Smoking and medication-overuse headache: Exploring the potential link between nicotine dependence and analgesic overuse

Abstract

Background

Despite consistent epidemiological evidence identifying smoking as a risk factor for medication-overuse headache (MOH), the mechanisms underlying this association remain incompletely elucidated. The aim of this work was to explore the relationship between the severity of analgesic dependence, headache-related disability, nicotine dependence, psychological distress, and addiction-related personality traits in patients with MOH.

Methods

This multicenter cross-sectional study was conducted on 442 patients with primary headache disorders. Participants underwent structured face-to-face interviews and were asked to fill out the following questionnaires: Headache Impact Test–6 (HIT-6), Severity of Dependence Scale (SDS), Depression Anxiety Stress Scales-12 (DASS-12), and Substance Use Risk Profile Scale (SURPS). Smoking status was documented for all participants. Current smokers were asked to complete Fagerström Test for Nicotine Dependence questionnaire (FTND).

Results

This study included 442 patients with primary headache disorders, of whom 150 had MOH and 292 did not. Patients with MOH (n = 150) reported significantly higher monthly headache days (MHD), acute medication days (AMD), HIT-6, DASS-12, and SURPS scores than those without MOH (n = 292) (all P-values < 0.001). Smoking prevalence and FTND scores were significantly higher among MOH patients than those without MOH (all P-values < 0.001). Smokers demonstrated higher MHD, AMD, prevalence of MOH, DASS-12, and SURPS scores than non-smokers (all P-values < 0.05). Among smokers, FTND correlated positively with MHD, AMD, HIT-6, DASS-12, and SURPS (all P-values < 0.001). In patients with MOH, SDS scores showed positive correlations with AMD, HIT-6, DASS-12, and SURPS (all P-values < 0.05).

Conclusion

Severity of dependence on analgesics in patients with MOH is strongly associated with headache burden, nicotine dependence, psychological distress, and addiction-related personality traits.

Graphical abstract

This is a visual representation of the abstract.

Keywords

medication-overuse headache smoking nicotine dependence dependence on acute medications substance use risk

Introduction

Medication-overuse headache (MOH) is a challenging and disabling condition, defined as a headache occurring on ≥15 days per month in patients with a pre-existing primary headache disorder, developing as a consequence of the regular overuse of acute or symptomatic headache medications for more than three months, and eventually leading to paradoxical worsening of headache frequency and severity.¹ MOH is estimated to affect approximately 63 million people, imposing a significant financial burden on the health care system.²

Hagen, Linde³ identified smoking as a distinct risk factor for MOH based on an 11-year follow-up study. Nevertheless, the detailed mechanism underpinning the association between smoking and MOH has not been explored.

In general, smoking is a highly addictive behavior that certainly engages brain addiction-related pathways.⁴ Likewise, the core behavioral display of MOH is loss of control over the use of painkillers, involving the neurobiological pathway of drug dependence.⁵ Accordingly, MOH is placed within the substance-related disorders spectrum.⁶

From another perspective, smoking is linked to prevalent psychiatric comorbidities, including depression, anxiety, and stress, that in turn reinforce the cycle of smoking behavior.⁷ Congruently, depression and anxiety disorders can lower the pain threshold and amplify perception of pain (central sensitization), which can eventually cause MOH.^8,9

Shared neurobiological, genetic, and environmental factors drive this bidirectional relationship between MOH and psychiatric comorbidities. Aletred serotonergic and noradrenergic systems, brain reward systems (dopaminergic), and glutamate hyperexcitability are key overlapping neurochemical mechanisms.^10,11 On the other hand, MOH represents a state of chronic pain, which triggers the hypothalamic-pituitary-adrenal (HPA) axis, which is strongly linked to the development of anxiety and emotional dysregulation.¹² Besides the functional brain alterations, there is also an overlapping structural alteration. Reduced Gray Matter Volume (GMV) in areas responsible for emotional processing, such as the prefrontal cortex, hippocampus, and amygdala, was observed in patients with chronic pain conditions.¹³ Finally, there is a substantial shared genetic liability between MOH and mental health issues, which predispose individuals to both conditions.¹⁴ The primary objectives of the present study were to assess the frequency of smoking, level of nicotine dependence, psychological profile, and headache burden in patients with MOH compared to those without MOH.

Methods

Study design

This multicenter cross-sectional observational study was conducted on 442 patients diagnosed with primary headache disorders according to International Classification of Headache Disorders, 3rd edition (ICHD-3).¹⁵ Patients were consecutively recruited from specialized headache centers at four university hospitals in Egypt: Kasr Al Ainy (Cairo university), Fayoum University, Ain Shams university, and Al Azhar university. Consecutive recruitment was used to minimize selection bias. Patient enrollment was done between March 2025 and November 2025. This study is reported in accordance with the STROBE guidelines for multicenter cross-sectional study.

