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Original Article

Illicit drug use in cluster headachepatients and in the general population:A comparative cross-sectional survey

Paolo Rossi1,2, Marta Allena2,3, Cristina Tassorelli2,3,

Grazia Sances3, Cherubino Di Lorenzo4, Jessica V Faroni1 and

Giuseppe Nappi2,3,5

Abstract

Background: The rate of illicit drug use in cluster headache (CH) patients is unknown.Methods: Two hundred and ten CH patients (162 males and 48 females) attending two headache clinics provided infor-mation about their lifetime use (once or more in their lifetime, LTU), recent use (once or more in the past year, RU), andcurrent use (once or more in the past 30 days, CU) of illicit drugs. General population data (IPSAD Italia20072008)served as the control group.Results: LTU of each illicit drug but hallucinogens, RU of cannabis, cocaine, amphetamines and ecstasy, and CU of cannabisand cocaine were significantly higher in the male CH patients than in the general population, whereas no difference wasfound between the CH women and the controls. In the CH group, 28.5% of patients reported having used illicit drugs forthe first time after CH onset and 71.5% before CH onset. Compared with the controls, the male CH group showed agreater prevalence both of lifetime sustained intensive use of any illicit drug and of current intensive use of cannabis.Conclusion: The results of this study indicate that male CH patients are prone to overindulge in illicit drug use. This findingpossibly reflects a common biological susceptibility that predisposes these subjects to CH and to addictive behaviour.

Keywords

Cluster headache, headache, illicit drugs, cannabis, addiction, comorbidity

Date received: 17 September 2011; revised: 10 January 2012; 8 March 2012; 27 April 2012; accepted: 13 May 2012

Introduction

Investigation of psychiatric and psychological comor-

bidities in headache has focused far more on migraine

and tension-type headache than on cluster headache

(CH). High-quality studies in this field (that is, studies

including adequate CH patient and control groups and

using specific psychometric instruments or indicators)are lacking (1). Most of the hypotheses on personality

traits, psychological features and coping style in CH

patients, such as those which suggest that these individ-

uals are characterised by impulsiveness, aggressive

behaviour, emotional ability, anxiety and poor social

contacts, have not been validated by solid observa-

tional data (16).

To date, the abuse of tobacco in most CH patients is

the most consistent finding in this population. This

observation was documented by Kudrow in the early

1970s (7) in a small group of CH patients and

subsequently confirmed by other groups (8,9). More

recently, Manzoni investigated a large cohort 340

subjects of male CH patients and confirmed a very

high percentage of smokers among people with this

type of headache: 78.9% vs 35% in the general popu-

lation (POP), with chronic CH patients appearing more

1INI Grottaferrata, Italy2University Centre for Adaptive Disorders and Head Pain (UCADH),

Italy3Headache Science Centre, IRCCS C. Mondino National Institute of

Neurology Foundation and University of Pavia, Italy4Don Carlo Gnocchi Foundation ONLUS, Italy5Sapienza University of Rome, Italy

Corresponding author:

Paolo Rossi, INI Grottaferrata, via S. Anna snc 00046, Grottaferrata,

Rome 00046, Italy.

Email: paolo.rossi90@alice.it

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inclined to smoke than episodic CH sufferers (10). The

high prevalence of chronic use of nicotine in CH has

also been confirmed in more recent studies, including

non-clinic-based populations of CH patients in differ-

ent countries (1113). The significance of this associ-

ation as regards the pathophysiology of CH is

unclear, with some authors considering nicotine apotential trigger factor and others hypothesising the

existence of a common genetic link predisposing

people to both CH and nicotine addiction (12,14).

Data on CH patients use of other non-illicit drugs

are more controversial than those relating to their

smoking. In Manzonis study, CH patients significantly

overused coffee and alcohol, too, which suggests that

they have a tendency to overindulge in certain lifestyle

behaviours (10). However, in a recent study by Schu rks

et al., conducted in Germany in a large clinic- and non-

clinic-based CH population, the CH patients proved

less likely than the general population to show hazard-

ous drinking behaviour (15). Since alcohol is a well-

known trigger of CH attacks during the active periods

of the disease, these findings may indicate the presence

of alcohol-avoidance behaviour in CH patients with

frequent attacks.

