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10 Articles in Volume 9, Issue #5
Dextrose Prolotherapy for Recurring Headache and Migraine Pain
Diagnosis of Low Back Pain
Ethics, Education, and Policy: Relationship and Mutual Reliance
Human Chorionic Gonadotropin in Pain Treatment
Musculoskeletal Ultrasound
Painful Herpetic Reactivation and Degenerative Musculoskeletal Injury
Post-stroke Pain
Preventive Medications for Chronic Daily Headache
The Pathophysiology of Neuropathic Pain
Use of Pulsed Radiofrequency in Clinical Practice

Preventive Medications for Chronic Daily Headache

Chronic daily headache (CDH) is a common problem, affecting approximately 3 to 4% of the population.1 CDH poses a significant therapeutic challenge to both physician and patient.

For those with moderate or severe CDH, preventive medications are often utilized in an effort to limit analgesics and decrease headache frequency and/or severity. The primary first-line preventives include antidepressants (primarily selective serotonin reuptake inhibitors and tricyclics) and anticonvulsants.2 Antidepressants have been as attractive choice in those with comorbid depression and anxiety. Tricyclic antidepressants have been known to have enhanced efficacy over SSRI’s, but are not as well tolerated. The anticonvulsants sodium valproate and topiramate have emerged as effective drugs for use in CDH.3

Other medications that have shown some benefit in CDH prophylaxis include beta blockers, calcium channel blockers, NSAIDs, gabapentin, and muscle relaxants.

Unfortunately, due to a lack of efficacy and/or the presence of side effects, the preventive medications are not always a useful long-term solution. The failure of the preventives often frustrates physicians and patients. The purpose of this paper was to retrospectively evaluate preventive medications in a large number of daily headache patients.

Materials and Methods

Primary Objective and Endpoint: This study is a retrospective investigation of the continuation rates for different classes of headache preventive medications. Overall, headache relief, defined as at least 50% improvement in headache frequency and/or severity, served as the primary endpoint.

Inclusion Criteria:

  • at least 17 years of age with diagnosis of CDH or transformed migraine (TM)4
  • moderate or severe intensity of the CDH
  • current or past use of at least two classes of daily preventive medications for at least six months

Exclusion Criteria:

  • continuous analgesic rebound headache that had not been resolved
  • non-compliance with daily use of preventive medications
  • evidence of renal insufficiency or impaired liver function upon routine laboratory evaluations
  • the presence of any medical condition that could interfere with the absorption, metabolizing and excretion of any of the preventive medications

Design: Six hundred forty six patients, aged between 17 to 74, with moderate or severe chronic daily headache were evaluated. All were long-term patients at the Robbins Headache Clinic, a private clinic with both physician-referred and self-referred patients. Evaluation was accomplished via chart review and patient interviews by the treating neurologist. Four main classes of preventive medications were evaluated:

  1. SSRIs
  2. anticonvulsants (sodium valproate and topiramate)
  3. tricyclic antidepressants
  4. beta blockers

Patients in the study were assessed to determine which preventive medications they remained on for the long term. A determination was also made as to which preventive medications were discontinued due to lack of efficacy or presence of side effects.

Statistical Analysis: Patient data was tabulated using SPSS Sigma Stat 2.03. Chi-square analysis was performed on the tabulated data. To assure accuracy, a power analysis of the Chi-square was utilized, using an alpha value of 0.05.

Long-term Relief with Preventive Medications

Of the 646 patients, 249 (46%) stated that at least one of the four categories of daily preventive medications provided long-term relief without significant side effects. However, 54% (291 patients) had discontinued the daily preventive medications due to lack of efficacy or side effects—or a combination of the two. Each patient had utilized at least two classes of daily preventives.

Relief with Individual Classes of Preventive Medications

Selective serotonin reuptake inhibitors and anticonvulsants had the highest success rate. Thirty-six percent of patients who had utilized SSRI’s stated that they were effective for headache and wished to continue on them long-term. Thirty-one percent of the patients who had utilized tricyclics continued on these long-term, while only 22% of patients on beta blockers did so (see Table 1). Chi-square analysis revealed that there was a significant difference (X2=27.4, df=6, p

Reasons for Discontinuing Preventive Medications

Most patients who discontinued the medications did so due to a lack of efficacy. Beta blockers were the least effective of the preventive medications, with 58% of all patients who had taken them discontinuing, primarily due to lack of efficacy. Approximately 1/5 of patients in each class noted that significant side effects contributed to their discontinuation of the medication (see Table 1).


