical evidence-based approach to the diagnosis of the functional gastrointestinal disorders. Am J Gastroenterol. 2010;105:743. doi: 10.1038/ajg.2010.64. [DOI] [PubMed] [Google Scholar]
- 13.Benz T, Lehmann S, Gantenbein AR, Sandor PS, Stewart WF, Elfering A, et al. Translation, cross-cultural adaptation and reliability of the German version of the Migraine Disability Assessment (MIDAS) questionnaire. Health Qual Life Outcomes. 2018;16:42. doi: 10.1186/s12955-018-0871-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Gupta V. Constipation-related migraine is linked to the effect of the Valsalva maneuver on the eye: a case report and a mechanistic review. WebmedCentral Neurol. 2010;1:WMC001433. [Google Scholar]
- 15.Shekhar C, Monaghan PJ, Morris J, Issa B, Whorwell PJ, Keevil B, et al. Rome III functional constipation and irritable bowel syndrome with constipation are similar disorders within a spectrum of sensitization, regulated by serotonin. Gastroenterology. 2013;145:749–57. doi: 10.1053/j.gastro.2013.07.014. [DOI] [PubMed] [Google Scholar]
- 16.Afridi MI, Siddiqui MA, Ansari A. Gastrointestinal somatization in males and females with depressive disorder. JPMA. 2009;59:675. [PubMed] [Google Scholar]
- 17.Beghi E, Allais G, Cortelli P, D’amico D, De Simone R, d’Onofrio F, et al. Headache and anxiety-depressive disorder comorbidity: the HADAS study. Neurol Sci. 2007;28:S217–S9. doi: 10.1007/s10072-007-0780-6. [DOI] [PubMed] [Google Scholar]
- 18.Machnes-Maayan D, Elazar M, Apter A, Zeharia A, Krispin O, Eidlitz-Markus T. Screening for psychiatric comorbidity in children with recurrent headache or recurrent abdominal pain. Pediatr Neurol. 2014;50:49–56. doi: 10.1016/j.pediatrneurol.2013.07.011. [DOI] [PubMed] [Google Scholar]
- 19.Artto V, Anttila V, Rantanen K, Kallela M, Farkkila M. Valsalva maneuver as migraine inducer: a case report of a woman with patent foramen ovale and an ischemic stroke. Headache. 2009;49:146–7. doi: 10.1111/j.1526-4610.2008.01143.x. [DOI] [PubMed] [Google Scholar]
- 20.Keszthelyi D, Troost FJ, Masclee AA. Irritable bowel syndrome: methods, mechanisms, and pathophysiology: methods to assess visceral hypersensitivity in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2012;303:G141–54. doi: 10.1152/ajpgi.00060.2012. [DOI] [PubMed] [Google Scholar]
- 21.Noseda R, Burstein R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain. Pain. 2013;154:S44–53. doi: 10.1016/j.pain.2013.07.021. [DOI] [PubMed] [Google Scholar]
- 22.Burnett BB, Gardner A, Boles RG. Mitochondrial inheritance in depression, dysmotility and migraine? J Affective Disord. 2005;88:109–16. doi: 10.1016/j.jad.2005.05.009. [DOI] [PubMed] [Google Scholar]
- 23.Machnes-Maayan D, Elazar M, Apter A, Zeharia A, Krispin O, Eidlitz-Markus T. Screening for psychiatric comorbidity in children with recurrent headache or recurrent abdominal pain. Pediatr Neurol. 2014;50:49–56. doi: 10.1016/j.pediatrneurol.2013.07.011. [DOI] [PubMed] [Google Scholar]
- 24.Cole JA, Rothman KJ, Cabral HJ, Zhang Y, Farraye FA. Migraine, fibromyalgia, and depression among people with IBS: a prevalence study. BMC Gastroenterol. 2006;6:26. doi: 10.1186/1471-230X-6-26. [DOI] [PMC free article] [PubMed] [Google Scholar]