In a clinical descriptive study of chronic CH patients,

Donnet et al. reported that 26% of these patients were

regular cannabis consumers (16). However, the use of

illicit drugs in CH patients has never been investigated

systematically. Acquisition of data on the use of illicit

drugs in CH patients may be important in order to ascer-

tain whether these patients are prone to overindulge in

addictive behaviours.The aim of this study was to examine the rate of

illicit drug use in a clinic-based sample of CH patients

compared, in the same period of time, with POP data.

Patients and methods

This cross-sectional study included a primary well-char-

acterised study sample formed by CH patients and

POP data serving as comparison data.

Patient study sample

Consecutive patients aged between 18 and 65 years,

with CH diagnosed according to the International

Classification of Headache Disorders and attending

two headache centres (INI Grottaferrata and IRCCS

C. Mondino, Pavia) for a first or follow-up visit were

evaluated over an 18-month period (January 2007June

2008). Non-Italian patients were included only if they

had lived in Italy since before the age of 10 years. No

other specific inclusion criteria relating to either clinical

picture or socio-demographic profile were applied, and

we thus recruited all patients able to provide reliable

information about their headache history and undergo

other assessments relevant to the protocol. A total of

210 CH patients were recruited; the group included

162 males and 48 females.

All the patients gave their written informed consent

to their participation in the study, which had been

approved by the local ethics committee.

The POP comparison data: the Italian Population

Survey on Alcohol and Drugs (IPSAD)

The POP data used in this study were obtained from the

IPSADItalia 20072008. IPSAD is a yearly survey

monitoring alcohol, tobacco and drug consumption in

the general population and is consistent, in terms of

methods, with that carried out by the European

Monitoring Centre for Drugs and Drug Addiction

EMCDDA in several EU countries (17). The

IPSADItalia 20072008 sample was formed by

random selection of census data held by local councils

involved in the survey (18). The councils were selected to

ensure that all Italian regions and provinces were repre-

sented. The youngest age-classes were oversampled

(1519 years, 5 1000, 2025 years, 4.51000, 2529

years, 3 1000, 3034 years, 2.51000, 3539 years

and 4044 years 2 1000, 4549 years and 5054

years, 1.5 1000, 5559 years and 6064 years,

11000). Participation in the survey was voluntary,

anonymous and at no cost to the interviewee (the ques-

tionnaires investigating illicit drug use and other vari-

ables were returned in pre-paid envelopes). The study

had a responder rate of 35.1% with the final samplenumbering 10,940 subjects, including the 4757 males

and 6183 females comprising the POP group in our

study.

Table 1 summarises the socio-demographic profile of

the two groups (CH patients and POP).

The comparison data were obtained from open-

access publications (18) and, partly, from the National

Council of Research, Epidemiologic Unit, Pisa.

In Italy the use of cannabis, cocaine and opioids is

higher than the European average, especially in young

age classes, although it is similar to that observed in the

EU countries that are comparable to Italy for numberof inhabitants and other demographic and economic

variables (i.e. Spain, France, Germany and UK (18).

In contrast, the use of stimulants is lower than the

European average (18).

Data collection and definitions

Comprehensive information regarding socio-demo-

graphic status and smoking was obtained directly

from each patient. Information regarding headache

characteristics was obtained from each patients

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medical history and included CH subtype diagnosis

(episodic cluster headache (ECH) or chronic cluster

headache (CCH)), disease duration, age at onset of

CH, mean bout frequency, mean bout duration and

mean number of attacks per day.

Information regarding illicit drug use was obtainedby means of a short questionnaire filled in anonym-

ously and voluntarily by the patients at the end of

the visit.

