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Rejoinder to commentary by Drs. Boaz Musafia and Gilad Rosenberg

Published online by Cambridge University Press:  11 January 2022

Pei-Yin Pan Open the ORCID record for Pei-Yin Pan [Opens in a new window] ,
Samuele Cortese Open the ORCID record for Samuele Cortese [Opens in a new window]  and
Sven Bölte Open the ORCID record for Sven Bölte [Opens in a new window]
Pei-Yin Pan*
Affiliation:
Department of Women's and Children's Health, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Stockholm, Sweden
Samuele Cortese
Affiliation:
Faculty of Environmental and Life Sciences & Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, Centre for Innovation in Mental Health, School of Psychology, University of Southampton, Southampton, UK Solent NHS Trust, Southampton, UK Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, UK Hassenfeld Children's Hospital at NYU Langone, New York University Child Study Center, New York City, New York, USA
Sven Bölte
Affiliation:
Department of Women's and Children's Health, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Stockholm, Sweden Child and Adolescent Psychiatry, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden Curtin Autism Research Group, Curtin School of Allied Health, Curtin University, Perth, Western Australia
*
Author for correspondence: Pei-Yin Pan, E-mail: [email protected]
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Invited Letter Rejoinder
Information
Psychological Medicine , Volume 53 , Issue 9 , July 2023 , pp. 4286 - 4287
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Copyright
Copyright © The Author(s), 2022. Published by Cambridge University Press

We appreciate the commentary by Drs. Boaz Musafia and Gilad Rosenberg on our systematic review and meta-analysis of headache in attention-deficit/hyperactivity disorder (ADHD) (Pan et al., Reference Pan, Jonsson, Şahpazoğlu Çakmak, Häge, Hohmann, Nobel Norrman and Bölte2021). In view of the high consumption of caffeinated beverages among youths (Babu, Church, & Lewander, Reference Babu, Church and Lewander2008), the association between caffeine and paediatric headache is an issue which is potentially highly relevant. While we agree with the suggestion to consider caffeine withdrawal as a possible mechanism underlying headache among youths with ADHD, in our view additional evidence is needed on the links between caffeine withdrawal, administration of ADHD medications, and headache among children with ADHD. We provide here a concise overview of relevant literature to support our statement.

Caffeine consumption in youths with ADHD

Increased caffeine consumption has been indeed reported for adolescents with ADHD in some studies (Cusick, Langberg, Breaux, Green, & Becker, Reference Cusick, Langberg, Breaux, Green and Becker2020; Walker, Abraham, & Tercyak, Reference Walker, Abraham and Tercyak2010), and it might be associated with ADHD symptom severity (Martin et al., Reference Martin, Cook, Woodring, Burkhardt, Guenthner, Omar and Kelly2008). This raises the possibility for an attempt of ‘self-medication’ owing to the positive effects of caffeine on arousal and physical performance (Torres-Ugalde, Romero-Palencia, Roman-Gutierrez, Ojeda-Ramirez, & Guzman-Saldana, Reference Torres-Ugalde, Romero-Palencia, Roman-Gutierrez, Ojeda-Ramirez and Guzman-Saldana2020). Caffeine has also been considered an alternative treatment for ADHD symptoms, due to its decreasing effects on impulsivity, and improvement of executive performance (Leon, Reference Leon2000).

Caffeine has been shown to produce reinforcing effects and addictive properties via the striatal adenosine A2A- dopamine D2 receptor heteromer (Ferré, Reference Ferré2016). In addition, secondary reinforcement effects might emerge by the favours of caffeinated beverages (Myers & Izbicki, Reference Myers and Izbicki2006). Thus, another explanation for the higher consumption of caffeine in youths with ADHD might be dysregulation of reward pathways, which are associated with substance misuse (Grimm et al., Reference Grimm, van Rooij, Hoogman, Klein, Buitelaar, Franke and Plichta2021).