Eligibility criteria

Patients aged 18 years or older who fulfilled the ICHD-3 diagnostic criteria for primary headache disorders, with or without coexisting medication-overuse headache (MOH),¹⁵ were eligible for inclusion. Medication overuse was defined as the regular intake of acute headache medications on ≥10 days per month for triptans, ergotamines, opioids, or combination analgesics, and on ≥ 15 days per month for simple analgesics such as paracetamol or NSAIDs, for more than three months. . For the cluster headache subgroup, we included only patients with chronic cluster headache and patients with episodic cluster headache who were in an active bout lasting at least one month at the time of assessment. Patients with episodic cluster headache who presented at the very beginning of a bout were not included, as meaningful estimation of monthly headache days (MHD), acute medication days (AMD), and Headache Impact Test-6 (HIT-6) scores would not have been feasible at such an early stage.

The following patients were excluded from the study: former smokers, patients using smoked tobacco products other than cigarettes (e.g., waterpipe or vapes), drug abusers, patients with major psychiatric disorders (e.g., psychosis or major depression) that could interfere with reliable assessment, and patients with chronic medical illness that requires regular use of analgesics or impacts psychological status. Pregnant patients were also excluded.

Clinical assessment

All participants underwent a comprehensive face-to-face clinical assessment conducted by a trained neurologist. Collected data included demographics, body mass index (BMI), type of primary headache disorder according to ICHD-III,¹⁵ disease duration, monthly headache days (MHD), and acute medication days (AMD), defined as the number of days per month on which acute headache medications were used.

Smoking status was documented for all participants. Current smokers were asked to report the average number of cigarettes smoked per day. To explore patients’ perceptions of the relationship between cigarette smoking and headache, current smokers were additionally asked a structured set of questions addressing: (i) the primary reasons for smoking, (ii) whether patients noticed headache onset following smoking, (iii) whether they smoked to relieve headache attacks, and (iv) whether they intentionally avoided smoking because it triggered or worsened headache.

The severity of nicotine dependence in smokers was assessed using the Fagerström Test for Nicotine Dependence (FTND). It is a six-item questionnaire that demonstrated good reliability and validity in the assessment of the degree of physical dependence on nicotine. The total score ranges from 0 to 10, with higher scores indicating greater nicotine dependence.¹⁶

All participants, irrespective of smoking status, were asked to complete a battery of validated self-administered questionnaires:

Headache Impact Test–6 (HIT-6)¹⁷: It is a 6-item scale designed to assess the impact of headache on quality of life over the preceding month. Total score ranges from 36 to 78, with higher scores indicating greater headache-related disability.

Severity of Dependence Scale (SDS)¹⁸: It is a brief, easily administered scale originally designed to assess the severity of psychological dependence across various substances. In the context of headache research, SDS has been widely used to evaluate dependence-like behaviors associated with the overuse of acute headache medications which constitute a core feature of MOH.¹⁹ The scale consists of 5 items explicitly concerned with impaired control, preoccupation and anxieties about drug use. Each item is rated on a 4-point Likert scale (0 to 3) yielding a total score ranging from 0 to 15, with higher scores indicating greater severity of dependence.

Depression Anxiety Stress Scales–12 (DASS-12)²⁰: It comprises 12 items equally distributed across three subscales: depression, anxiety, and stress (four items per subscale). Each item is rated on a 4-point Likert scale (0 to 3). The total score ranges from 0 to 21 with higher scores denote greater symptom severity.

Substance Use Risk Profile Scale (SURPS)²¹: It is designed to assess four personality traits associated with vulnerability to addictive behaviors (hopelessness, anxiety sensitivity, impulsivity, and sensation seeking). In headache research, it may provide insight into personality-related vulnerability to medication overuse. It comprises 23 items, each item is rated on a 4-point Likert scale (1 to 4) with higher scores indicating greater overall personality-based vulnerability for addictive behaviors.

Outcome

Primary outcomes

Frequency of smoking and level of nicotine dependence (FTND) in MOH vs. non-MOH patients.

Differences in headache burden (MHD, AMD, HIT-6) and psychological profile (DASS-12, SDS, SURPS) between patients with and without MOH and between smokers and non-smokers.

Secondary outcomes

Correlations between nicotine dependence (FTND) and both headache burden and psychological characteristics of smokers with primary headache disorders.

Correlations between severity of dependence on acute headache medications (SDS) and both headache burden and psychological profile of patients with MOH.