The questionnaire included the EMCDDA core

items for assessing period prevalence of drug use in

the general population (17). In detail, it included ques-

tions about the patients use during the previous month

(last-30-days prevalence, often called current use

(CU)), during the previous year (last-12-months preva-

lence, often called recent use (RU)), and during their

lifetime (that is, any use during their lifetime (LTU)) of

several substances (cannabis, opioids, cocaine, ecstasy,amphetamines and hallucinogens). In accordance with

the EMCDDA guidelines, for each drug two basic

items (age at first use and frequency of use in the past

30 days) were included to investigate patterns of use,

which provide valuable insight into the incidence and

intensity of use and their correlates. Data regarding the

frequency of use in the previous 30 days were used to

identify current intensive users, defined as patients who,

in the previous 30 days, had used cannabis for 20 days

or more, or one or more of the other drugs for 10 days

or more. Moreover, in order to have, for each drug, an

additional measure of lifetime intensity of use, we asked

responders also to specify how many years they had

used the drug(s) intensively in their lifetime. Patients

presenting with intensive use of any illicit drug for

at least six months in their lifetime were defined as

sustained intensive users (SIUs).

Statistical analysis

Descriptive statistics (means, standard deviations (SD)

and proportions) were used to describe each variable.

Bivariate comparisons of groups were performed using

the Chi-square test and Fishers test (where applicable)

for categorical variables, the t-test for continuous

variables. The analyses were sex-matched for all

comparisons.

In order to find possible predictors of illicit drug use

in CH patients, a binary logistic regression analysis wasadopted. Three independent analyses were performed

by a backward conditional method to predict the

LTU, the RU and the CU of at least one of the illicit

drugs. In each model, as possible predictors we con-

sidered age, gender, educational level, occupational

status (student/employed/unemployed), economic

income, age at cluster onset, type of cluster (episodic/

chronic) and a measure of CH severity.

As a measure of severity, we considered the mean

number of headache attacks per year of disease

when analysing LTU; the number of CH attacks in

Table 1. Demographic characteristics of cluster headache (CH) patients and the general population sample (POP).

Males

p-value

Females

p-valueCH (n162) POP (n 4757) CH (n48) POP (n 6183)

Age (/%)

1524 12.3 32.20.05 27 25.8 >0.05

3544 30.8 22.1 0.05

4554 18.5 13.2 >0.05 8.2 13 >0.05

5564 7.4 6.9 >0.05 23.2 6.2* 0.05 34.7 51 >0.05

Married 52.6 48.8 >0.05 50 46,8 >0.05

Divorced 6.7 1.4 0.05*

Level of education (%)

Primary 3 1 >0.05* 2.2 2 >0.05*

Middle 34.5 44.8 >0.05 30.4 41.2 >0.05

Secondary 48 40.7 >0.05 54.4 42.4 >0.05

University or postgraduate degree 14.2 13.5 >0.05 13 14.4 >0.05

: Chi-square test with Yates correction; *: Fishers exact test.

Rossi et al. 3

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the last 12 months when analysing RU; and the number

of attacks in the last month when analysing CU.

A level of p< 0.05 was considered significant.

Analysis was performed using SPSS for Windows,

version 11 (SPSS, Inc, Chicago, IL).

Results

Study population

Of the 224 CH patients recruited during the study

period, 210 (93.7%) agreed to participate in the study

(114 came from INI and 96 from the Pavia centre). All

but two were Caucasians and 98.1% were Italian.

Almost 83% of the patients had ECH, 13.4% had

CCH (females 10.8%, males 19.6%, Fishers test

p> 0.05) and 4% were newly diagnosed at the time of

the study (follow-up visits subsequently established a

diagnosis of ECH in all these cases). Ninety-one per

cent of patients were recruited during an active phase,

82.7% at a follow-up visit and 17.3% at a first visit. The

mean age at CH onset was 27.5 9.1 years (males

27.8 9.1, females 26.57.4, p> 0.05) and the mean

age at study enrolment was 41 years 10.8 (males

41.3 11.2, females 40.8 9.4, p>0.05). The ECH

patients recorded a mean bout frequency of 1.05 0.7

per year (males 1.2 0.58, females 0.92 0.4, t 11.3,

p< .005); their mean number of attacks per day was

2.15 1.3 (males 2.16 1.49, females 1.96 1.54,

p> 0.05), and their mean bout duration was 51.3 24

days (males 54.6 39.7, females 41.3 24, t 2.1,p< 0.05).

