Abstract
Background
Preventive therapy is a key element of migraine management, and there is limited evidence comparing monotherapy and combination regimens of established agents.
Objective
To compare nortriptyline monotherapy and combination therapy in the treatment of recurrent migraine of moderate frequency.
Methods
This was a single-center, retrospective, descriptive paper involving 252 patients diagnosed with episodic migraine. The studied patients received either nortriptyline monotherapy (n = 45), nortriptyline/flunarizine (n = 84), or nortriptyline/flunarizine/tizanidine (n = 123).
Results
Headache frequency reduced in all therapeutic regimens (p < 0.0001). Triple therapy (from 9.8 ± 0.5 to 2.8 ± 1.0 days/month at 4 months) showed the greatest improvement, followed by dual therapy (from 8.8 ± 1.1 to 3.7 ± 1.1). There was marginal improvement with monotherapy (from 7.8 ± 0.6 to 5.7 ± 2.2). Patients who received combination therapy had significantly higher adherence than those on monotherapy (≈75% vs 55.6%; p = 0.027). Side effects were reported in 25% of patients, mainly mild. More than 75% of patients indicated a medium-to-high level of satisfaction.
Conclusions
Combination therapy using nortriptyline was linked to greater decreases in the frequency of headache and enhanced adherence than monotherapy. Tolerability, as well as patient satisfaction, were satisfactory. These practical findings confirm rational polytherapy when monotherapy proves ineffective.
This is a visual representation of the abstract.
Introduction
Migraine is a neurological disease with episodes of moderate to severe headache, usually accompanied by nausea, photophobia, phonophobia, and functional disability. 1 It is highly prevalent and disabling, with a significant impact on global health. 2 Episodic migraine (EM), defined as migraine days less than 15 per month, has a higher spread prevalence (12–15%) compared to chronic migraine (CM; 1–2.2%), which has a greater morbidity due to more pervasive headache (over 15 days per month). 3
EM has often been mistaken for a condition that is relatively harmless. However, accumulating evidence proves that even moderate-frequency EM that is usually characterized by 6–10 headache days each month is accompanied by significant disability, diminished quality of life, and impaired daily functioning.3,4 Patients with EM tend to complain of occupational performance impairment, social participation, and negative psychological well-being, and disability scores that can be nearly similar to those found in CM groups. 3 Societal cost is not limited to personal pain; it also includes direct healthcare costs, loss of productivity, and additional economic effects. 4 Therefore, due to the level of morbidity, preventive therapy should be considered to try to reduce the frequency of headache attacks.
Preventive therapy is one of the main pillars of managing migraine, especially among patients with frequent or debilitating attacks. 5 The main goals of prophylaxis are not limited to symptom management but to reach a clinically significant decrease in attack frequency, usually set at least 50% of monthly migraine days, in addition to changes in attack severity and duration. 6 Preventive care should also be implemented to increase the sensitivity of acute treatment, reduce migraine-related morbidity, improve overall quality of life, and reduce the risk of illness progression, such as the emergence of CM and medication-overuse headache. 7 Guideline-based frequency thresholds provide valuable guidance, but in clinical practice, there is always an inherent element of individualization in deciding on the frequency for specific frequency ranges, given functional impairment, comorbidity, and patient preferences. 8
Traditionally, migraine prevention has been guided by a monotherapy paradigm. 9 The general recommendations of clinical guidelines include initiating prophylaxis with a single agent, with preference for this method because it is relatively simple, less likely to cause adverse effects, and increases treatment adherence. 10 Some of the monotherapy classes that are commonly used include the tricyclic antidepressants (TCAs), calcium channel blockers, beta-blockers, and antiepileptic drugs or neuromodulators.10–12 Evidence regarding migraine prophylaxis has largely been based on randomized controlled trials (RCTs) of individual agents, thereby strengthening the monotherapy paradigm in both research and guideline development. 11
Although theoretically effective, monotherapy is often linked to a partial clinical response. Many patients experience partial decreases in headache prevalence or discontinued treatment due to adverse effects. 11 This therapy-based reality has necessitated the pragmatic integration of combination therapy into everyday clinical practice, especially in tertiary centers or when treating patients with prior treatment experience. 13 Combination regimens can be particularly effective because they target multiple pathophysiological pathways and may have additive or synergistic effects. Although adverse effects can occur at low doses, we hypothesize that, due to reduced individual dosage, combining agents can improve tolerability compared with high-dose monotherapy. This strategy is usually widely used in practice; however, it is not widely studied in the migraine population.11,14
The current literature on migraine prophylaxis reveals several important evidence gaps. Single-agent RCTs have largely predominated, resulting in a dearth of head-to-head trials and a relative paucity of studies assessing combination regimens.15,16 Also, older drugs commonly used are not fully represented in recent studies, which frequently focus on newer groups of drugs. 17 As a result, the effectiveness, adherence, and tolerability of commonly used combination treatments remain poorly defined. 11 This gap between controlled trial settings and clinical practice is illuminated.
