Medication overuse headache and its specific clinical

markers

Cefaleia por uso excessivo de medicação e seus marcadores clínicos específicos

Nelson Barrientos U.

1,2

, Philippe Salles G.

, Anna Milán S.

, Paulina Meza C.

, Raúl Juliet P.

, Alan Rapoport

Director, DIPRECA`s Hospital Headache Unit, Santiago, Chile. Neurology Professor, Head of the Neurology

Department at the Universidad de Santiago de Chile (USACH) and at the Universidad Diego Portales (UDP)

Neurologist, DIPRECA`s Hospital, Chile

The David Geffen School of Medicine at UCLA, Los Angeles, CA USA

Barrientos NU, Salles PG, Milán AS, Meza PC, Juliet RP, Rapoport A. Medication overuse headache and

its specific clinical markers. Headache Medicine. 2016;7(3):64-9

ORIGINAL ARTICLE

ABSTRACT

Introduction: Clinical markers of medication overuse

headache (MOH) are based on headache classification

developed by the International Headache Society (IHS). This

classification include only two criteria: 1) frequency of

headache must be 15 or more days per month for at least

three or more months; 2) the number of days of overuse

medication must be either 10 or 15 days per month

depending on the type of medication. However, patients often

present with associated clinical markers that are overlooked

by most physicians at the first visit. Methods: This is a

prospective, longitudinal and observational study of 76

patients admitted to DIPRECA´s hospital Headache Unit.

They were all diagnosed with MOH according to the criteria

established by the his ICHD III beta. Patients were given

standard therapeutic approach that included detoxification,

prescription of preventative medications and a standardized

follow-up of 6 months. Symptoms of interest were recorded

at each appointment and Zung, MIDAS and HIT-6 (headache

impact test) scales were applied. Results: Overused

medications included nonsteroidal anti-inflammatory drugs

(NSAIDs), triptans and ergots. The most significant associated

features were headache at awakening, awaking by headache,

attentional difficulties, depression, cervical pain and

myofascial pain syndrome. All symptoms improved with

therapy as well as MIDAS and HIT-6 scores. Discussion: In

evaluating patients with MOH consider both the ICHD III

beta diagnostic criteria and the common and specific

symptoms seen in most cases of MOH.

Keywords: Medication overuse headache, Chronic migraine,

ICHD-III beta, Depression, Early morning awakening

headache, Quality of life, MIDAS, HIT-6.

INTRODUCTION

Medication overuse headache (MOH) is a secondary

headache usually seen in patients with chronic daily

headache (CDH), in whom most meet diagnostic criteria

for chronic migraine. These patients usually have 15 or

more headache days in which the episodes last at least 4

hours a day for three months or longer. In addition, they

must be taking analgesic medication(s) for at least 10 or

15 days per month depending on the medication.

(1,2,3)

Chronic daily headache reaches a prevalence of 4-5% in

the United States.

(4,5)

The annual incidence of new onset

chronic migraine (CM) in patients with episodic migraine

(EM) averages 2.5%

(6,7)

and MOH prevalence in the ge-

neral population is estimated to be of 1-2%, mostly affecting

women. At dedicated headache centers, MOH accounts

for 70% of the new patients or more.

(4,3)

A survey by Rapoport

showed that MOH has become the third most common

cause of headache in the United State,

(8)

a relevant aspect

since of its high socio-economic impact.

(2,4,9)

A meta-analysis revealed that the most frequent

headache diagnoses in patients with MOH were migraine

(65%), tension-type headache (27%) and migraine associated

with other headaches (8%).

(10)

Other studies confirmed

migraine to be the most common headache that precedes

MOH.

(2,4,3)

In the United States, triptans in conjunction with

opioids were the mostly abused headache drugs, in spite of

the widespread use of NSAIDS and/or butalbital containing

64 Headache Medicine, v.7, n.3, p.64-70, Jul./Aug./Sep. 2016

medications.

(11)

This pattern of headache drug abuse was

not found in other headache populations.

(4)

Regardless of the initial headache syndrome or the

specific medication being overused, the mainstays of our

treatment are: 1) detoxification from the overused

medication, 2) non-pharmacological and 3)

pharmacological preventive treatment, with 4) proper use

of symptomatic medications.

(12,13)

Patients with MOH have

MIDAS scores three times higher as compared to those

who have episodic migraine who are not overusing

medications.