Compared with the POP group, the male CH group

included a significantly lower proportion of patients

in the age range 1524 years (12.3% vs 32.2%,

Chi-square 28.1, p0.05*

Ecstasy (%) 13.5 4.2 0.0001 4.1 2.1 >0.05*

Hallucinogens (%) 8.6 5 >0.05 4.1 2.3 >0.05*

Tobacco (%) 92.5 65.2

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Conversely, in the CH females, no significant differ-

ences in LTU of any illicit drug were found (Table 2).

RU of illicit drugs

RU of cannabis, cocaine, amphetamines and ecstasy

was significantly higher in the CH males than inthe POP group (Table 3, cannabis 27.7% vs 17.3%,

Chi-square 9.7, p 0.05), heroin and cocaine

Table 3. Prevalence of recent use (RU, previous 12 months) of illicit drugs in cluster headache

(CH) patients and in the sex-matched general population (POP).

Drugs

Males

p-value

Females

p-value

CH

(n 162)

POP

(n4757)

CH

(n 48)

POP

(n 6183)

Cannabis (%) 27.7 17.3 0.001 14.5 12 >0.05

Opioids (%) 0 0.6 >0.05* 0 0.2 >0.05*

Cocaine (%) 8.6 2.9 0.0001 2.1 1.2 >0.05*

Amphetamines (%) 1.8 0.6 0.02* 2.1 0.3 >0.05*Ecstasy (%) 3 1 0.02* 2.1 0.4 >0.05*

Hallucinogens (%) 0.6 1 >0.05* 0 0.4 >0.05*

Tobacco (%) 86.4 37.9 0.05* 0 0.2 >0.05*

Cocaine 4.3 1.1 0.0005 0 0.7 >0.05*

Amphetamines 0 0.3 >0.05* 0 0.1 >0.05*

Ecstasy 0 0.3 >0.05* 0 0.2 >0.05*

Hallucinogens 0 0.2 >0.05* 0 0.1 >0.05*

Tobacco 80.2 31.9

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(0% vs 11%, Fishers test p> 0.05) and in the CH

female group (Fishers test, all p> 0.05).

Age at first use of illicit drugs

The age at first use of cannabis was significantly lower

in the male CH patients than in the POP subjects

(16.8 4.2 vs 18.4 5.2 years, t3.87, p< 0.001), as

was the age at first use of cocaine (18.65.3 years vs

22 4.9 years, t3.5, p 0.05). Table 6

Current intensive use of illicit drugs

The rate of current intensive use of cannabis was

significantly higher in the male CH patients (11.2%)

than in the POP group (2.19%, Chi-square53.2,

p< 0.001). No significant difference was found in cur-

rent intensive use of other illicit drug (cocaine, CH

1.6% vs POP 0.2%, Fishers test p> 0.05; opioids,

CH 0% vs POP 0.13%, Fishers test p>

0.05; amphet-amines/ecstasy, CH 0% vs POP 0.05%, Fishers test

p> 0.05; hallucinogens, CH 0% vs POP 0.07%,

Fishers test p> 0.05). In the CH females, no significant

difference was found in the prevalence of current inten-

sive use of any of the illicit drugs surveyed (cannabis,

CH 2.1% vs POP 1.8%, Fishers test p>0.05; cocaine,

CH 0% vs POP 0.1%, Fishers test p>0.05; opioids

CH 0% vs POP 0.05%, Fishers test p> 0.05; amphet-

amines/ecstasy, CH 0% vs POP 0.03%, Fishers test

p> 0.05; hallucinogens, CH 0% vs POP 0.03%,

Fishers test p> 0.05).

Lifetime sustained intensive use

The prevalence of lifetime SIU of any illicit drug was

significantly higher in the CH males (22.8%) than in the

POP group (4.8%, Chi-square108, p< 0.0001). In the

women with CH no significant difference was found

in the prevalence of SIU (5.2% vs 1.7%, Fishers test

p>0.05).

Episodic vs chronic CH and patients in active

phase vs patients in remission phase

No significant difference was found between the ECH

and CCH patients in any of the illicit drug use param-

eters considered, or in current use of cigarettes (CCH

80.5% vs ECH 73.1%, p> 0.05).

In the same way no significant difference was found

in any of the illicit drug use parameters betweenthe 189 patients investigated in the active phase and

the 21 patients in remission phase (Fishers test, all

p>0.05).