Ethics statement

Written informed consent was obtained from all participants included in the study. Data were confidential and anonymous. Ethical approval was obtained from the Scientific Research Ethics Committee of the Faculty of Medicine, Fayoum University (Approval number: R 786).

Sample size

The sample size was calculated using EpiCalc 2000, version 1.02, 1997. Based on 51.4% prevalence rate of primary headache disorders in Fayoum Governorate in Egypt,²² a null hypothesis of 44.5%, and an alpha level of significance of 0.05, a total sample size of at least 408 participants was required to achieve a statistical power of 80.0%.

Statistical methods

Data were analyzed using SPSS version 25 (IBM Corp., Armonk, NY, USA). The Kolmogorov–Smirnov test was used to test the normality of data. Quantitative data such as age, BMI, disease duration, MHD, AMD, HIT-6, SDS, DASS-12, SURPS, and FTCD were expressed as median (IQR). Categorical data such as sex, type of headache, number of cigarettes/day, and beliefs about the relationship between smoking and headaches were expressed as number (%). Mann-Whitney U-test was used to compare between patients with and without MOH and between smokers and non-smokers in quantitative variables, whereas chi-square test was used to compare between these groups in terms of categorical variables. Spearman correlation was used to correlate FTCD and SDS with age, BMI, disease duration, MHD, AMD, HIT-6, DASS-12, and SURPS. A multivariable logistic regression analysis was done to identify factors associated with MOH. P-value < 0.05 was considered statistically significant. All tests were two-tailed.

Results

Demographic and clinical characteristics of patients with and without MOH

This cross-sectional study included 442 patients with primary headache disorders: 150 patients with MOH and 292 patients without MOH. No statistically significant differences were found between both groups in terms of age (P-value = 0.420), sex (P-value = 0.192), BMI (P-value = 0.472), or the type and duration of primary headache disorders (P-value = 0.777, 0.216 respectively). However, patients with MOH reported significantly higher MHD (20 vs. 7, P-value < 0.001), AMD (17.5 vs. 5, P-value < 0.001), and HIT-6 total scores (65 vs. 60, P-value < 0.001) than those without MOH (Table 1).

Table 1.

Demographics and clinical characteristics of patients with and without MOH.

		Patients with MOH (n = 150)	Patients without MOH (n = 292)	P-value
Age [median (IQR)]		34 (27–41)	34 (28.25–40)	0.420
Sex [n (%)]	Males	56 (37.3%)	91 (31.2%)	0.192
Sex [n (%)]	Females	94 (62.7%)	201 (68.8%)	0.192
BMI [median (IQR)]		27.46 (24.43–30.93)	26.99 (24.24–30.49)	0.472
Type of primary headache disorder [n (%)]	Tension	51 (34.0%)	90 (30.8%)	0.777
	Migraine	89 (59.3%)	180 (61.6%)
	Cluster	10 (6.7%)	22 (7.5%)
Duration of primary headache disorder in years [median (IQR)]		3 (2–8)	4 (2–8)	0.216
Duration of MOH in years [median (IQR)]		1 (0.5–3)	-	=
MHD [median (IQR)]		20 (15–30)	7 (4–10)	<0.001*
AMD [median (IQR)]		17.5 (15–25)	5 (2–7)	<0.001*
HIT-6 [median (IQR)]		65 (61.75–69)	60 (56–64)	<0.001*
SDS [median (IQR)]		9 (7–12)	-	-
DASS-12 [median (IQR)]	DASS-D (depression)	4 (2–8)	3 (1–4)	<0.001*
	DASS-A (anxiety)	6 (4–8.25)	4 (2–6)	<0.001*
	DASS-S (stress)	7 (5–9)	4 (3–7)	<0.001*
	Total score	18 (11–24)	12 (6.25–17)	<0.001*
SURPS [median (IQR)]	Hopelessness	15 (12.75–19)	14 (12–16)	<0.001*
	Anxiety sensitivity	15 (13–16)	14 (12–16)	0.162
	Impulsivity	13 (10–16)	12 (10–14)	<0.001*
	Sensation seeking	13 (11–16)	12.5 (10–15)	0.026*
	Total score	56 (50–64)	52.5 (45.25–58)	<0.001*
Number of cigarettes/day [n (%)]	Non-smokers	104 (69.3%)	250 (85.6%)	<0.001*
	Less than 10	6 (4.0%)	26 (8.9%)
	11–20	24 (16.0%)	11 (3.8%)
	21–30	12 (8.0%)	2 (0.7%)
	More than 31	4 (2.7%)	3 (1.0%)
FTND [median (IQR)]		6 (4–9)	3 (2–5)	<0.001*

AMD: Acute Medication Days, BMI: Body mass index, DASS-12: Depression Anxiety Stress Scales–12, FTND: Fagerström Test for Nicotine Dependence, HIT-6: Headache Impact Test–6, MHD: Monthly Headache Days, MOH: Medication-overuse headache, SDS: Severity of Dependence Scale, SURPS: Substance Use Risk Profile Scale.