In the current study, only 46% of the patients obtained significant long-term relief from a preventive medication. While there are a variety of preventive medications available including, but not limited to, sodium valproate, antidepressants, beta blockers, muscle relaxants, NSAIDs, gabapentin and topiramate, many patients cannot tolerate these medications or find that efficacy is lacking. Among those who do benefit, side effects such as weight gain and fatigue may, over time, cause them to discontinue the medication. The patient may also experience a decline in efficacy over time. Most of the new breakthrough medications have been in the abortive category—particularly the triptans. Currently there is a lack of new or novel headache preventives.

A number of the medications have been studied on a short-term basis for the prevention of chronic daily headache. A review of the available studies on preventives for CDH indicated that:

  1. the majority of studies were open-label
  2. the studies were conducted over relatively short periods of time
  3. most of the studies resulted in a significant decrease in headache severity and frequency5

However, over time, a decline in efficacy is often observed. In addition, many patients discontinue the medications due to adverse events, particularly weight gain and fatigue. In the current study, patients needed to have remained on the medication for at least six months with continued efficacy.

There are differing subgroups of patients who suffer from CDH. The majority evolve into transformed migraine (usually over a period of years). What were once episodic headaches become daily, or near-daily, occurrences. Some patients have CDH from the outset, usually with episodic migraine as well.6 It is reasonable to assume that different classes of medications would alleviate transformed migraine versus the CDH without migrainous features.

Chronic overuse of analgesics may cause or exacerbate daily headaches. For these patients, withdrawal of the analgesics often leads to an improvement in the headaches. In fact, the usual preventive medications may be ineffective for those who are overusing analgesics.7-9 There is no doubt that CDH sufferers are difficult to treat successfully and medication overuse is a significant factor. Initially, studies indicated a widely varying success rate for the treatment of CDH, ranging between 47% and 97%.10,11 However, in the span of four years, many of the patients who had been able to discontinue their analgesics relapsed into medication abuse (44% in one study, 60% in another study.)12 Even after one year, 30 to 35% of patients relapsed into overuse of the analgesics.10 These patients usually have a poor quality of life. One major contributing factor to the medication overuse is the failure of preventive medications to adequately decrease the CDH.

Botulinum toxin has been successfully used for some CDH patients.13-15In addition, atypical neuroleptics appear to provide some benefit in a small group of patients.6 Long-acting opioids is helpful for a small number of refractory headache patients.16 What is needed is more research into the pathophysiology of CDH, which may lead to more effective treatments than are presently available.


Many medications have been utilized in an effort to decrease severity and/or frequency of CDH. Short-term (less than six months) studies often demonstrate success at preventing CDH. However, the long-term success of these medications for CDH has not been demonstrated. In fact, while antidepressants and anticonvulsants demonstrated reasonable long-term efficiency, the majority of patients do not obtain adequate long-term relief from CDH preventive medications.

This retrospective study evaluated continuation rates (at least six months) for different classes of CDH preventives. 646 moderate or severe CDH patients were evaluated. Among those who discontinued the medications, a determination was made as to whether the medication was stopped due to lack of efficacy versus the presence of adverse effects.

Of those 646 patients, only 46% stated that they remained on a preventive for six months or longer. Thirty-six percent of the patients continued (more than six months) on selective serotonin reuptake inhibitors (SSRI’s). Thirty-five percent continued long-term on anticonvulsants, while 31% continued on tricyclic antidepressants. Only 22% remained on beta blockers long-term. Lack of efficacy was cited as the primary reason for discontinuation. Approximately 1/5 of patients discontinued the preventive primarily due to adverse events.

There is a lack of agreement between the results of short-term studies and those which we observed anecdotally regarding long-term success of daily preventive medications. We need longer-term studies, at least nine to twelve months in length, in order to adequately evaluate the daily preventives. In addition, we need a new approach to more effective daily preventive medications for chronic daily headache.

Table 1. Continuation Rates of the Daily Preventive Medications
Class of Medication N Continued for at least 6 months Discontinued; not due to side effects Discontinued; partly due to side effects
Tricyclics 380 119 (31%) 173 (46%) 88 (23%)
SSRI’s 326 118 (36%) 131 (40%) 77 (24%)
Sodium Valproate
or Topiramate
344 116 (35%) 147 (44%) 72 (21%)
Beta blockers 340 76 (22%) 198 (58%) 66 (20%)


Last updated on: December 27, 2011
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