Back to List

Title:
Author:
Date:
Source:

Selected Strategies for Refractory Chronic Daily Headache
 
Posted August 2001
 

ABSTRACT
For those with severe, refractory chronic daily headache (cdh) who are unresponsive to the usual preventive regimens, the therapeutic options are limited. This study summarized the results of a number of third-line treatments for refractory cdh.

Fifty-nine patients had been maintained on daily triptans for at least six months. The majority (72%) were on 50 mg. of sumatriptan daily. Most of the remaining patients had utilized sumatriptan alternating with naratriptan, or naratriptan alone. This was a retrospective study of patients who had self selected triptans because of excellent efficacy. Sixty-one percent of the patients had utilized the triptans for more than one year. Side effects were minimal in this patient population. Routine lab tests and EKGs (EKGs were done in 23 of 59 patients) were normal. Rebound was not encountered in this study; however, the patients who had demonstrated rebound headache due to triptans were generally not maintained on the daily triptans.

Three forms of long-acting opioids were compared in a separate study.Patients were interviewed after 6 months of opioid therapy. After 6 months, 51% of the slow-release (SR) morphine patients, as well as 51% of those on methadone, reported moderate or excellent relief. Thirty-six percent of those on controlled-release (CR) oxycodone had moderate or excellent relief. By the end of 6 months, 46% of the patients had discontinued morphine, 48% had discontinued methadone, while 63% had stopped the CR oxycodone. Low doses of these medications were utilized, with average doses of SR morphine 40 mg., methadone 10 mg., and CR oxycodone 32 mg. daily. Constipation, somnolence, and nausea were commonly reported by those on SR morphine, as well as those on CR oxycodone. Fatigue, dizziness, and constipation were the most frequently encountered side effects with methadone.

Quality of life, both at work and at home, was greatly improved in the patients who remained on the opioids. Addictive behavior was observed in 6% of the SR morphine patients, 3% of those on methadone, and 13% of the CR oxycodone patients. Prescription opiate abuse in the past did not translate into overuse of the long-acting opioids. Tolerance was observed in 56% of those on SR morphine, 35% of those who continued on methadone, and 63% of the CR oxycodone patients. Every effort was made not to accelerate doses.

A retrospective study of 94 cdh patients who had been placed on stimulants assessed efficacy after 6 months of therapy. The number of patients who continued on the medication for at least 6 months, achieving moderate or excellent relief, was as follows:

Methylphenidate:14/34 (41%) Average dose = 25 mg. daily
Dextroamphetamine:9/21 (43%) Average dose = 15 mg. daily
Adderall™:10/20 (50%) Average dose = 20 mg. daily
Phentermine:6/19 (32%) Average dose = 30 mg. daily

Overall, 39/94 patients (41%) did well for at least 6 months.

32/94 (34%) of patients discontinued the stimulants because of lack of efficacy (efficacy was either none or mild). Prior to the 6 months, 23/94 (24%) of patients discontinued the medication primarily due to adverse events. The most common side effects were anxiety and insomnia.

Forty-two cdh patients were given intravenous dihydroergotamine (iv dhe) as an outpatient, and observed in a prospective non-blinded fashion.They were usually given 1 mg. of dhe twice daily for 2 days (less if side effects occurred). Assessment was done, using a visual analog scale, at 2 days and 6 weeks.Thirty-nine of 42 patients completed the study. Thirty-one of thirty nine (80%) had excellent results at 2 days. By 6 weeks, only 14 of 39 (36%) of the patients reported moderate or excellent relief from the intravenous dhe. Adverse advents were generally minimal but included nausea, increased headache, muscle tension, diarrhea, leg cramps, and burning at the injection site.

