Trigeminal neuralgia and its comorbidities: A nationwide disease trajectory study

Jacob Worm; Isabella Friis Jørgensen; Ólafur Birgir Davídsson; Henrik Hjalgrim; Timo Röder; Sisse Rye Ostrowski; Ole Birger Pedersen; Christian Erikstrup; Mie Topholm Bruun; Bitten Aagaard Jensen; Erik Sørensen; Henrik Ullum; Gyða Björnsdóttir; Thorgeir Thorgeirsson; Hreinn Stefánsson; Ólafur Árni Sveinsson; Kari Stefansson; Henrik Winther Schytz; Lars Bendtsen; Søren Brunak; Thomas Folkmann Hansen; Stine Maarbjerg; Karina Banasik; Jacob Bay; Jens Kjærgaard Boldsen; Thorsten Brodersen; Søren Brunak; Kristoffer Burgdorf; Mona Ameri Chalmer; Maria Didriksen; Khoa Manh Dinh; Joseph Dowsett; Christian Erikstrup; Bjarke Fenstraa; Frank Geller; Daniel Gudbjartsson; Thomas Folkmann Hansen; Lotte Hindhede; Henrik Hjalgrim; Rikke Louise Jacobsen; Gregor Jemec; Bitten Aagaard Jensen; Katrine Kaspersen; Bertram Dalskov Kjerulff; Lisette Kogelman; Margit Anita Hørup Larsen; Ioannis Louloudis; Agnete Lundgard; Susan Mikkelsen; Christina Mikkelsen; Ioanna Nissen; Mette Nyegaard; Sisse Rye Ostrowski; Ole Birger Pedersen; Alexander Pil Henriksen; Palle Duun Rohde; Klaus Rostgaard; Michael Schwinn; Kari Stefansson; Hreinn Stefánsson; Erik Sørensen; Unnur Porsteinsdóttir; Lise Wegner Thørner; Mie Topholm Brun; Henrik Ullum; Thomas Werge; David Westergaard

doi:10.1097/j.pain.0000000000003428

Trigeminal neuralgia and its comorbidities: A nationwide disease trajectory study

Jacob Worm, Isabella Friis Jørgensen, Ólafur Birgir Davídsson, Henrik Hjalgrim, Timo Röder, Sisse Rye Ostrowski, Ole Birger Pedersen, Christian Erikstrup, Mie Topholm Bruun, Bitten Aagaard Jensen, Erik Sørensen, Henrik Ullum, Gyða Björnsdóttir, Thorgeir Thorgeirsson, Hreinn Stefánsson, Ólafur Árni Sveinsson, Kari Stefansson, Henrik Winther Schytz, Lars Bendtsen, Søren BrunakThomas Folkmann Hansen, Stine Maarbjerg^*, Karina Banasik, Jacob Bay, Jens Kjærgaard Boldsen, Thorsten Brodersen, Søren Brunak, Kristoffer Burgdorf, Mona Ameri Chalmer, Maria Didriksen, Khoa Manh Dinh, Joseph Dowsett, Christian Erikstrup, Bjarke Fenstraa, Frank Geller, Daniel Gudbjartsson, Thomas Folkmann Hansen, Lotte Hindhede, Henrik Hjalgrim, Rikke Louise Jacobsen, Gregor Jemec, Bitten Aagaard Jensen, Katrine Kaspersen, Bertram Dalskov Kjerulff, Lisette Kogelman, Margit Anita Hørup Larsen, Ioannis Louloudis, Agnete Lundgard, Susan Mikkelsen, Christina Mikkelsen, Ioanna Nissen, Mette Nyegaard, Sisse Rye Ostrowski, Ole Birger Pedersen, Alexander Pil Henriksen, Palle Duun Rohde, Klaus Rostgaard, Michael Schwinn, Kari Stefansson, Hreinn Stefánsson, Erik Sørensen, Unnur Porsteinsdóttir, Lise Wegner Thørner, Mie Topholm Brun, Henrik Ullum, Thomas Werge, David Westergaard