(2,14)

MOH patients also have an increased

risk of mood disorders and anxiety.

(15-18)

Sleep disorders

are more frequent among patients with MOH that in those

presenting episodic headaches.

(19)

It is usually agreed that by most headache specialists

that an structured approach for treating MOHs includes:

a) educating patients to stop taking the medicine abused

(day 1), b) detoxification from the overused medications

with the help of an antiemetic and analgesic, if needed

(days 1-7), c) institution of a preventive medicine between

days 1-7, d) prescription of an appropriate use of analgesics

and e) follow-up visits for at least six months.

(20,21)

Preventive medications considered useful are

valproate,

(21-23)

topiramate,

(21,24,25)

onabotulinumtoxinA

(21,26)

and quetiapine, the last one used as an add-on therapy

during detoxification.

(27)

While treating MOH, a treatment can be considered

as successful if a reduction in the headache days of 50%

or more is attained after 3 months of therapy.

(9)

Success rates of MOH therapy are reported to fall around

70%. These results are commonly based on in-patient treatment,

rescue medication and continued support. In addition, the

70% success rates reported were based on different outcome

measures and therefore difficult to compare.

(28)

Some factors that appear to negatively affect the results

are the high use of medicines at the beginning of detoxification,

the reuse of previously abused drugs, failure to improve after

two months of treatment, smoking and alcohol use. Although

psychiatric comorbidities are not related to relapse after one

year of treatment, those patients with lesser depression and/or

anxiety scores had better results after four years of

detoxification.

(4,16-18)

Treatment of MOH undoubtedly has a

positive impact on the quality of life of these patients.

(29,30)

OBJECTIVES

To determine the following in patients with MOH:

headache frequency and intensity, if the patient awakens

in the morning with headache, if the patient is awakened

at dawn by headache, inattention, depression, cervical pain

and myofascial pain syndrome.

To describe the evolution of these symptoms during

the 6 month follow-up and their impact on quality of life in

relation to treatment.

MATERIAL AND METHODS

The present study was approved by the Ethics and

Research Committee of DIPRECA Hospital and all patients

were fully informed and agreed to participate in the study.

Patients allowed the use of their medical record data and

gave consent regarding the use of their clinical records for

research purposes, anonymously.

This was a prospective, longitudinal observational,

study on 76 consecutive patients who met the IHS criteria

for medication overuse headache. They were admitted to

DIPRECA´s Hospital Headache Unit between March 2014

and April 2015. Patients were given follow-up neurological

evaluations at month 1, 2, 3 and 6.

During the initial evaluation, relevant clinical data

were considered and recorded in a standardized record,

including headache frequency and intensity as recorded

on a visual analog scale (VAS), medication use and overuse,

awakening times and reasons, attention difficulties, cervical

pain and myofascial pain syndrome.

The Zung scale was used for evaluation of depression

and the MIDAS and HIT-6 scales for evaluation of disability

and impact on quality of life.

For statistical analysis, parametric tests the 2 test, and

nonparametric Student t test, with the SSSP program were

used.

The detoxification and treatment protocol used in our

Headache Unit at DIPRECA Hospital consists of suspension

of the overused medication and initiation of a joint

pharmacological support therapy during the first 3 months.

In the first month we attempt an ambulatory therapy,

utilizing different medications from those overused by the

patient. We use injectable NSAIDs, not to exceed 2 vials of

diclofenac 75 mg IM, secondly oral quetiapine 25 mg/

day, and then treatment with sodium divalproex ER 500

mg daily for 3 months as a preventive approach. An

alternative treatment is onabotulinumtoxinA 100 IU, within

the first 2 weeks of treatment.

During the second and third months of treatment

injectable NSAIDs were replaced by oral analgesics if

necessary, not to exceed 10 days of use per month, while

maintaining the use of quetiapine and divalproex sodium

ER in the same dose for 3 months.

MEDICATION OVERUSE HEADACHE AND ITS SPECIFIC CLINICAL MARKERS

Headache Medicine, v.7, n.3, p.64-70, Jul./Aug./Sep. 2016 65

If progress is satisfactory, an assessment to decide

whether to maintain treatment during the third month is

made and monitoring continues.