Caffeine withdrawal headache in children and adolescents

Although caffeine dependence in teenagers has been reported (Bernstein, Carroll, Thuras, Cosgrove, & Roth, Reference Bernstein, Carroll, Thuras, Cosgrove and Roth2002), the profile of withdrawal headache in youths is understudied. A small double-blind placebo-controlled trial of including nine caffeine consumers (⩾37 mg/d, 109 ± 70 mg/d) investigated the symptoms after overnight caffeine abstinence among children with habitual caffeine consumption (Heatherley, Hancock, & Rogers, Reference Heatherley, Hancock and Rogers2006). Following caffeine abstinence, the consumers reported an increase in headache severity with placebo (1.5 to 1.58 on a scale ranging from 1 to 5), but this did not occur with the administration of 50 mg of caffeine.

Research in adults has shown that subjective response to caffeine and the susceptibility to withdrawal symptoms could be variable across individuals and influenced by genetic variants (Rogers et al., Reference Rogers, Hohoff, Heatherley, Mullings, Maxfield, Evershed and Nutt2010). For example, a large epidemiological study of adults revealed a low incidence of withdrawal headache even among those with high caffeine consumptions (Sjaastad & Bakketeig, Reference Sjaastad and Bakketeig2004). Therefore, more studies are needed to enhance our knowledge on caffeine withdrawal headaches in youths, such as the frequency and risk factors.

The mechanisms of caffeine associated headache

Caffeine has several effects on headaches, including relieving acute pain, triggering chronic headaches in case of overuse, and withdrawal headaches (Alstadhaug & Andreou, Reference Alstadhaug and Andreou2019). It has long been used as an adjuvant to commonly used analgesics to enhance pain relief in adults (Derry, Derry, & Moore, Reference Derry, Derry and Moore2014), partly through a blockade of the A2A receptor with central dopaminergic mechanisms involved (Ferré et al., Reference Ferré, Diamond, Goldberg, Yao, Hourani, Huang and Kitchen2007). However, caffeine-induced headache has also been reported among habitual consumers, both children and adults, and headache improves after caffeine discontinuation (Hering-Hanit & Gadoth, Reference Hering-Hanit and Gadoth2003; Lee, Choi, Choi, & Chung, Reference Lee, Choi, Choi and Chung2016). The proposed pathophysiology involves several mechanisms (Alstadhaug & Andreou, Reference Alstadhaug and Andreou2019). Repetitive exposure to caffeine could lead to up-regulation of adenosine receptors and the compensatory increased levels of plasma adenosine, which has been reported to elicit headaches. In addition, caffeine might increase the predisposition to migraine via interfering the circadian system, sleep, and pain processing at the posterior hypothalamus. All these mechanisms remain speculative.

Taken together, we think it is relevant for clinicians working managing ADHD in youths to take caffeine consumption into consideration when addressing headaches, but there is insufficient evidence to inform specific clinical guidelines. We suggest further studies are needed to explore the profiles of caffeine withdrawal headaches among youths. From a clinical standpoint, as mechanisms underlying the effects of caffeine on headaches are complex, we suggest that gaining insight on the specific aetiology of caffeine associated headaches is crucial to inform management strategies.

Financial support

Dr Pan is supported by Tri-Service General Hospital, the Ministry of National Defense, Taiwan (R.O.C), and the Swedish Research Council.

Conflict of interest

The authors declare no direct conflicts of interest with respect to the authorship, and/or publication of this article. Dr Bölte discloses that he has in the last 3 years acted as an author, consultant or lecturer for Medice and Roche. He receives royalties for textbooks and diagnostic tools from Hogrefe, Kohlhammer and UTB. Bölte is a shareholder in SB Education/Psychological Consulting AB and NeuroSupportSolutions International AB. Dr Cortese declares honoraria and reimbursement for travel and accommodation expenses for lectures from the following non-profit associations: Association for Child and Adolescent Central Health (ACAMH), Canadian ADHD Alliance Resource (CADDRA), British Association of Pharmacology (BAP), and from Healthcare Convention for educational activity on ADHD.

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