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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Abstract

There is a limited understanding of risk factors and comorbidities in trigeminal neuralgia, a disease characterized by paroxysms of severe unilateral facial pain and a higher incidence in women. We aim to identify temporally associated comorbidities involving trigeminal neuralgia by analyzing nationwide disease trajectories. Using data from 7.2 million unique individuals in the Danish National Patient Register between 1994 and 2018, each individual diagnosed with trigeminal neuralgia was compared with 10,000 matched controls to identify co-occurring diseases. The sequential disease associations were identified in sex-stratified disease trajectories. A Cox-regression analysis investigated whether treatment with carbamazepine or oxcarbazepine, as compared with gabapentin, pregabalin, or lamotrigine, was associated with stroke risk. Finally, we investigated the stroke polygenic risk score and its association with stroke incidence in a subset of genotyped individuals with trigeminal neuralgia. We included 7141 individuals with trigeminal neuralgia (64.2% female, mean age at diagnosis 58.7 years) and identified 18 diseases associated with subsequent trigeminal neuralgia. After diagnosis, trigeminal neuralgia was associated with 9 diseases, including ischemic stroke (relative risk 1.55). Carbamazepine or oxcarbazepine treatment increased the ischemic stroke risk (hazard ratio 1.78; 95% confidence interval 1.47-2.17); however, the polygenic risk of stroke showed no association. In the Danish population, a trigeminal neuralgia diagnosis is temporally associated with 27 diseases revealed in systematic disease trajectories. Trigeminal neuralgia itself and its first-line treatment, but not a stroke polygenic risk score, was associated with an increased risk of ischemic stroke indicating that vascular risk factors should be routinely assessed in individuals with trigeminal neuralgia.

Original language	English
Journal	Pain
Volume	166
Issue	4
Pages (from-to)	879-887
Number of pages	9
ISSN	0304-3959
DOIs	https://doi.org/10.1097/j.pain.0000000000003428
Publication status	Published - Apr 2025

Keywords

Antiseizure medication
Cardiovascular disease
Cohort study
Comorbidity
Epidemiology
Facial pain
Ischemic stroke
Neuropathic pain
Risk factor

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10.1097/j.pain.0000000000003428

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Worm, J., Jørgensen, I. F., Davídsson, Ó. B., Hjalgrim, H., Röder, T., Ostrowski, S. R., Pedersen, O. B., Erikstrup, C., Bruun, M. T., Jensen, B. A., Sørensen, E., Ullum, H., Björnsdóttir, G., Thorgeirsson, T., Stefánsson, H., Sveinsson, Ó. Á., Stefansson, K., Schytz, H. W., Bendtsen, L., ... Westergaard, D. (2025). Trigeminal neuralgia and its comorbidities: A nationwide disease trajectory study. Pain, 166(4), 879-887. https://doi.org/10.1097/j.pain.0000000000003428

@article{fbc3680a0dbf49bb993ecec16c9a19c7,

title = "Trigeminal neuralgia and its comorbidities: A nationwide disease trajectory study",

abstract = "There is a limited understanding of risk factors and comorbidities in trigeminal neuralgia, a disease characterized by paroxysms of severe unilateral facial pain and a higher incidence in women. We aim to identify temporally associated comorbidities involving trigeminal neuralgia by analyzing nationwide disease trajectories. Using data from 7.2 million unique individuals in the Danish National Patient Register between 1994 and 2018, each individual diagnosed with trigeminal neuralgia was compared with 10,000 matched controls to identify co-occurring diseases. The sequential disease associations were identified in sex-stratified disease trajectories. A Cox-regression analysis investigated whether treatment with carbamazepine or oxcarbazepine, as compared with gabapentin, pregabalin, or lamotrigine, was associated with stroke risk. Finally, we investigated the stroke polygenic risk score and its association with stroke incidence in a subset of genotyped individuals with trigeminal neuralgia. We included 7141 individuals with trigeminal neuralgia (64.2% female, mean age at diagnosis 58.7 years) and identified 18 diseases associated with subsequent trigeminal neuralgia. After diagnosis, trigeminal neuralgia was associated with 9 diseases, including ischemic stroke (relative risk 1.55). Carbamazepine or oxcarbazepine treatment increased the ischemic stroke risk (hazard ratio 1.78; 95% confidence interval 1.47-2.17); however, the polygenic risk of stroke showed no association. In the Danish population, a trigeminal neuralgia diagnosis is temporally associated with 27 diseases revealed in systematic disease trajectories. Trigeminal neuralgia itself and its first-line treatment, but not a stroke polygenic risk score, was associated with an increased risk of ischemic stroke indicating that vascular risk factors should be routinely assessed in individuals with trigeminal neuralgia.",