The clinical importance of established preventive agents should be reconsidered. A TCA, nortriptyline, has been used for many years as a preventive treatment of migraine, and it achieves its therapeutic action by altering the central pain pathways, such as serotonergic and noradrenergic. 18 Calcium channel blocker flunarizine has also been shown to be effective in migraine prophylaxis, possibly by inhibiting cortical spreading depression and neurogenic inflammation.18,19 Tizanidine is a central 2-adrenergic agonist that can play a role in pain modulation and the reduction of muscle tension associated with it, producing mechanistic complementarity with other agents. 20 The medications are especially applicable in healthcare facilities, where newer medicines, including anti-CGRP agents, can be costly or scarce due to their availability. 21
Treatment patterns for migraine prevention in the real world are inherently inconsistent and depend on the clinician's experience, patient characteristics, and the characteristics of the healthcare system.22,23 Regarding the latter, access to specific therapies varies widely, both in Brazil and across different countries. While single agents like TCAs and beta-blockers may be freely given by public health systems, compounded combinations, although very inexpensive and tailored individually, may provide a higher level of adherence. Despite these problems, there are suggestions for standardizing this care, including criteria for initiating prophylaxis, evaluating the effectiveness of preventive treatment, and indicating combination therapy when monotherapy proves ineffective. 24 Clinical experience provides important information on treatment adherence, side effects, and patient outcomes, which may not be well reflected in RCTs. This kind of practice-based evidence is critical to strengthening external validity and making practical clinical decisions.25,26
Since few comparative data have been used to assess monotherapy and combination therapy with widely prescribed preventive agents, this should be further researched. It is important to understand how these strategies work in real-world clinical settings to make practical treatment decisions and maximize patient outcomes. The aim of this study was to evaluate the effectiveness, tolerability, and treatment adherence of nortriptyline monotherapy compared with nortriptyline-based combination regimens (including flunarizine and tizanidine) in patients with EM in a real-world clinical setting. Primary outcomes focused on reductions in headache frequency, while secondary outcomes included treatment adherence, adverse effects, and patient-reported satisfaction.
Methods
Study design and patients
This was a single-center, retrospective, observational, and descriptive study. The study population consisted of a non-random, convenience sample of 787 consecutive patients diagnosed with EM according to the criteria of the International Classification of Headache Disorders (ICHD-3) 27 at a clinic specializing in headache treatment between 2018 and 2024. Of this population, 252 patients were treated with nortriptyline (45/252; 17.9%), nortriptyline plus flunarizine (84/252; 33.3%), or nortriptyline plus flunarizine plus tizanidine (123/252; 48.8%). There was no sample size calculation. All patients were eligible according to the inclusion/exclusion criteria. This study is reported in accordance with STROBE guidelines for the retrospective observational study.
Inclusion and exclusion criteria
Patients over 18 years of age, regardless of sex, diagnosed with migraine with a frequency of between 6 and 10 headache days per month in the previous three months, and who were prescribed nortriptyline or nortriptyline plus flunarizine or nortriptyline plus flunarizine plus tizanidine, were included in the study. Patients diagnosed with migraine concurrently with another primary headache; with any secondary headache; who received different medications or anti-CGRP therapies for migraine prevention, and pregnant women were excluded from the study.
Data collection
Patients with migraine were evaluated by the same specialist in initial consultations lasting at least 1 h. The patient population was those who were diagnosed with EM with and/or without aura, and received preventive agents consisting of nortriptyline, or nortriptyline plus flunarizine, or nortriptyline plus flunarizine plus tizanidine. The drug combinations were prescribed in compounded capsules containing two or three substances. Nortriptyline monotherapy was used with commercially available capsules of 10 or 25 mg. The prevention was administered as a single dose immediately after dinner. Nortriptyline was prescribed at a dose of 20 or 25 mg/day; tizanidine at a dose of 2–4 mg/day; and flunarizine at a constant dose of 2 mg/day. All patients received an initial dose of 20 mg nortriptyline, 20 mg nortriptyline plus 2 mg flunarizine, or 20 mg nortriptyline plus 2 mg flunarizine plus 2 mg tizanidine during the first 7 days. After that, higher doses were started, except for flunarizine, which remained at 2 mg.