SIU versus non-intensive users with CH

The age at onset of CH in the male SIUs was signifi-

cantly lower than in the non-intensive users (24.3 9.1

vs 2911.6, t 2.35, p< 0.05), while bout frequency in

these subjects was higher than in the non-intensive

users (1.4 0.7 vs 10.6, t3.5, p< 0.001). No signifi-

cant difference was found in bout duration, attack fre-quency, attack duration or rates of CCH (t-test, all

p>0.05). In female SIUs with CH no difference was

found versus non-intensive users in any of the clinical

parameters considered (t-test all, p> 0.05).

Age-matched prevalence of illicit drug use in males

Because age is an important determinant of levels of

illicit drug use, data regarding the prevalence of illicit

drug use in males have been analysed by age-classes.

In the age group 2534 years, LTU of amphetamines

Table 5. Age at first use of illicit drugs (data are presented as mean age in years and SD) in cluster headache (CH) patients and

in the sex-matched general population (POP).

Males

p-value

Females

p-valueCH POP CH POP

Cannabis 16.8 (4.2) 18.4 (5.2) 0.05

Cocaine 18.6 (5.3) 22 (4.9) 0.0005 23.2 (7.1) 23.5 (4.8) >0.05

Opioids 17.5 (2) 20.8 (4.7) 0.03 22.1 (3.8) 22.2 (4.4) >0.05

Amphetamines/ecstasy 19.6 (2.8) 20 (4) >0.05 20.5 (3.2) 21.6 (4.2) >0.05

: t-test.

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(Chi-square 5.87, p0.01) and ecstasy (Chi-

square7.8, p

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increased rates of occasional, sustained and regular use

of illicit drugs, mainly cannabis and cocaine, whereas

CH women did not show similar addictive behaviour.

As expected, tobacco use was significantly higher in CH

males and females than in the POP sample.

The finding of gender-related differences in illicit

drug use needs to be interpreted cautiously, since itpossibly reflects methodological problems, i.e. the

small sample size that does not allow an age-matched

comparison and limits the statistical power necessary to

disclose significant differences and the use of data

obtained from very skewed samples. However, under

these premises, it may be hypothesised that gender-

related differences in illicit drug use is related to a

more attenuated clinical expression of CH in women.

Indeed, in our study bout frequency and bout duration

were both significantly lower in the women than in the

men, and isolated clinical descriptive studies from the

literature have indicated that women with CH may not

show exactly the same clinical and epidemiological

characteristics as men with CH (1921). Thus, in men,

the phenotypic expression of CH may be accompanied

by comorbid addictive behaviour leading to illicit drug

use. Further studies including a greater number of

female patients are necessary to better define the

gender-related differences in CH clinical expression

and comorbidity.

The cross-sectional design of this study precludes def-

inite assumptions of causality between CH and addictive

behaviour in males. For example, we cannot exclude the

possibility that exposure to illicit drugs and/or nicotine

is a factor triggering the development of CH (22).However, the marked differences in the neuropharma-

cological properties of the different drugs of addiction

and the observation that almost 30% of CH patients

started to use illicit drugs after CH onset make this

hypothesis unlikely. Alternatively, the use of illicit

drugs may constitute an attempt to manage CH-related

discomfort. Indeed almost 30% of CH patients reported

that they first started using illicit drugs after CH onset,

and illicit drugs may have some effect on CH symptoms

(2325). It has been well established that CH is often

misdiagnosed, undertreated and mismanaged

(11,13,26). Web sites devoted to CH actively promotetherapeutic use of illicit drugs, and, by doing so, they

possibly create or reinforce a specific interest in and

demand for these drugs for CH (27). However, it

appears an unlikely explanation because the majority

of CH patients started to use illicit drugs before CH

onset, not all illicit drugs have the potential to improve

CH symptoms and no difference in illicit drug use was

found either between CCH and ECH, or between CH

patients in active and remission phase.