keywords = "Antiseizure medication, Cardiovascular disease, Cohort study, Comorbidity, Epidemiology, Facial pain, Ischemic stroke, Neuropathic pain, Risk factor",

author = "Jacob Worm and J{\o}rgensen, {Isabella Friis} and Dav{\'i}dsson, {{\'O}lafur Birgir} and Henrik Hjalgrim and Timo R{\"o}der and Ostrowski, {Sisse Rye} and Pedersen, {Ole Birger} and Christian Erikstrup and Bruun, {Mie Topholm} and Jensen, {Bitten Aagaard} and Erik S{\o}rensen and Henrik Ullum and Gy{\dh}a Bj{\"o}rnsd{\'o}ttir and Thorgeir Thorgeirsson and Hreinn Stef{\'a}nsson and Sveinsson, {{\'O}lafur {\'A}rni} and Kari Stefansson and Schytz, {Henrik Winther} and Lars Bendtsen and S{\o}ren Brunak and Hansen, {Thomas Folkmann} and Stine Maarbjerg and Karina Banasik and Jacob Bay and Boldsen, {Jens Kj{\ae}rgaard} and Thorsten Brodersen and S{\o}ren Brunak and Kristoffer Burgdorf and Chalmer, {Mona Ameri} and Maria Didriksen and Dinh, {Khoa Manh} and Joseph Dowsett and Christian Erikstrup and Bjarke Fenstraa and Frank Geller and Daniel Gudbjartsson and Hansen, {Thomas Folkmann} and Lotte Hindhede and Henrik Hjalgrim and Jacobsen, {Rikke Louise} and Gregor Jemec and Jensen, {Bitten Aagaard} and Katrine Kaspersen and Kjerulff, {Bertram Dalskov} and Lisette Kogelman and Larsen, {Margit Anita H{\o}rup} and Ioannis Louloudis and Agnete Lundgard and Susan Mikkelsen and Christina Mikkelsen and Ioanna Nissen and Mette Nyegaard and Ostrowski, {Sisse Rye} and Pedersen, {Ole Birger} and Henriksen, {Alexander Pil} and Rohde, {Palle Duun} and Klaus Rostgaard and Michael Schwinn and Kari Stefansson and Hreinn Stef{\'a}nsson and Erik S{\o}rensen and Unnur Porsteinsd{\'o}ttir and Th{\o}rner, {Lise Wegner} and Brun, {Mie Topholm} and Henrik Ullum and Thomas Werge and David Westergaard",

note = "Publisher Copyright: {\textcopyright} 2024 International Association for the Study of Pain.",