RESULTS

A total of 76 patients met the diagnostic criteria for

MOH, all consented to the present study, all received

detoxification treatment, and all completed 6 months of

follow-up for this study.

The demographic characteristics of the study population

reveals an average age of 41.17 years (16-68), with a

female predominance (80.26%). The average length of

painkiller overuse was two years, but for some patients over

a decade. Nine of our patients had a history of prior MOH

treatment (11.8%), with little use of preventive drugs. Among

the significant comorbidities overweight, obesity and

depression are highlighted. (Table 1 and Table 2)

according to the clinical experience of the authors. This

group of patients was remarkable for their low use of opioids

and barbiturates. (Figures 1 and 2)

Frequency of headache attacks

Regarding the frequency of headache attacks during

the initial evaluation of our patients, we found an average

of 22.25 days of headache per month (range between

15 and 30 days of pain), with a gradual decrease in

frequency after the initiation of therapy and

discontinuation of the overused drug. There was a

statistically significant reduction in headache frequency,

as compared to the initial frequency, for each assessment

during follow-up (95%, Paired sample test, p <0.001);

this reached a minimum of 3.86 average headache days

in the third month, which was maintained during the sixth

month of monitoring. There was no statistical difference

when comparing the frequency between the third and

sixth months (95% CI, Paired sample test, p 0.321). It is

noteworthy that only 2 patients persisted with an attack

BARRIENTOS NU, SALLES PG, MILÁN AS, MEZA PC, JULIET RP, RAPOPORT A

Overused Medications

The most overused medication were the nonsteroidal

anti-inflammatories (NSAIDs) (84.21%), followed by ergots

(35.52%), triptans (34.21%), the combination of NSAIDs

with ergots (14.47%), or triptans (15.78%). This seemed

representative of the situation of patients nationwide,

Figure 1. Medications overused

Figure 2. Mix of medications overused

66 Headache Medicine, v.7, n.3, p.64-70, Jul./Aug./Sep. 2016

frequency of greater than 15 days per month at 3 months

follow-up, and 9 patients were actually headache free at

6 months follow-up. (Figure 3)

Waking up in the morning with headache

As Figure 4 shows, waking up in the morning with

headache was the most frequently reported symptom before

detoxification treatment began and it decreased progressively

once management of MOH was initiated.

This symptom was reported at the initiation of the study

in 98.7%, at the end of the first month in 50%, at the end

of the 2nd month in 30.7%, at the end of the 3rd month

in 14.7% and at the end of the 6th month in 21%. The

difference was significant comparing initiation and month

3. (χ

p < 0.001)

This headache is typically mild and located in frontal

and periorbital areas. (Figure 5).

Headache Intensity

There was a progressive decline in the intensity of

pain during headache crises, highlighting a mean baseline

intensity of 7.3±1.2, decreasing to 5.2±1.5 ) at 1 month,

to 4.1 (SD 1.8 ) at 2 month, to 3,1±2.1 at 3 month

and to 2.7±2.7 at 6 months, respectively. The average

pain intensity decrease was statistically significant from

the initial intensity (Paired sample test, p < 0.001) with

no significant difference comparing the third and sixth

months. (Figure 4)

Being awakened at dawn by headache: Being

awakened at dawn by headache is a frequently reported

symptom in patients with MOH. In this series it is the second

most frequently observed symptom, seen in 88.15% of

patients on study entry, and improving to 24% at the end

of month 1, 16% at month 2, 9.2% at month 3 and 17.1%

at month 6; this was significant when compared to baseline

(χ

test, p < 0.001), and not significant comparing month

3 and 6. This headache is typically holocraneal and always

severe and 76% of the patient are headache free by the 1st

month. (Figures 5 and 6).

Cervical Myofascial Syndrome

The cervical myofascial syndrome is a non-

inflammatory disorder manifested by localized pain and

stiffness, associated with trigger points and limited cervical

movement. The three basic components of this syndrome

include: a palpable band in the affected muscle, the

presence of trigger points and referred pain patterns. It was

clinically evaluated for each patient by history and physical

examination. Myofascial pain was also frequently reported

Figure 3. Average of headache frequency during follow-up

Figure 5. Acompanying symptoms in the first evaluation

MEDICATION OVERUSE HEADACHE AND ITS SPECIFIC CLINICAL MARKERS

Figure 4. Headache intensity

Other Clinical Symptoms

During the initial evaluation of patients, almost all

patients reported waking up with headache in the morning.