Botulinum toxin A was given to 87 patients in an open label, non blinded study.Seventy-nine patients completed the study. Thirty-six of 79 (46%) did not respond to the injections. Fifty-four percent were considered positive responders. Among these, 44% of the positive responders had only a mild response. Forty-seven percent had a moderate response, while 9% achieved an excellent response. During months 2 and 3, among the mild responders, most of these (63%) continued to have a mild response in the 2^nd month, and by the 3^rd month the majority (68%) had no response. For the moderate responders (20 of 43=47% of total responders), 70% of these patients continued to have a moderate response during the 2^nd month. During the 3^rd month, 50% of these moderate responders declined to no response while 40% continued to have a moderate response, with 10% having a mild response. During the 2^nd month for the 4 excellent responders, all 4 continued to remain excellent. Adverse advents were very mild in this study.

Third-line strategies for refractory chronic daily headache patients are occasionally helpful. There are advantages and disadvantages to each of the stronger approaches. While there is only a modest success rate for any third-line strategy with refractory patients, it may be worthwhile to consider one or more of these alternative strategies in selected severe patients.


INTRODUCTION

Many patients with severe, refractory chronic daily headache (cdh) do not respond to the usual preventive regimens. The typical first and second-line preventive medications include antidepressants, anticonvulsants, beta blockers, nsaids, calcium channel blockers, and muscle relaxants. One retrospective study of 560 patients concluded that only 46% of patients obtained long-term benefit from any preventive medication. The primary problem was lack of efficacy. Many patients cannot tolerate the usual preventive medications, often due to excessive weight gain or sedation. In others the preventives may be effective for a number of months, and then the medication loses effectiveness.

Some cdh sufferers are experiencing rebound headache; it is important to address this issue prior to concluding that the person is refractory.For those with refractory moderate or severe cdh, where rebound headache is not an issue, the third-line choices are limited. They include, among others, monoamine oxidase inhibitors, long-acting opioids, stimulants, intravenous dihydroergotamine (iv dhe), daily triptans, and botulinum toxin injections. This study summarizes this author's experience with selected third-line approaches for refractory cdh.

METHODS

The patients in each of the following studies were all long-term patients at the Robbins Headache Clinic. To be considered to have refractory cdh, they had to have failed at least 3 preventive medications, either due to lack of efficacy or intolerable side effects. Patients with significant rebound headache were excluded. The daily triptan and stimulant studies were retrospective, while prospective non-blinded studies were done for long-acting opioids, iv dhe, and botulinum toxin.

RESULTS

1. DAILY TRIPTANS


DESIGN AND METHODS

Retrospective evaluation was completed on 59 patients with chronic daily headache who had been on a daily dose of a triptan medication (sumatriptan or naratriptan) for a minimum of 6 months. The age of the patients ranged from 22 to 63; the median age was 48. The mean age of headache onset was 19.Fifty-five of 59 patients had either chronic tension-type headache or transformed migraine. Four patients had chronic cluster headache. Fifty-two of the 55 patients with chronic daily headache experienced migraine headache as well. These patients had all been refractory to multiple preventive and abortive medications. They felt that the severity and/or frequency of the headaches was at least 50% improved on the daily triptan. The patients in this study had all self-selected daily triptans; they realized, after years of cdh, on a daily dose of a triptan they experienced much less headache.


RESULTS

Fifty-nine percent of the patients utilized sumatriptan alone (tablets or nasal spray). Twenty-nine of these 35 patients utilized sumatriptan tablets alone, with the majority (72%) maintained on 50 mg. daily. Twenty patients utilized sumatriptan alternating with naratriptan, or naratriptan alone. Tolerance was noted in 25% of patients. Four of these patients had increased the dose; three other patients changed from sumatriptan to naratriptan. Thirty-nine percent of the patients had been on triptans for six to twelve months, whereas 61% had utilized the triptans for more than one year. Twenty-two percent were on daily triptans for at least three years. All patients (except one) had been on three or more preventive medications; the most commonly utilized of these were antidepressants, ß-blockers, sodium valproate, calcium channel blockers, and nsaids. Sixty-nine percent of the patients were concurrently on preventive medications with the daily triptans. Seventy-six percent of the patients used abortive medications in addition to the daily triptans; however, analgesic overuse was no longer present in these patients. Previous overuse of abortive medications was identified in 66% of patients.