*P-value < 0.05 is considered significant.

Psychological profile of the included patients

Patients with MOH had significantly higher DASS-12 depression scores (4 vs. 3, P-value < 0.001), DASS-12 anxiety scores (6 vs. 4, P-value < 0.001), DASS-12 stress scores (7 vs. 4, P-value < 0.001), and DASS-12 total score (18 vs. 12, P-value < 0.001) in comparison to patients without MOH (Table 1).

Similarly, SURPS scores were significantly higher in MOH patients for hopelessness score (15 vs. 14, P-value < 0.001), impulsivity score (13 vs. 12, P-value < 0.001), sensation seeking score [13 vs. 12.5, p = 0.026], and SURPS total score (56 vs. 52.5, P-value < 0.001) than patients without MOH. Anxiety sensitivity did not differ significantly (P-value = 0.162) (Table 1).

Smoking status and patient beliefs regarding the relationship between smoking and headaches

Smoking status differed significantly between groups (P-value < 0.001). Among MOH patients, 30.7% were smokers compared to 14.4% of non-MOH patients. Higher cigarette consumption was observed in MOH patients (≥21 cigarettes/day: 10.7% vs. 1.7%). FTND scores were significantly higher in MOH patients (6 vs. 3, P-value < 0.001) (Table 1).

Among the 88 smokers identified, the primary motivations for smoking were habit (94.3%), stress relief (88.6%), concentration (72.7%). and to relieve headaches (68.2%). When asked about the temporal relationship between smoking and headache, only 9.1% reported that headaches sometimes started after smoking, while 58.0% were unsure. Regarding the relieving effect of smoking on headaches, 3.4% reported “always,” 23.9% “often,” and 47.7% “sometimes.” Only a small minority of smokers (6.8%) reported always avoiding smoking because it triggered or worsened their headache symptoms, while 50% stated they never avoided it for that reason (Table 2).

Table 2.

Beliefs about the relationship between smoking and headaches.

		Smokers (n = 88)
Why do you smoke? [n (%)]	Stress relief	78 (88.6%)
	Habit	83 (94.3%)
	Social reasons	8 (9.1%)
	To concentrate	64 (72.7%)
	To relieve headache	60 (68.2%)
	Pleasure	19 (21.6%)
Do you notice your headache starts after smoking? [n (%)]	Sometimes	8 (9.1%)
	No	29 (33%)
	Not sure	51 (58.0%)
Do you smoke to relieve a headache? [n (%)]	Always	3 (3.4%)
	Often	21 (23.9%)
	Sometimes	42 (47.7%)
	Rarely	9 (10.2%)
	Never	13 (14.8%)
Do you avoid smoking because it triggers or worsens headache? [n (%)]	Yes	6 (6.8%)
	Sometimes	38 (43.2%)
	No	44 (50%)

Clinical and psychological profile of patients in relation to their smoking status

Smokers had significantly higher MHD (15 vs. 10, P-value = 0.032), AMD (15 vs. 6, P-value < 0.001), and prevalence of MOH (52.3% vs. 29.4%; P-value < 0.001) in comparison to those who have never smoked. SDS scores were slightly higher in smokers than non-smokers (10 vs. 9), though not statistically significant (P-value = 0.063). DASS-12 anxiety scores (6 vs. 4, P-value < 0.001), stress scores (7 vs. 5, P-value = 0.001), and total scores (17 vs. 12, P-value = 0.002) were significantly higher in smokers than non-smokers. Similarly, smokers demonstrated significantly higher hopelessness scores (16 vs 14, P-value < 0.001), anxiety sensitivity scores (15 vs 14, P-value = 0.005), impulsivity scores (14 vs 12, P-value < 0.001), sensation seeking scores (13 vs 12, P-value = 0.005), and total SURPS score (58 vs 53, P-value < 0.001) in comparison to those who have never smoked (Table 3).

Table 3.

Clinical and psychological profile of the included patients in relation to their smoking status.