The reason for choosing these treatments was based exclusively on the first author's three decades of clinical experience, primarily with headache patients. In addition to preventive treatments, they were prescribed rizatriptan or eletriptan in combination with naproxen, diclofenac, or indomethacin for use on 2 days per week.
All patients were given clear, emphatic instructions, both verbal and written, regarding migraine and its treatment. They were asked to return for follow-up appointments at 2 and 4 months and to complete a pain diary provided at the first appointment. Furthermore, all participants were questioned at the second follow-up appointment, 4 months later, to provide information on the characteristics of their pain and their satisfaction with the treatment. To assess treatment satisfaction, a Likert scale was used, 28 and the following question was asked of all patients: How satisfied are you with your migraine treatment? The responses were divided into four verbal descriptors: “none,” “low,” “medium,” and “high.” Patients were required to choose only one option.
Statistical analysis
Once the information was organized in a database, the Epi Info™ 7 program, version 7.2.5, was used for statistical analysis. Quantitative variables were expressed as mean, standard deviation, and minimum and maximum values, while qualitative variables were expressed as absolute and relative frequencies. The chi-square test with Yates’ correction and the Student's t-test were used to compare the means of paired samples. All tests were performed at the 0.05 significance level to reject the null hypothesis.
Ethics approval
The study was approved by the Institutional Review Board. All patients signed a data use commitment agreement.
Results
The sample consisted of 252 patients with EM, with a mean age of 42.4 ± 13.3 years (range, 18 to 83 years), of whom 195 were women (77.4%) and 57 were men (22.6%). The average duration of headache history was 23.6 ± 14.1 years, ranging from 1 to 70 years, and the average monthly headache frequency in the last 3 months was 9.1 ± 1.1 days, ranging from 6 to 10 days per month (Table 1).
Distribution of sample data according to the diagnosis of 252 patients with episodic migraine who were treated prophylactically with polytherapy.
Group 1: nortriptyline; Group 2: nortriptyline + flunarizine; Group 3: nortriptyline + flunarizine + tizanidine.
SD: standard deviation.
Our analysis demonstrated that combination therapy elicited more significant changes in mean monthly headache days (mean MHD) (baseline 9.8 ± 0.5 to 2.8 ± 1.0 at 4 months) than nortriptyline monotherapy (7.8 ± 0.6 to 5.7 ± 1.0; p = 0.0001) and higher adherence (74.8 vs 55.6; p = 0.027; Figure 1).
Reduction in the mean monthly headache days (mean MHD) after 2 and 4 months according to prophylactic treatment.
There was greater adherence to treatment among patients using combination therapy with two drugs compared with those using monotherapy (loss to follow-up: 25.2% vs 44.4%; p = 0.027; Table 2).
Treatment adherence in 252 patients with episodic migraine using monotherapy versus combination therapy.
*p-values calculated using the chi-square test, comparing “nortriptyline” versus “nortriptyline + flunarizine + tizanidine.”
Of the 252 patients who were treated, 63 (25%) experienced adverse effects related to the use of prophylactic medications. The main adverse effects occurred in this order: constipation (11.9%), dry mouth (10.7%), weight gain (8.3%), somnolence (6.7%), and dizziness (5.5%; Table 3).
Presence of adverse effects related to the use of prophylactic medications.
Group 1: nortriptyline; Group 2: nortriptyline + flunarizine; Group 3: nortriptyline + flunarizine + tizanidine.
Over 75% of migraine patients demonstrated a medium to high level of satisfaction with prophylactic treatment (Table 4).
Levels of satisfaction with prophylactic treatment in 178 patients with migraine who returned after 4 months.
Group 1: nortriptyline; Group 2: nortriptyline + flunarizine; Group 3: nortriptyline + flunarizine + tizanidine.
