Headache Medicine, v.7, n.1, p.23-27, Jan./Feb./Mar. 2016 23

Analysis of nortriptyline's prophylaxis on hemodialysis

headache patients - a pilot study

Análise de profilaxia da nortriptyline em hemodiális de pacientes com enxaqueca

- estudo piloto

Bruna Mendonça Lima

, Paulo Sergio Faro Santos

, Alan Chester Feitosa de Jesus

Neurologist, Member of the Brazilian Headache Society

Resident medical, Department of Neurology, Neurological Institute of Curitiba;

Member of the Brazilian Headache Society

Neurologist, Member of the Brazilian Headache Society; Member of the Brazilian Neurology Academy

Lima BM, Santos PSF, Jesus ACF. Analysis of nortriptyline's prophylaxis on hemodialysis headache patients -

a pilot study. Headache Medicine. 2016;7(1):23-7

ORIGINAL ARTICLE

ABSTRACT

Background: Headache is the most common neurological

symptom of patients on hemodialysis treatment. However,

this condition is usually treated only after the pain has already

begun. Objective: Determine the efficacy and tolerability

of nortriptyline as a prophylactic treatment for patients

diagnosed with hemodialysis headache. Methods: This study

is an open and a prospective clinical trial. Twelve patients

with hemodialysis headache were studied in this trial. They

were asked to take nortriptyline (25 mg per day) during three

months as a prophylaxis for their headaches. Weekly

interviews were made to register eventual headaches.

Additionally, other clinical features were analyzed such as

the intensity of pain, its location, side effects of the drug and

use of abortive medications. Results: There was a significant

reduction (p < 0.05) in the intensity as well as frequency of

pain. The duration of the episodes also decreased.

Conclusions: Our findings suggest that nortriptyline 25 mg

is capable of reducing not only the frequency, but also the

intensity of the pain in the hemodialysis headache. However,

further studies are necessary.

Keywords: Prophylaxis; Nortriptyline; Headache; Dialysis

RESUMO

Introdução: Cefaleia é o sintoma mais comum dos paci-

entes em tratamento com hemodiálise. Porém, esta condi-

ção normlmente é tratada apenas depois da dor ter inici-

ado. Objetivo: Determinar a eficácia da nortriptilina como

um tratamento profilático para paciente diagnosticados com

cefaleia da diálise. Métodos: Este estudo é um ensaio

clínico aberto e prospective. Doze pacientes com cefaleia

da diálise foram estudados neste ensaio. Eles foram convi-

dados a tomar nortriptilina (25mg por dia) durante três

meses como profilaxia para a cefaleia. Entrevistas sema-

nais foram realizadas para registrar eventuais episódios de

cefaleia. Além disso, outras características clínicas foram

analizadas, tais como intensidade da dor, localização, efei-

tos adversos da medicação e uso de medicação abortiva.

Resultados: Houve redução estatisticamente significativa

(p < 0.05) da intensidade e da frequência da dor. A dura-

ção dos episódios também reduziram. Conclusão: Nos-

sos achados sugerem que a nortriptilina 25 mg é capaz de

reduzir não apenas a frequência, mas também a intensida-

de da dor na cefaleia da diálise. Entretanto, mais estudos

são necessários.

Palavras-chave: Profilaxia; Nortriptilina; Cefaleia; Diálise

INTRODUCTION

According to Kidney Disease Outcomes Quality

Initiative, renal insufficiency is the final stage (from five) of

chronic renal disease (CRD) and it is characterized by a

reduction of glomerular filtration rate to values lower than

60 mL/min/1.73m

for three months or more, regardless

of the cause of the decreased function. In this stage,

substitutive renal therapies, such as peritoneal dialysis,

hemodialysis and continued substitutive renal therapy, are

24 Headache Medicine, v.7, n.1, p.23-27, Jan./Feb./Mar. 2016

LIMA BM, SANTOS PSF, JESUS ACF

recommended.

(1)

In 2009, a study in Brazil showed that

77.589 patients were on dialytic therapy and 93% of them

received hemodialysis.

(2)

Headache is the most frequent neurological symptom

of hemodialytic patients, diagnosed in 56% of them. The

pharmacological treatment for this pain is dipirone.

Nevertheless, in 14% of these patients, no options of

treatment are mentioned.

(3)

The first study about a specific

type of headache related to hemodialysis was published in

1972. This study intended to find causes for the pain's

onset by discussing crucial aspects like trigger factors;

biochemical and psychological changes secondary to

hemodialysis. The kidney's role in pathophysiology of the

hemodialysis headache and the influence of other

medications used by these patients are also mentioned in

this resarch.

(4)

Only in 1988, the International Headache Society

(IHS) published the Classification and Diagnostic Criteria

for Headache Disorders, Cranial Neuralgias and Facial

Pain recognizing this disease as a headache associated

with metabolic abnormalities.

(5)

The most recent diagnostic criteria are the 3

edition,

beta, the International Classification of Headache published

in 2013,

(6)

but as the survey was conducted before this

period, we considered the criteria of 2003

(7)

described

below. There was no significant change between the two

editions.