year = "2025",

month = apr,

doi = "10.1097/j.pain.0000000000003428",

language = "English",

volume = "166",

pages = "879--887",

journal = "Pain",

issn = "0304-3959",

publisher = "Lippincott Williams and Wilkins",

number = "4",

}

Worm, J, Jørgensen, IF, Davídsson, ÓB, Hjalgrim, H, Röder, T, Ostrowski, SR, Pedersen, OB, Erikstrup, C, Bruun, MT, Jensen, BA, Sørensen, E, Ullum, H, Björnsdóttir, G, Thorgeirsson, T, Stefánsson, H, Sveinsson, ÓÁ, Stefansson, K, Schytz, HW, Bendtsen, L, Brunak, S, Hansen, TF, Maarbjerg, S, Banasik, K, Bay, J, Boldsen, JK, Brodersen, T, Brunak, S, Burgdorf, K, Chalmer, MA, Didriksen, M, Dinh, KM, Dowsett, J, Erikstrup, C, Fenstraa, B, Geller, F, Gudbjartsson, D, Hansen, TF, Hindhede, L, Hjalgrim, H, Jacobsen, RL, Jemec, G, Jensen, BA, Kaspersen, K , Kjerulff, BD, Kogelman, L, Larsen, MAH, Louloudis, I, Lundgard, A, Mikkelsen, S, Mikkelsen, C, Nissen, I, Nyegaard, M, Ostrowski, SR, Pedersen, OB, Henriksen, AP, Rohde, PD, Rostgaard, K, Schwinn, M, Stefansson, K, Stefánsson, H, Sørensen, E, Porsteinsdóttir, U, Thørner, LW, Brun, MT, Ullum, H, Werge, T & Westergaard, D 2025, 'Trigeminal neuralgia and its comorbidities: A nationwide disease trajectory study', Pain, vol. 166, no. 4, pp. 879-887. https://doi.org/10.1097/j.pain.0000000000003428