		Smokers (n = 88)	never-smoked (n = 354)	P-value
MHD [median (IQR)]		15 (6–20)	10 (5–20)	0.032*
AMD [median (IQR)]		15 (5–20)	6 (3–15)	<0.001*
HIT-6 [median (IQR)]		62 (58–66)	62 (57–66)	0.380
MOH [n (%)]		46 (52.3%)	104 (29.4%)	<0.001*
SDS [median (IQR)]		10 (8–12)	9 (8–11)	0.063
DASS-12 [median (IQR)]	DASS-D (depression)	4 (2–7.0000	3 (1–5)	0.070
	DASS-A (anxiety)	6 (3.25–9)	4 (2–7)	<0.001*
	DASS-S (stress)	7 (4–9)	5 (3–7)	0.001*
	Total score	17 (9–24)	12 (7–19)	0.002*
SURPS [median (IQR)]	Hopelessness	16 (14–20)	14 (12–16)	<0.001*
	Anxiety sensitivity	15 (14–16)	14 (12–16)	0.005*
	Impulsivity	14 (12–16)	12 (10–14)	<0.001*
	Sensation seeking	13 (12–16)	12 (10–15)	0.005*
	Total score	58 (52–66)	53 (46–59)	<0.001*

AMD: Acute Medication Days, DASS-12: Depression Anxiety Stress Scales–12, HIT-6: Headache Impact Test–6, MHD: Monthly Headache Days, MOH: Medication-overuse headache, SDS: Severity of Dependence Scale, SURPS: Substance Use Risk Profile Scale.

*P-value < 0.05 is considered significant.

A subgroup analysis of cluster headache patients was conducted to examine their clinical and psychological profile in relation to their smoking status. The results revealed that cluster headache patients who smoked demonstrated significantly higher AMD (P-value = 0.046), SDS total score (P-value = 0.037), and SURPS total score (P-value = 0.019) compared to those who have never smoked (Table 4).

Table 4.

Clinical and psychological profile of patients with cluster headache in relation to their smoking status.

		Cluster headache patients who smoke (n = 16)	Cluster headache patients who never smoked (n = 16)	P-value
MHD [median (IQR)]		12.5 (6.25–28.75)	15 (4–30)	0.731
AMD [median (IQR)]		12 (5.25–28.75)	4.5 (2.25–14)	0.046*
HIT-6 [median (IQR)]		64.5 (58–70.5)	61.5 (59.25–66)	0.584
SDS [median (IQR)]		12 (9–12)	7 (4 - .)	0.037*
DASS-12 [median (IQR)]	DASS-D (depression)	2.5 (1–7.25)	4 (2–6)	0.469
	DASS-A (anxiety)	5.5 (3–8.75)	4 (2.25–7)	0.287
	DASS-S (stress)	6.5 (4–8)	5 .(3.25–8)	0.389
	Total score	14 (8–23.25)	13.5 (10–20.75)	0.865
SURPS [median (IQR)]	Hopelessness	16.5 (14.25–19.5)	14 (13–15.75)	0.006*
	Anxiety sensitivity	14.5 (12.5–16)	12.5 (10–15)	0.043*
	Impulsivity	14 (12–15.75)	11 (9–13.5)	0.019*
	Sensation seeking	13.5 (12–16.75)	12 (7.5–15.5)	0.233
	Total score	57 (54–64.25)	45.5 (43.25–59)	0.019*

AMD: Acute Medication Days, DASS-12: Depression Anxiety Stress Scales–12, HIT-6: Headache Impact Test–6, MHD: Monthly Headache Days, SDS: Severity of Dependence Scale, SURPS: Substance Use Risk Profile Scale.

*P-value < 0.05 is considered significant.

Correlations between nicotine dependence and clinical characteristics of smokers

FTND total scores in smokers correlated negatively with age (r = –0.215, p = 0.044). Whereas, there were statistically significant positive correlations between FTND total scores and MHD (r = 0.520, P-value < 0.001), AMD (r = 0.505, P-value < 0.001), HIT-6 total scores (r = 0.384, P-value < 0.001), DASS-12 total scores (r = 0.613, P-value < 0.001), and SURPS total scores (r = 0.611, P-value < 0.001) (Table 5).

Table 5.

Correlations between FTND in smokers and their demographics and clinical characteristics.

	FTND
	(r) Coef.	P-value
Age	−0.215	.044*
BMI	0.006	0.954
Duration of primary headache disorders in years	0.130	0.227
MHD	0.520	<0.001*
AMD	0.505	<0.001*
HIT-6 total score	0.384	<0.001*
DASS-12 total score	0.613	<0.001*
SURPS total score	0.611	<0.001*

(r) Coef.: Spearman correlation coefficient.

*P-value < 0.05 is considered significant.

Correlations between severity of dependence on medications and clinical characteristics of MOH patients

There were statistically significant positive correlations between SDS total scores in MOH patients and duration of MOH (r = 0.183, P-value = 0.025), AMD (r = 0.395, P-value < 0.001), HIT-6 total scores (r = 0.342, P-value < 0.001), DASS-12 total scores (r = 0.270, P-value = 0.001), and SURPS total scores (r = 0.242, P-value = 0.003) (Table 6).