Side effects were minimal in this patient population. Seven reported fatigue, 3 patients experienced paresthesias, 3 reported mild chest or throat pressure, and there were no cases of new cardiac symptoms during the course of treatment. However, this patient population had self-selected the use of daily triptans. The patients who had reported significant side effects did not continue on the medications for six months. Routine blood tests were normal in 47 of 59 patients.Of the twelve abnormal blood test results, none were felt to be due to the triptans. EKG was done in 23 of 59 patients. Nineteen were normal; the four abnormal results were not felt to be related to the triptans. Echocardiography was done on five patients; all were normal.

Rebound to triptans was not encountered in this study. The patients who had demonstrated sensitivity to rebound had discontinued daily triptan use prior to six months. The most commonly seen associated medication problems were irritable bowel syndrome, ulcer, gastritis, hypertension, asthma, and arthritis. Sixty-eight percent of patients were diagnosed as having an anxiety disorder (usually mild). Fifty-four percent had chronic depression and 47% were diagnosed as having insomnia.

ADVANTAGES AND DISADVANTAGES OF DAILY TRIPTANS

Advantages include: lack of weight gain or sedation, minimal short-term side effects.
Disadvantages include: cost, and long-term safety is not known.



2. LONG-ACTING OPIOIDS


DESIGN AND METHODS

Patients received one of three forms of long-acting opioids for severe, refractory, chronic daily headache. Patients were interviewed after six months of opioid therapy. Sixty-seven patients were given sustained-release (SR) morphine sulfate, 66 patients were placed on methadone, and 52 were treated with controlled-release (CR) oxycodone. This was a prospective, non-blinded study. Efficacy was judged via a visual analog scale. The patients kept a daily headache calendar.

RESULTS

By the end of six months, 46% of the patients had discontinued morphine, 48% had discontinued methadone, while 63% had discontinued CR oxycodone. Low doses of these medications were utilized, with average doses of SR morphine 40 mg., methadone 10 mg., or CR oxycodone 32 mg. daily.

After six months, 51% of the SR morphine patients, as well as 51% of those on methadone, reported moderate or excellent relief. After six months, 36% of those on CR oxycodone reported moderate or excellent relief. Constipation, somnolence, and nausea were commonly reported by those on SR morphine, as well as those on CR oxycodone. Fatigue, dizziness, and constipation were the most frequently encountered side effects with methadone.

Quality of life, both at work and at home, was improved in those who continued on the methadone and CR oxycodone. This was not measured in the SR morphine group. Work performance and relationships greatly improved in the patients who remained on the opioids.

Addictive behavior toward the drug was observed in 6% of the SR morphine patients, in 3% of those on methadone, and with 13% of the CR oxycodone patients. Previous prescription opiate abuse did not translate into overuse of the long-acting opioids. Of the patients on SR morphine, 33% previously overused prescription opioids, and the majority of those patients (64%), had moderate or excellent relief at six months, without overuse of the medication. Only one of the sixteen patients who had previously overused opioids abused the methadone. Seven of these sixteen patients (44%) did well on maintenance methadone.

Tolerance was observed in 56% of patients of those who continued on SR morphine, in 35% of those on methadone, and in 63% of the CR oxycodone patients. Every effort was made not to accelerate doses. Withdrawal symptoms were more severe with methadone than with the other opioids.

ADVANTAGES AND DISADVANTAGES OF LONG-ACTING OPIOIDS

Advantages include: Efficacy, no cardiovascular effects, once or twice daily dosing. Opioids may also help those with other chronic pains.
Disadvantages include: Addiction potential, constipation and sedation, regulatory and malpractice concerns, inconvenient to prescribe, withdrawal may be difficult, frequent tolerance.