Discussion
The present retrospective study compared the actual effectiveness of nortriptyline monotherapy with that of nortriptyline-based combination therapies in patients with EM with 6–10 headache days per month. The main result was significantly higher reductions in headache frequency per month with combination therapy, especially the triple regimen (nortriptyline + flunarizine + tizanidine) at 2 and 4 months. In addition, adherence rates were significantly higher among patients on combination therapy, supporting the notion that perceived efficacy is the primary factor in persistence. Similar reports have been made by Dozza and Krymchantowski, 29 who state that the number of medications does not necessarily affect adherence, and by Ramsey et al., 30 who identify a wide range of variability, with quality and effectiveness affecting tolerability. The overall adverse effects profile was consistent with the established tolerability characteristics of the involved medications. Satisfaction was mostly medium-high (>75%) on the Likert scale. 28
These results are like the multimodal advantages of combination strategies. 31 The observed efficacy is consistent with findings that TCAs are effective for migraine prevention, 32 flunarizine is effective as primary prophylaxis, 33 and tizanidine exhibits central antinociceptive action. 20 These results are further put into perspective by the clinical focus on pharmacodynamic outcomes. 34
Our findings demonstrate that combination prophylaxis was associated with greater reductions in the frequency of monthly headaches than nortriptyline monotherapy.35,36 Comparisons of nortriptyline plus flunarizine and triple therapy also demonstrated greater improvements at 2 and 4 months, with reductions in headache days of 8.8 to 3.7 and 9.8 to 2.8 days/month, respectively (p < 0.0001), suggesting additive effects when different pathways are targeted. Combination regimens were also associated with higher treatment adherence rates (p = 0.027), consistent with the existing literature suggesting that better efficacy leads to better persistence. 37
The adverse-effect profile was also consistent with the established pharmacology of TCAs and flunarizine, and the polytherapy groups did not exhibit disproportionate increases, confirming the tolerability of lower-dose combinations.38,39 Flunarizine 2 mg/day, which is lower than the standard dose, showed clinical efficacy and may reduce adverse effects, including weight gain and somnolence. 40 These are consistent with new approaches that promote the use of rational polytherapy, especially in patients who respond suboptimally to single agents. 41
Despite these promising findings, several limitations should be considered. The retrospective design essentially restricts causal inference and creates the possibility of potential confounding by indication. The process of allocating treatment was not random and was subject to the clinician's judgment, which may have been biased. The frequency of baseline headaches differed across groups, though the higher-frequency groups showed larger improvements; this issue is partially mitigated. Also, only about 38% of patients had full documentation of their adverse effects, which may be inaccurate in representing tolerability outcomes.
Loss to follow-up, though an outcome of interest per se, can also introduce bias, since patients who did not respond to treatment are less likely to return for follow-up. Satisfaction measures (patient-reported) were clinically important but subjective and not validated against standardized disability measures (MIDAS or HIT-6). Another way to improve interpretability would be to use prospective studies with randomized designs, standardized outcome measures, and extended follow-up periods.
This clinical study indicates that combination therapy with nortriptyline can yield greater improvements in headache frequency and adherence than monotherapy in patients with moderate-frequency EM. These results provide practice-based data in favor of personalized preventive treatment and emphasize the potential usefulness of rational polytherapy, especially in settings with limited availability of more modern treatments. These observations need to be confirmed through further controlled studies to establish the optimal combination paradigms.
Conclusions
This retrospective real-world analysis shows that combination treatment with nortriptyline has a higher clinical value than one-on-one treatment in patients with EM who have 6 to 10 headache days a month. Regimens containing a combination therapy, specifically triple therapy, were linked to significantly greater changes in the monthly headache frequency, improved therapy compliance, tolerability was predominantly acceptable, and overall patient satisfaction was medium to high. Notably, improved results were observed even though the headache frequency at baseline was increased, confirming a true therapeutic effect. The adverse-effect profile was also consistent with existing pharmacology and did not appear to be disproportionately elevated in polytherapy. These results validate the practical clinical implementation of rational combination therapy in cases where monotherapy is not completely responding. Though the methodological drawbacks of retrospective designs must be interpreted with great caution, the findings do offer valuable practice-based evidence that cannot be neglected, supplementing randomized trial information. These observations should be validated by prospective, controlled studies to better select patients and establish the optimal dosing regimens.
Clinical implications
Combination prophylaxis may offer superior frequency reduction in moderate-frequency episodic migraine.
Improved efficacy may enhance adherence and persistence.
Lower-dose polytherapy may preserve tolerability.
Supports individualized preventive treatment strategies.
Footnotes
ORCID iDs
Consent for publication
All authors agree to publish the article “Monotherapy versus combination therapy in the prophylaxis of episodic migraine: A retrospective study” with Cephalalgia Reports.
Author contributions
All authors have reviewed the final version to be published and agreed to be accountable for all aspects of the work.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data availability statement
The original contributions presented in the study are included in the article; further inquiries can be directed to the corresponding author.