Table 6.

Correlations between SDS in patients with MOH and their demographics and clinical characteristics.

	SDS
	(r) Coef.	P-value
Age	−0.005	0.952
BMI	−0.107	0.193
Duration of MOH	0.183	0.025*
MHD	0.153	0.061
AMD	0.395	<0.001*
HIT-6 total score	0.342	<0.001*
DASS-12 total score	0.270	0.001*
SURPS total score	0.242	0.003*
FTND total score	0.083	0.582

(r) Coef.: Spearman correlation coefficient.

*P-value < 0.05 is considered significant.

Factors associated with MOH

A multivariable logistic regression analysis was done to identify factors associated with MOH. The independent variables included in the model were duration of the primary headache disorder, headache type, MHD, smoking status, HIT-6 total score, DASS-12 total score, and SURPS total score. In this adjusted model, smoking remained significantly associated with MOH (B = 1.132, OR = 3.101, 95% CI: 1.468–6.553, P-value = 0.003). In addition, MHD (OR = 1.200, 95% CI: 1.157–1.245, P-value < 0.001), HIT-6 total score (OR = 1.065, 95% CI: 1.017–1.115, P-value = 0.008), and DASS-12 total score (OR = 1.042, 95% CI: 1.001–1.085, P-value = 0.044) were independently associated with MOH. Headache type was also significantly associated with MOH, with both tension-type headache (OR = 4.309, 95% CI: 1.284–14.459, P-value = 0.018) and migraine (OR = 3.675, 95% CI: 1.135–11.898, P-value = 0.030) showing significant associations in the model (Table 7).

Table 7.

Factors associated with MOH.

		B	Wald chi square	P-value	Odds ratio	95% C.I. for EXP(B)
		B	Wald chi square	P-value	Odds ratio	Lower	Upper
Duration of primary headache disorder in years		−0.009	0.111	0.739	0.991	0.941	1.044
Type of headache	Tension headache	1.461	5.592	0.018*	4.309	1.284	14.459
Type of headache	Migraine	1.301	4.714	0.030*	3.675	1.135	11.898
MHD		0.182	94.194	< 0.001*	1.200	1.157	1.245
Smoking		1.132	8.792	0.003*	3.101	1.468	6.553
HIT-6 total score		0.063	7.090	0.008*	1.065	1.017	1.115
DASS-12 total score		0.041	4.056	0.044*	1.042	1.001	1.085
SURPS total score		0.010	0.335	0.563	1.010	0.976	1.045
Constant		-9.849	29.965	0.000	0.000

DASS-12: Depression Anxiety Stress Scales–12, HIT-6: Headache Impact Test–6, MHD: Monthly Headache Days, MOH: Medication-overuse headache, SURPS: Substance Use Risk Profile Scale.

*P-value < 0.05 is considered significant.

Discussion

Previous studies indicate that MOH is frequently associated with unhealthy lifestyle behaviors, greater psychological distress, and maladaptive personality traits.^23–27 Smoking has been identified as a risk factor for the development and relapse of medication overuse in longitudinal and follow-up studies.^28,29 Elevated levels of anxiety and depressive symptoms are consistently reported in affected patients,^23,30 along with increased impulsivity and traits related to substance-use vulnerability.^25,31

To our knowledge, the current study is the first to provide a multidimensional clinical and psychosocial evaluation of patients with MOH, with particular emphasis on the relationship between smoking and MOH, allowing for a more comprehensive understanding of the interplay between smoking, psychological factors, and medication dependence in MOH.

Patients with MOH in our study experienced greater headache-related disability and psychological distress, as shown by higher HIT-6 and DASS-12 scores (depression, anxiety, stress, and total). These findings align with prior studies, including Sarchielli et al.,²³ who reported that MOH patients often present with more complex psychiatric profiles, such as moderate to severe anxiety and depression. Moreover, a cross-sectional survey conducted in 10 countries of the European Union found that chronic migraine patients who developed MOH had higher rates of depression and anxiety than those who did not.²⁴

Higher levels of psychological distress seen in patients with MOH may be attributed to possible interconnected mechanisms that imply a bidirectional relationship.³² Psychological distress, including stress, depression, and anxiety symptoms, may trigger headaches and predispose individuals to increased reliance on acute headache medications as a maladaptive coping strategy, thereby increasing the risk of medication overuse and MOH development.^33–35 On the other hand, long-term acute medication use increases neuronal excitability in the amygdala complex, which may contribute to the development of anxiety and depression in MOH.³⁶ Chronic medication use can also impair descending inhibitory pain pathways and cause central sensitization, thereby heightening both pain perception and its associated emotional distress. Furthermore, dysregulation of stress-response systems, such as the hypothalamic–pituitary–adrenal axis, may further increase psychological distress in individuals with persistent headache conditions.^12,37–40