3. STIMULANTS


Stimulants can be an effective adjunctive third-line therapy for selected patients with refractory headaches; they are also utilized for severe refractory depression. Stimulants may help to offset the sedation and weight gain that so often accompanies headache preventive medications.

DESIGN AND METHODS

This was a retrospective study of 94 refractory cdh patients. These were all long-term patients at the Robbins Headache Clinic. They were assessed, by chart review and interview with the treating neurologist, after 6 months of therapy with the medication. Relief was assessed via a visual analog scale (vas), and was judged to be none, mild, moderate, or excellent. While the primary reason for adding a stimulant was to help the headaches, many of these refractory cdh patients were also placed on the stimulants due to excessive fatigue, and/or because of excessive weight gain. Patients with anxiety that was more than mild, or those with moderate to severe insomnia, were usually not given these medications.

RESULTS

The number of patients who continued on the medication for at least 6 months, and achieved moderate or excellent relief was as follows:

Methylphenidate: 14/34 (41%) Average dose = 25 mg. daily
Dextroamphetamine:9/21 (43%) Average dose = 15 mg. daily
Adderall™:10/20 (50%) Average dose = 20 mg. daily
Phentermine:6/19 (32%) Average dose = 30 mg. daily

Overall, 39/94 (41%) did well for at least 6 months.

32/94 (34%) of patients discontinued the stimulants because of lack of efficacy (efficacy was either none or mild). Prior to the 6 months, 23/94 (24%) of patients discontinued the medication primarily due to adverse events. The most common side effects were anxiety and insomnia.

ADVANTAGES AND DISADVANTAGES OF STIMULANTS

Advantages include:Lack of sedation or weight gain (these medications can partially offset those problems), and these are compatible with many of the other headache preventives. Stimulants may help to offset the sedation of the long-acting opioids. They may also help for those with severe depression, and for the headache patients with attention deficit disorder.
Disadvantages include: Insomnia, anxiety, addiction potential, regulatory or malpractice concerns. Withdrawal and tolerance may present problems. The more restricted stimulants are inconvenient to prescribe.



4. IV DHE (Outpatient)


DESIGN AND METHODS

Forty-two patients with refractory chronic daily headache were entered into an open label study at the Robbins Headache Clinic. They kept a headache calendar, with severity assessed on a 1 to 10 visual analog scale. The patients charted on the calendar for 1 month prior to and 6 weeks post-treatment. A member of the Robbins Headache Clinic staff called the patient on day 2 after the intravenous dhe to evaluate the response. Return vists were scheduled at 3, 6, and 10 weeks. The patients had been refractory to the usual preventive medications, and an attempt was made to not change any daily preventive medications over the 6-week studyperiod.Of the 42 patients enrolled, 36 were female and 6 were male.Ages ranged from 20-53. The IV DHE was given according to the following protocol:

Repetitive IV Dihydroergotamine Outpatient Protocol

1. Give 5 to 10 mg. metoclopramide by mouth (P.O.).Measure blood pressure.


2. Thirty minutes later, with patient lying at a 30 degree incline to minimize gastric distress, administer 0.5 mg. DHE over one minute via IV push. Measure blood pressure and pulse.


3. If no adverse effects occur in the next 20 minutes, give second dose of 0.5 mg. dhe via IV push. Observe, and measure blood pressure and pulse.


4. Discharge patient to usual daily activities for six hours. Patients may be allowed to return to work and to drive, if not feeling sleepy.


5. When patient returns to the office in six hours, give 5 to 10 mg. metoclopramide p.o. (Patients may be instructed to take premedication 30 minutes prior to returning to the office.)