The most likely hypothesis is that male CH patients

are prone to overindulge in addictive behaviours (both

tobacco and illicit drug use), possibly because of a

common biological susceptibility that predisposes

them to both CH and addiction. According to this

line of reasoning, it is noteworthy that in our sample,

the age at first use of cannabis, cocaine and opioids was

significantly lower in the male CH patients than in the

control group. Recent research on addiction suggeststhat age at first use of addictive substances is genetically

influenced and linked to more severe addictive behav-

iour (28,29). Thus, our finding might indicate that male

CH patients have a more marked genetic predisposition

to try addictive substances. Consistent with this

hypothesis is the finding that current intensive use of

cannabis and sustained intensive use of any illicit drug

were more prevalent in CH males than in controls.

The neuropeptide orexin (also known as hypocretin)

has recently been implicated in both drug addiction (30)

and CH susceptibility (3133) and thus emerges as a

potential candidate to explain the present findings.

Several possible limitations of this study preclude the

drawing of definite conclusions regarding some aspects

of illicit drug use in CH patients. First, as recom-

mended by the EMCDDA, in order to overcome a

birth cohort effect and differences in the age profile of

the CH patients and general population, the measures

of illicit drug use would have been better analysed by

age groups. Unfortunately, on account of the low

prevalence of CH and the difficulty in recruiting a

large sample of CH patients within the study period,

this analysis could not be performed in women. In men,

the study lacked the statistical power necessary to dis-

close significant differences in the use of less prevalentdrugs and in age groups including fewer subjects.

Indeed, due to the combined effect of age at onset of

CH (infrequent in the second decade), the time of spe-

cialist consultation and diagnosis (usually delayed by

several years in relation to CH onset), and oversam-

pling of the youngest age-classes in the POP, young

subjects were under-represented in the male CH

group, whereas those aged 3544 years were over-repre-

sented. Similarly, due to the presence of two peaks of

onset in CH in women (third and sixth decade) and

oversampling of the youngest age-classes in the POP,

young subjects were under-represented and older sub-jects over-represented in the female CH sample. Since

illicit drug use decreases with age, the differences in the

age profile of the CH and POP groups might have

resulted in underestimation of the differences in illicit

drug use parameters, especially in the female groups.

Unfortunately, we could not adopt a regression-based

approach using age as a covariate that would have been

more appropriate for the unavailability of the database

regarding the POP survey.

The second limitation is that especially in women the

comparisons between samples was too skewed, so there

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is a much larger sample in the POP data versus CH.

This calls into question the validity of the results with

respect to gender differences.

The third limitation is that, since the patient sample

was selected in a headache centre setting, our results

cannot be applied to the CH population as a whole.

Fourth, the study used self-reported data on sub-stance use without the possibility of verifying in an

objective manner the answers to the survey questions.

Considering the nature of the survey, it may have led to

an under-reporting of illicit drug use even if literature

data suggest that if anonymity and confidentiality are

protected, as in our study, peoples self-reporting of

illicit drug is a reliable method (34).

Fifth, since illicit drug use differs in different geo-

graphical areas, ideally the controls should have been

selected from the same geographical region as the CH

cases. However, the CH patients enrolled in the two

participating centres came from 12 of Italys 20 admin-

istrative regions (and 39 of its 100 provinces). Thus,

the use of data from a control group representative of

the national population represented the best possible

compromise.

Sixth, possibly due to the nature of the topic of the

survey, as well as the method with which the data were

gathered, the response rate obtained in the general

population, 35.1%, may result in an information dis-

tortion in the collected data. In fact it may be hypoth-

esised that the non-respondent group may be engaged

in a much heavier use of drugs (in which case the data

gathered would underestimate the issue), or that, on the

other hand, drug users took advantage of the anonym-ous nature of the survey to participate in it and

thus affirm their drug use (in which case, the data gath-

ered would be inflated). The former hypothesis is the

more likely one, even if there is no clear evidence to

support it (18).

Finally, we did not investigate the role of genetic,

psychological (e.g. victimization, psychiatric comorbid-

ity), social (e.g. disadvantaged familial and social net-

work), economic (e.g. low income) and specific

situational factors potentially influencing drug use (35).

Further studies including larger non-clinic-based

populations of CH patients and exploring socio-environmental and neurobiological factors are neces-

sary to better understand the nature of the association

between cluster headache and addictive behaviour.

Funding

Funded by the Ministry of Health to IRRCS Mondino

Institute Current Research for 2009-2011 triennium.

Conflict of interest statement

None declared.

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