In addition to psychological distress, personality characteristics may also influence the vulnerability to MOH. This study found that people with MOH had higher SURPS scores in hopelessness, impulsivity, and sensation-seeking, as well as higher total scores, compared to those without MOH. These findings suggest that people with MOH may have personality traits that make them more likely to take risks or act compulsively.⁴¹ This interpretation is consistent with neurobiological findings in MOH, including orbitofrontal hypometabolism,⁴² ventromedial prefrontal cortex dysfunction,⁴³ changes in midbrain and orbitofrontal gray matter,^44,45 and altered resting-state connectivity related to reward processing and inhibition control.⁴⁵ Higher hopelessness in these patients may show a stronger tendency toward negative emotions and fewer effective coping mechanisms.^41,46,47 Higher impulsivity and sensation-seeking may also lead to reward-driven behaviors, like frequent medication use for headache relief.³¹ These results are similar to earlier studies^48–50 showing that certain personality traits, especially high impulsivity and emotional instability, are linked to a higher risk of MOH.

While psychological comorbidities are well established in patients with MOH, emerging evidence suggests that lifestyle factors, particularly tobacco use, may also play a meaningful role in shaping the clinical burden of MOH, influencing relapse risk, and interacting with behavioral dependence mechanisms.^25,29 These observations underscore the importance of addressing smoking in parallel with psychological comorbidities during both assessment and management. In the present study, our findings supported the growing perspective that tobacco use should be considered an integral component of the biopsychosocial framework underlying MOH pathophysiology and management, rather than merely a coincidental lifestyle habit.

Most of the smokers in the present study reported that they smoke out of habit (93.4%) and (88.6%) for stress relief, highlighting the behavioral and psychological motivations behind tobacco use in the primary headache disorder patient population. Smoking has been previously linked to an increased risk of MOH, which may be partly explained by interactions among maladaptive personality traits, psychological distress, and addictive behaviors.^29,50 More than 30 percent of our MOH patients were smokers, compared to only 14.4 percent of those without MOH. The frequency of MOH was also significantly higher among smokers than non-smokers (52.3% and 29.4%, respectively), and smoking remained significantly associated with MOH after adjustment. This further supports a strong association between tobacco use and medication overuse.

Although smoking is well known to be common among patients with cluster headache,^51,52 our study found no significant differences between smokers and non-smokers in headache burden. However, smokers had higher acute medication use, greater severity of dependency on acute medications, and more addictive personality traits, indicating an increased vulnerability to dependence-related behaviors rather than a true difference in underlying headache burden between smokers and non-smokers. These findings align with the broader literature suggesting that both smokers and cluster headache patients exhibit behavioral and neurobiological features overlapping with addiction and compulsive drug-seeking behavior, which can increase medication consumption independent of headache severity.^53–55

Among smokers, greater nicotine dependence was associated with higher headache frequency, increased acute medication use, greater headache-related disability, higher psychological distress, and elevated maladaptive personality traits. Patients with MOH also demonstrated higher cigarette consumption and greater nicotine dependence compared to those without MOH, indicating overlapping patterns of substance dependence, headache burden, and psychosocial vulnerability. These findings suggest that smoking in MOH patients may function as an unhealthy stress-coping mechanism and reflect a wider vulnerability tendency characterized by reward-seeking and compulsive behaviors. This profile could facilitate dependence on both nicotine and medication. Neurobiological research indicates that long-term use of nicotine and analgesics can modify the mesolimbic reward system, weaken inhibitory control,⁵⁶ and disturb stress-response pathways,⁵⁷ thus possibly reinforcing both smoking and excessive headache medication use.⁵⁸

These findings are consistent with prior evidence indicating that MOH is associated with unhealthy lifestyle behaviors and stress.^59,60 Woldeamanuel et al.⁶⁰ reported in a previous study that daily smoking, lack of physical activity, and obesity increase the risk of MOH, especially among those experiencing high stress. In our study, patients with MOH not only showed higher rates of smoking and greater nicotine dependence, but also higher levels of psychological distress. Although our study design limits causal conclusions, these findings align with the hypothesis that stress might influence the relationship between smoking and MOH, and it could contribute to headache chronicity and medication overuse.

It has to be mentioned that the relatively short reported duration of the primary headache disorder in the MOH patients in the present study may initially appear unexpected; however, this finding can be plausibly interpreted within the context of healthcare system constraints in Egypt. As a lower-middle-income country, access to effective preventive migraine therapies such as onabotulinumtoxinA and CGRP monoclonal antibodies is often limited because of high out-of-pocket costs and insufficient insurance reimbursement. Consequently, many patients remain undertreated with respect to preventive strategies and instead rely predominantly on acute medications to manage frequent attacks. This pattern may lead to persistently high headache frequency despite a relatively short disease duration and can accelerate progression to MOH.