This was followed in frequency by being awakened by

headache at dawn and myofascial pain syndrome,

difficulties in attention, neck pain, and psychiatric

comorbidities such as depression (assessed by the Zung

scale). These findings are presented in Figure 4.

Headache Medicine, v.7, n.3, p.64-70, Jul./Aug./Sep. 2016 67

by these patients: at the start of the study 83.78% (61

patients) had myofascial pain, decreasing to 81.08% (60

patients) at 1 month follow-up, 55.55% (40 patients) at 2

months, 36.48% (27 patients) at 3 months and 35% (26

patients) at 6 months. A response was seen after treatment

initiation with statistically significant differences from

baseline to 6 month (95 % χ

: p < 0.001). (Figure 6)

Cervical Pain

Neck pain as a separate symptom from myofascial

syndrome is assessed by the patient's history during the

interview, and is also a common symptom in these patients.

Prior to initiation of treatment 72.97% (54 patients) reported

neck pain, and a significant decrease during follow-up

assessments was noted. During the first month 71.62% (53

patients) had neck pain, 52.77% (38 patients) at month

2, 32.43% at month 3 and 29.72% at 6 months. (Figure

6) Statistically significant differences were noted comparing

baseline to 6 months (95% χ

: p < 0.001).

Attentional Difficulties

Difficulty in sustaining a focus of attention on a parti-

cular task is also common among these patients. To evaluate

this symptom we asked the following questions in relation

to the three months prior to the first visit: "Have you noticed

more difficulty in sustaining attention regarding tasks that

require sustained mental effort?", "Are you easily distracted

by minor stimuli?", " have you noticed major difficulty in

completing work related tasks or during other entertaining

activities?", "Are you more forgetful than before?"

The presence of inattention was considered as an

affirmative response to any of the questions above. Initially

78.94% (60 patients) reported attention problems, at the end

of the first month 61.33%, 45.33% at month 2, 34.21% (26

patients) at month 3 and 32.9% (25 patients) at month 6.

There was a statistically significant difference from baseline

at month 6 (95% χ

: p < 0.001). (Figure 5).

Depression

In order to evaluate depression we used the Zung Scale

abbreviated and validated for South American

populations.

(31)

This validated version established the cutoff

for mild depression at 15-20 points, 23-24 points for mild

for moderate depression, 21-27 for moderate depression

and 27-40 points for severe depression.

At the initial assessment 41 patients had scores of 24

or more points (53.9%) and 21 patients (27.37%) had

severe depression, with an average score of 24.41±5.226

points. At baseline, severe depression was detected in

27.37% of the sample, in 5.56% after one month of

protocol and in 0% of the sample at months two, three and

six. Within the first month the average depression score

was 20.11±4.61, after months 18.49±4.82,

16.24±4.68 after three months and 16.71±5.61 at 6

months. The last 3 values were under the cutoff for

depression.

Comparing the average values between the different

months up to month 3, there is a statistical difference in all

of them, as compared to baseline (95% CI Paired sample

test Sig two-tailed p <0.000), with no statistical difference

between the sixth and third month (p 0.363). (Figure 5)

Quality of Life

In order to evaluate quality of life we used the MIDAS

and HIT-6 scales, which are broadly used and validated for

this purpose.

(32,33)

Both scales demonstrated a poor quality

of life during the baseline assessment, with a fall in its severity

once detoxification treatment began. In regard to the MIDAS

scale, a larger grade signifies a worse quality of life with

more disability (Grade I: 0-5 points; Grade II: 6-10 points;

Grade III: 11-20 points; Grade IV: 21 or more points). This

scale was evaluated at baseline and at months 3 and 6.

The average score for all patients (n = 76) at initial

evaluation was 72.08±60.58 points, falling to

14.39±13.33 at month 3 and 11.96±18.51 at month

6, There is a significant difference when comparing the

baseline value with the average of 3 to 6 months (95% CI,

Paired sample test, p <0.0001), and no differences between

the third and six months (95% CI, Sig. 2-tailed 0.106). By

classifying the severity of the alteration of quality of life we

found 93.42% (71 patients) with severe limitations and

need for treatment (Grade IV) at baseline, and only 15.4%

(12 patients) in this category by 6 month follow-up. None

Figure 6. Changes in symptoms during follow-up assessments

BARRIENTOS NU, SALLES PG, MILÁN AS, MEZA PC, JULIET RP, RAPOPORT A

68 Headache Medicine, v.7, n.3, p.64-70, Jul./Aug./Sep. 2016

of the patients evaluated had scores for grade I on the

MIDAS scale (minor limitations and no needs for treatment)

in the initial assessment; however, 25% (n=19) and 52.3%

(n=39) were qualified as grade I at 3 and 6 months,

respectively. In Figure 7 the changes obtained in the

evaluation of this scale can be observed during follow-up.