TY - JOUR

T1 - Trigeminal neuralgia and its comorbidities

T2 - A nationwide disease trajectory study

AU - Worm, Jacob

AU - Jørgensen, Isabella Friis

AU - Davídsson, Ólafur Birgir

AU - Hjalgrim, Henrik

AU - Röder, Timo

AU - Ostrowski, Sisse Rye

AU - Pedersen, Ole Birger

AU - Erikstrup, Christian

AU - Bruun, Mie Topholm

AU - Jensen, Bitten Aagaard

AU - Sørensen, Erik

AU - Ullum, Henrik

AU - Björnsdóttir, Gyða

AU - Thorgeirsson, Thorgeir

AU - Stefánsson, Hreinn

AU - Sveinsson, Ólafur Árni

AU - Stefansson, Kari

AU - Schytz, Henrik Winther

AU - Bendtsen, Lars

AU - Brunak, Søren

AU - Hansen, Thomas Folkmann

AU - Maarbjerg, Stine

AU - Banasik, Karina

AU - Bay, Jacob

AU - Boldsen, Jens Kjærgaard

AU - Brodersen, Thorsten

AU - Brunak, Søren

AU - Burgdorf, Kristoffer

AU - Chalmer, Mona Ameri

AU - Didriksen, Maria

AU - Dinh, Khoa Manh

AU - Dowsett, Joseph

AU - Erikstrup, Christian

AU - Fenstraa, Bjarke

AU - Geller, Frank

AU - Gudbjartsson, Daniel

AU - Hansen, Thomas Folkmann

AU - Hindhede, Lotte

AU - Hjalgrim, Henrik

AU - Jacobsen, Rikke Louise

AU - Jemec, Gregor

AU - Jensen, Bitten Aagaard

AU - Kaspersen, Katrine

AU - Kjerulff, Bertram Dalskov

AU - Kogelman, Lisette

AU - Larsen, Margit Anita Hørup

AU - Louloudis, Ioannis

AU - Lundgard, Agnete

AU - Mikkelsen, Susan

AU - Mikkelsen, Christina

AU - Nissen, Ioanna

AU - Nyegaard, Mette

AU - Ostrowski, Sisse Rye

AU - Pedersen, Ole Birger

AU - Henriksen, Alexander Pil

AU - Rohde, Palle Duun

AU - Rostgaard, Klaus

AU - Schwinn, Michael

AU - Stefansson, Kari

AU - Stefánsson, Hreinn

AU - Sørensen, Erik

AU - Porsteinsdóttir, Unnur

AU - Thørner, Lise Wegner

AU - Brun, Mie Topholm

AU - Ullum, Henrik

AU - Werge, Thomas

AU - Westergaard, David

PY - 2025/4

Y1 - 2025/4

N2 - There is a limited understanding of risk factors and comorbidities in trigeminal neuralgia, a disease characterized by paroxysms of severe unilateral facial pain and a higher incidence in women. We aim to identify temporally associated comorbidities involving trigeminal neuralgia by analyzing nationwide disease trajectories. Using data from 7.2 million unique individuals in the Danish National Patient Register between 1994 and 2018, each individual diagnosed with trigeminal neuralgia was compared with 10,000 matched controls to identify co-occurring diseases. The sequential disease associations were identified in sex-stratified disease trajectories. A Cox-regression analysis investigated whether treatment with carbamazepine or oxcarbazepine, as compared with gabapentin, pregabalin, or lamotrigine, was associated with stroke risk. Finally, we investigated the stroke polygenic risk score and its association with stroke incidence in a subset of genotyped individuals with trigeminal neuralgia. We included 7141 individuals with trigeminal neuralgia (64.2% female, mean age at diagnosis 58.7 years) and identified 18 diseases associated with subsequent trigeminal neuralgia. After diagnosis, trigeminal neuralgia was associated with 9 diseases, including ischemic stroke (relative risk 1.55). Carbamazepine or oxcarbazepine treatment increased the ischemic stroke risk (hazard ratio 1.78; 95% confidence interval 1.47-2.17); however, the polygenic risk of stroke showed no association. In the Danish population, a trigeminal neuralgia diagnosis is temporally associated with 27 diseases revealed in systematic disease trajectories. Trigeminal neuralgia itself and its first-line treatment, but not a stroke polygenic risk score, was associated with an increased risk of ischemic stroke indicating that vascular risk factors should be routinely assessed in individuals with trigeminal neuralgia.

AB - There is a limited understanding of risk factors and comorbidities in trigeminal neuralgia, a disease characterized by paroxysms of severe unilateral facial pain and a higher incidence in women. We aim to identify temporally associated comorbidities involving trigeminal neuralgia by analyzing nationwide disease trajectories. Using data from 7.2 million unique individuals in the Danish National Patient Register between 1994 and 2018, each individual diagnosed with trigeminal neuralgia was compared with 10,000 matched controls to identify co-occurring diseases. The sequential disease associations were identified in sex-stratified disease trajectories. A Cox-regression analysis investigated whether treatment with carbamazepine or oxcarbazepine, as compared with gabapentin, pregabalin, or lamotrigine, was associated with stroke risk. Finally, we investigated the stroke polygenic risk score and its association with stroke incidence in a subset of genotyped individuals with trigeminal neuralgia. We included 7141 individuals with trigeminal neuralgia (64.2% female, mean age at diagnosis 58.7 years) and identified 18 diseases associated with subsequent trigeminal neuralgia. After diagnosis, trigeminal neuralgia was associated with 9 diseases, including ischemic stroke (relative risk 1.55). Carbamazepine or oxcarbazepine treatment increased the ischemic stroke risk (hazard ratio 1.78; 95% confidence interval 1.47-2.17); however, the polygenic risk of stroke showed no association. In the Danish population, a trigeminal neuralgia diagnosis is temporally associated with 27 diseases revealed in systematic disease trajectories. Trigeminal neuralgia itself and its first-line treatment, but not a stroke polygenic risk score, was associated with an increased risk of ischemic stroke indicating that vascular risk factors should be routinely assessed in individuals with trigeminal neuralgia.

KW - Antiseizure medication

KW - Cardiovascular disease

KW - Cohort study

KW - Comorbidity

KW - Epidemiology

KW - Facial pain

KW - Ischemic stroke

KW - Neuropathic pain

KW - Risk factor

UR - http://www.scopus.com/inward/record.url?scp=85206841828&partnerID=8YFLogxK

U2 - 10.1097/j.pain.0000000000003428

DO - 10.1097/j.pain.0000000000003428

M3 - Journal article

C2 - 39365662

AN - SCOPUS:85206841828

SN - 0304-3959

VL - 166

SP - 879

EP - 887

JO - Pain

JF - Pain

IS - 4

ER -

Trigeminal neuralgia and its comorbidities: A nationwide disease trajectory study

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