This explanation is supported by a recent Egyptian real-world study demonstrating that systemic barriers, including limited insurance coverage and financial constraints, reduce access to preventive therapies and are associated with increased reliance on over-the-counter acute medications, thereby heightening the risk of MOH development.⁶¹

Strength and limitations

This multicenter study is the first to provide a comprehensive biopsychosocial assessment of MOH by concurrently evaluating headache impact, smoking habits, nicotine and medication dependence, psychological stress, and personality traits using validated tools. Additional correlations examined the association between dependence severity and clinical features and indicated a possible shared vulnerability mechanism for MOH and smoking. However, the study's cross-sectional nature precludes establishing causality among smoking, psychological factors, and MOH. In addition, reliance on self-reported data may introduce recall and reporting biases. Residual confounding by unmeasured psychosocial or lifestyle factors cannot be excluded and may have influenced the observed associations. Furthermore, smoking was assessed only in terms of cigarette use, while other forms of tobacco consumption (e.g., waterpipe or shisha) were not separately evaluated. Another limitation is the lack of detailed lifetime smoking history, including age at initiation and total duration of smoking, as the study focused primarily on current smoking behavior and nicotine dependence severity. Prospective longitudinal studies incorporating comprehensive smoking history are needed to better clarify the temporal relationship between smoking and the development of MOH.

Conclusion

This study demonstrates that patients with MOH experience more severe headache, higher psychological distress, maladaptive personality traits, and greater smoking rates compared to patients without MOH. The absence of significant differences in age, sex, and BMI between patients with and without MOH reinforces the credibility of our findings and supports that the observed differences between the two groups are unlikely to be attributed to demographic factors. Both nicotine dependence and the severity of medication dependence are significantly linked to greater headache burden, emotional distress, and reward-related personality traits, suggesting a possible common vulnerability profile. These findings imply that smoking, psychological distress, addiction-related traits, and MOH are closely interrelated dimensions within a shared biopsychosocial vulnerability profile, rather than isolated factors. Accordingly, MOH may be better understood not only as a chronic headache disorder, but also as a biopsychosocial and dependence-related disorder in which psychological, behavioral, and neurobiological factors interact. Clinically, this highlights the need for comprehensive management strategies that address psychological distress, personality risk factors, and smoking behavior to identify high-risk patients, optimize outcomes, and prevent relapses.

Clinical implications

Smoking and nicotine dependence are significantly more prevalent in patients with MOH and are associated with greater headache burden, psychological distress, and addiction-related personality traits.

Nicotine dependence correlates positively with headache frequency, acute medication use, headache-related disability, psychological distress, and addiction-related personality traits.

The severity of dependence on analgesics in MOH is closely related to headche burden, psychological distress and addiction-related personality traits.

Footnotes

Acknowledgements

The authors used [Qwen 2.5 max and ChatGPT plus] in order to check writing mistakes and polish the manuscript language. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication. Authors report that the content has not been published or submitted for publication elsewhere.

ORCID iDs

Mona Hussein

Amr Hassan

Rehab Magdy

Ahmed Dahshan

Nourhan Abdelmohsen Taha

Ramez Reda Moustafa

Anter Mothenna Abdullah Nasser

Ethical considerations

Ethical approval was obtained from the Scientific Research Ethics Committee of the Faculty of Medicine, Fayoum University (Approval number: R 786). Data were confidential and anonymous.

Consent to participate

Written informed consent was obtained from all participants included in the study.

Consent for publication

The research article was submitted for publication in journal Cephalalgia.

Author contributions

MH participated in the study design, collection, analysis and interpretation of data and helped to draft manuscript. AH participated in the study design, collection of data and helped to draft manuscript. RM participated in the study design, interpretation of data and helped to draft manuscript. AD participated in the collection of data and helped to draft manuscript. OY participated in the collection of data and helped to draft manuscript. MA participated in the collection of data and helped to draft manuscript. NT participated in the collection of data and helped to draft manuscript. AE participated in the collection of data and helped to draft manuscript. MF participated in the collection of data and helped to draft manuscript. NM participated in the collection of data and helped to draft manuscript. AE participated in the collection of data and helped to draft manuscript. RM participated in the collection of data and helped to draft manuscript. AN participated in the collection of data and helped to draft manuscript. AE participated in the study design, interpretation of data and helped to draft manuscript. All authors read and approved the final manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

Authors report that the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Open practices

Not applicable.

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