A. At least three attacks of acute headache fulfilling

criteria C and D.

B. Patient is on hemodialysis.

C. Headache develops during at least half of

hemodialysis sessions.

D. Headache resolves within 72 hours after each

hemodialysis session and/or ceases altogether after

successful transplantation.

In previous research, there is only one case report of

an attempt to prevent hemodialysis headache. The author

of this report used an angiotensin-converting enzyme

inhibitor for his patient over ten months with good results

during this period. However, after this initial period, the

renal function became worse and the therapy had to be

discontinued.

(8)

Nortriptyline is the first metabolic product of

amitriptyline, a tricyclic antidepressant which is also used

in the control of chronic pains, such as headaches. This

drug is capable of blocking norepinephrine reuptake without

causing many anticholinergic effects. Therefore, fewer side

effects such as excessive somnolence, dry mouth and urinary

retention are reported.

(9)

The objective of this study was to verify the efficacy

and tolerability of nortiptyline (25 mg per day) as a

prophylactic therapy for hemodialysis headache patients

with chronic renal disease who had done hemodialysis at

a nephrology clinic in Sergipe.

METHODOL O G Y

This open and prospective clinical trial was conducted

in Nephrology Clinic of Sergipe. The trial was divided in

two phases: identification of the patients with hemodialysis

headache and analysis of their clinical evolution after

initiating the prophylactic medication.

Firstly, two hundred and forty eight patients on

hemodialysis were selected. One hundred and eighteen of

these patients, who were on hemodialytic therapy for more

than six months, were interviewed. These patients received

three sessions of hemodialysis per week, each session with

a mean duration of 4 hours. In the initial evaluation, we

tried to identify if they have had headache and the clinical

characteristics of each patient's pain: attacks related to

hemodialysis, intensity of these attacks according to VAS,

location and type of pain, mean duration of the episode,

abortive medications usage and presence of interdialytic

headache.

In the last phase of this research, patients who fulfilled

the diagnostic criteria for hemodialysis headache - those

who, in addition, were on hemodialysis for at least six

months and were able to see the VAS - were selected. Patients

with hemodialysis headache for less than six months or

with visual deficiency were excluded from this study. Patients

with some cognitive inability, who could not understand

the researchers' instructions, were also excluded.

During three-months of follow up (between August and

October of 2008), patients were interviewed weekly and

the questionnaire was updated with the new data from each

of them. The researcher prescribed nortriptilyne's capsules

(25 mg) to the patients. The correct usage of such

medication was verified every hemodialysis session.

The statistical analysis was gathered using the Statistical

Analysis System version 9.1. At the beginning, the

researchers provided a descriptive analysis of the data

obtained before the treatment (12 patients) and then from

the data of subsequent evaluations.

After that, the incidence of variables such as frequency,

onset, intensity and duration were estimated every month.

The average of quantitative variables and the frequency of

qualitative variables (use of abortive medications and pain's

quality) were also estimated. The Student's t test was applied

Headache Medicine, v.7, n.1, p.23-27, Jan./Feb./Mar. 2016 25

in order to compare the average of the qualitative variables

in the initial evaluation with each subsequent month. Then,

the data from linear regression of quantitative variables

was analyzed considering the three-month treatment.

The Ethic and Research Committee of Federal

University of Sergipe approved this study; process number

41.540.000.107-07. All patients included in the study

signed a permission term in accordance with Helsinki

Declaration rules.

RESULTS

From the twelve patients diagnosed with hemodialysis

headache, according to IHS criteria, at the beginning of

the research, eight continued in our study until the end.

During the interviews, the most common side effect

mentioned was excessive somnolence, reported by 36.36%

of the patients. A patient with a previous complaint of

intestinal constipation mentioned such symptom during the

evaluations. Besides these symptoms, hypotension,

palpitations and vertigo episodes were also mentioned by

9.1% (one) of the patients.

The location and quality of pain were evaluated in

the initial interview as described in Table 1.

Out of the twelve patients interviewed, nine used

abortive medication during the attacks. Most of the patients

stated that the pain began between the third and fourth

hour of hemodialysis; a fact that did not change after the

continued use of prophylactic medication.

A total of one hundred and eighteen interviews were

carried out. In sixty-two (52.5%), the patients denied having

pain, but in fifty-six (47.5%) they related pain. In 60.7% of

positive-pain answers, they mentioned use of abortive

medications. The average of the variables – attacks, monthly

frequency, onset during hemodialysis, intensity according

to VAS and crisis' duration in minutes – are presented in

the tables below.

After three months of daily use of nortriptilyne 25 mg,

the most frequent pain intensity and location were still

throbbing frontal (24%) followed by throbbing temporal

(14.29%), pression-like frontal (12.5%), burning frontal

(7.14%), throbbing in vertex (5.36%), throbbing

occipitofrontal (1.39%) and pression-like parietal (1.79%).