MEDICATION OVERUSE HEADACHE AND ITS SPECIFIC CLINICAL MARKERS

Figure 7. MIDAS Score

The results obtained with the HIT-6 scale are similar to

those obtained with the MIDAS scale. The HIT-6 scale

categorizes the results according to severity: very severe

(60 or more points), severe (56-59), moderate (50-55)

and mild or no impact (36-49). The average of all patients

in the initial evaluation of the HIT-6 was 65.5±6.675

points, falling to 51.15±8.52 at the first month,

45.75±9.75 at the second month, 41.3±10.48 at the

third month and 41.2±12.23 at the sixth month.

There were statistically significant differences when

comparing results from baseline. (Paired sample test, 95%

next 2-tail; p <0.001), with significant differences also

between the months 1, 2 and 3 of follow-up (p <0.001),

but with no statistical difference when comparing the third

and sixth month (p 0.175).

To categorize patients according to severity in the first

evaluation 81.58% (n= 62) were "very severe," 7.8 (n= 6)

"severe" and 10.5 score (n= 8) "moderate" noting that no

patient fulfilled score for "slight or no impact on their quality

of life". As with the MIDAS scale, we can see a progressive

increase in mild or no impact category (quality of life) after

treatment started, with 65 (85.5%) and 63 (82.25%) patients

reaching the mild category at 3 and 6 months, respectively;

there was a significant drop in the number of patients with

severe alterations in quality of life, with only 7 (9.2%) patients

in this category at 3 months follow-up. (Figure 8).

Figure 8. HIT-6 Score

DISCUSSION

Traditionally the diagnosis of MOH is made based on

the criteria set by the diagnostic classification of the IHS,

which basically takes into account the headache frequency

parameter (more than 15 days per month) and the number

of days of medication overuse, as well as the type of

medication. However, in clinical practice patients report

additional symptoms, namely awakening in the morning

with headache, being awakened at dawn by headache,

depression, inattention, cervical pain and myofascial pain

syndrome. These symptoms, despite not being included in

the diagnostic criteria, aid in the clinical evaluation process

and the monitoring of patients during the treatment of this

disease.

This paper demonstrates that the symptoms described

above are frequently observed in patients with MOH, as

they are seen in over 80-90% of patients. As such, we

consider them of great importance in strengthening the IHS

criteria and achieving greater accuracy and usefulness in

following outcomes during the management of this condition.

There are specific situations that may result in early

diagnosis of MOH, such as patients who overuse medication,

have a lower frequency of headaches than the 15 days a

month that the IHS criteria requires, but demonstrate some

of the symptoms described above. Early diagnosis can lead

to initiation of early treatment. The same situation pertains

to patients with chronic headache who do not meet the

criteria for medication overuse described in the IHS criteria.

In the authors' opinion these clinical markers, specific to

MOH, such as waking up in the morning with headache,

being awakened at dawn by headache and the myofascial

Headache Medicine, v.7, n.3, p.64-70, Jul./Aug./Sep. 2016 69

syndrome, are frequent occurrences and quite specific for

MOH. Depression, neck pain and inattention are

comorbidities, but helpful in combination. We suggest that

these symptoms we have delineated should be further

evaluated and possibly be included in MOH diagnostic

criteria in future ICHD versions.

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BARRIENTOS NU, SALLES PG, MILÁN AS, MEZA PC, JULIET RP, RAPOPORT A

Correspondence

N. Barrientos

Dipreca Hospital

Av Vital Apoquindo 1200 - Santiago, Chile

e-mail: barrientosymendoza@gmail.com>

Tel.: +562-2734015 Fax: +562-2751842

70 Headache Medicine, v.7, n.3, p.64-70, Jul./Aug./Sep. 2016