6. Thirty minutes later, administer 1.0 mg. dhe via IV push. Measure blood pressure and pulse.


7. Have the patient return the next day. Repeat steps 5-7 at 9 a.m. and at 3 p.m.


8. If adverse events occur, lower the dose or discontinue the dhe.

Therapeutic Response Scale
% Decrease in HA Frequency or Severity Rating
75%-100% Excellent
50%-75% Moderately effective
25-50% Mildly effective
0-25% No effect

RESULTS

The patients were assessed after 2 days and 6 weeks. Three of 42 patients dropped out prior to the 4 doses because of side effects. One patient had chest discomfort, and the other 2 experienced nausea. At 2 days, 31 of 39 (80%) patients had an excellent response to the DHE. After 6 weeks, 14 of 39 (36%) continued to have an excellent or a moderate response, with the remaining patients declining to their baseline headache pattern, with either no residual effect from the dhe or only a mild effect.

Nausea was the most frequently encountered side effect, and it usually lasted less than 1 hour. Eight of the original 42 patients experienced nausea. In these patients, the dose of the antiemetic was increased, and the dhe dose was decreased. A transient increase in headache, or an increase in muscle tension, was common, usually lasting less than 1 hour. Four patients experienced leg cramps, which were severe in two of those patients. This was treated with a muscle relaxant. Transient facial flushing occurred in one patient.Diarrhea was seen in 5 patients, lasting only 1 day. Burning at the injection site was occasionally seen, particularly when the dhe infiltrated. Tightness in the throat or chest occurred in 3 patients, and resolved quickly. Transient elevations in blood pressure, 10-20 points, occurred in 6 patients. Mild drowsiness was common due to metoclopramide. Restlessness from the antiemetic was observed in 2 patients.

ADVANTAGES AND DISADVANTAGES OF IV DHE

Advantages include: Relative safety, may be effective at breaking a long stretch of daily headaches, lack of sedation. May help to wean patients off of analgesics.

Disadvantages include: Effect is short-lived, inconvenient, and relatively expensive.

1. BOTULINUM TOXIN INJECTIONS


DESIGN AND METHODS

This was an open label, non-randomized non-blinded study. Eighty-seven participants, aged 23-67, were enrolled in the study, and 79 patients completed the study. Each patient had the diagnosis of moderate or severe chronic daily headache, refractory to the usual preventive medications. The patients recorded headache severity utilizing a visual analog scale for one month prior to treatment, and three months following treatment.

Each patient received low dose botulinum toxin A (BTA) injections, 12 injections of 2 units BTA each. The symmetrical injections, 6 on each side, were done frontally and temporally.

RESULTS

Thirty-six of 79 patients (46%) did not respond to the injections (response = at least a 2 point decrease on a 10 point vas). Forty-three of 79 (54%) were considered positive responders. Among the positive responders, 44% had a mild response (2 to 3 point decrease on the vas). Forty-seven percent had a moderate response (4 to 5 point decrease on the vas), while 9% had an excellent response (more than 5 point decrease on the vas).

Among the mild responders (19 of 43 = 44% of responders), in the second month, 16% declined to no response, 63% continued to have a mild response, while 10.5% of these mild responders had a moderate response and 10.5% reported an excellent response. During the 3^rd month with these mild responders, 68% now had no response, 10.5% had a mild response, 10.5% had a moderate response, and 10.5% reported an excellent response.

For the moderate responders (20 of 43 = 47% of total responders), during the 2^nd month 15% had no response, 15% had only a mild response, while 70% continued with a moderate response. During the 3^rd month, 50% declined to no response, 10% continued with a mild response, while 40% continued with a moderate response.

For the excellent responders, which were only 4 of 43 responders in total, during the 2^nd month all 4 remained excellent. During the 3^rd month 2 of the 4 declined to a mild response, 1 had a moderate response and 1 of the 4 patients continued with an excellent response.

Adverse events were generally mild, with 6 patients reporting mild ptosis, 2 with bilateral edema of the eyelids, and 2 reported a dramatic increase in headache.

ADVANTAGES AND DISADVANTAGES OF BOTULINUM TOXIN INJECTIONS

Advantages include: Relatively safe, may be long-lasting, few adverse events.

Disadvantages include: Expensive, inconvenient, efficacy unproven. While probably safe, long-term effects of repeated injections is not known.