The average duration of the episode before using

prophylactic medication was 5.45 hours and, after the

three-month treatment, this parameter changed to 3.15

hours.

After data analysis with the Student's t test, we observed

that there was a significant reduction (p < 0.05) in the

intensity and an even more significant reduction (p < 0.01)

in the frequency of the attacks (Table 5).

ANALYSIS OF NORTRIPTYLINE'S PROPHYLAXIS ON HEMODIALYSIS HEADACHE PATIENTS - A PILOT STUDY

26 Headache Medicine, v.7, n.1, p.23-27, Jan./Feb./Mar. 2016

LIMA BM, SANTOS PSF, JESUS ACF

DISCUSSION

In medical practice, a prophylactic treatment is based

on actions to prevent diseases. The main objectives of

headache prophylaxis are to decrease the frequency,

duration and intensity of the attacks; improve abortive

medication's efficacy; make the patient's quality of life better

and diminish his/her incapacity for daily activities.

(10)

The

prophylactic therapy of headache presents two strands: the

pharmacological, which is composed by the beta-

adrenergic blockers, tricyclic antidepressants, calcium

channel antagonists, anticonvulsants and others, and the

non-pharmacological measures consist of physiotherapy,

acupuncture, diet, among other.

(11)

Tricyclic antidepressants are the most common drug

used for headache prophylaxis. This class of antidepressant

medication acts through downregulation and antagonism

toward 5-HT2 receptors and reduction of beta-receptors'

density. Moreover, it promotes the inhibition of epinephrine

and serotonin reuptake, which increases these

neurotransmitters' availability in gap and improves central

antinociception by stimulating endogenous opioids.

(10-12)

Tricyclic antidepressants are safe drugs for chronic renal

patients, up to 1000 mg per day (the dose for depression

treatment). These drugs have a hepatic metabolization which

is important for dialytic patients. Nortriptyline, desipramine

and imipramine are better tolerated than amitriptyline by

patients with CRD.

(13)

In the present study, four patients abandoned the

program. Only one left due to side effects (hypotension).

The side effects found in this research were in accordance to

the ones already described for tricyclic antidepressants.

(10-12)

The most frequent are: vertigo syndrome, weight gain,

increase in appetite, somnolence, dry mouth, intestinal

constipation, neurogenic bladder, stained vision, reduction

of convulsive threshold, tachycardia and akathisia.

(10-12)

In the initial interviews, fifty-four percent (54%) of the

patients reported pain onset between the third and fourth

hour of hemodialysis, similar to what Antoniazzi et al.

(3)

found in their study (62% of the patients presented the

same onset pattern). The most prevalent pain intensity and

location mentioned by our patients was throbbing frontal.

This data is in keeping with the Göskan study from 2004.

(14)

In this study, the author described many characteristics of

hemodialysis headache patients and found that the most

frequent location of pain was frontotemporal (50%) and

the most frequent intensity was throbbing (87%).

(14)

After the use of prophylactic medication, there was no

statistical significance in the change of the pain's onset

and its total duration. However, there was a reduction of

the pain's mean-time for each patient. There was a statistical

significance in the difference of adjustable equations of

frequency and intensity variables, but respective coefficient

of determination values of these variables, obtained by

linear regression, were low. It does not invalidate the

information with Student's t test, but it exposes the fact that

the adjustable model does not explain alternations of the

dependent variables (frequency and intensity) properly. The

frequency and intensity had such a large variation in a

short time that more sustained observations are necessary.

In medical literature, there is only one case report of a

possible prophylactic therapy for hemodialysis headache

which used angiotensin-converting enzyme inhibitor without

success.

(8)

This study did not describe whether the prophylaxis

modified the onset of pain, its mean duration or the

frequency of attacks. The author reported that there was

no decrease in pain's intensity and that, after 10 months of

medication use, the treatment had to be interrupted because

of side effects.

(8)

CONCLUSIONS

It is important to find an efficient treatment for

hemodialysis headache. Most of our patients reported pain

in almost every session and, because of this, they tended to

use abortive medications excessively which contributed to

Headache Medicine, v.7, n.1, p.23-27, Jan./Feb./Mar. 2016 27

Correspondência

Paulo Sérgio Faro Santos

EInstituto de Neurologia de Curitiba

Rua Jeremias Maciel Perretto, 300

81210-310 - Curitiba, PR, Brasil

Fone/fax: + 41 3248.8580

dr.paulo.faro@gmail.com

the pain's chronification. The results of this study are

encouraging but insufficient to assure that the correct therapy

for hemodialysis headache is tricyclic antidepressants,

specifically nortriptyline.

Randomized, double-blinded, placebo-controlled

studies with more patients must be executed to confirm or

refute this research's data. For the time being, this study is

the beginning of a new research line which seems to have

promising results in the treatment of pain in hemodialysis

headache patients.

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Recebido: March, 03 2016

Aceito: March, 05 2016

ANALYSIS OF NORTRIPTYLINE'S PROPHYLAXIS ON HEMODIALYSIS HEADACHE PATIENTS - A PILOT STUDY