Skip to main content

Medication overuse and drug addiction: a narrative review from addiction perspective

A Correction to this article was published on 05 July 2021

This article has been updated

Abstract

Chronic headache is particularly prevalent in migraineurs and it can progress to a condition known as medication overuse headache (MOH). MOH is a secondary headache caused by overuse of analgesics or other medications such as triptans to abort acute migraine attacks. The worsening of headache symptoms associated with medication overuse (MO) generally ameliorates following interruption of regular medication use, although the primary headache symptoms remain unaffected. MO patients may also develop certain behaviors such as ritualized drug administration, psychological drug attachment, and withdrawal symptoms that have been suggested to correlate with drug addiction. Although several reviews have been performed on this topic, to the authors best knowledge none of them have examined this topic from the addiction point of view. Therefore, we aimed to identify features in MO and drug addiction that may correlate. We initiate the review by introducing the classes of analgesics and medications that can cause MOH and those with high risk to produce MO. We further compare differences between sensitization resulting from MO and from drug addiction, the neuronal pathways that may be involved, and the genetic susceptibility that may overlap between the two conditions. Finally, ICHD recommendations to treat MOH will be provided herein.

Background

Headache is one of the most common neurological disorders with estimated 3 billion people worldwide suffering with some type of headache disorder [1]. Most sufferers are individuals at their most productive ages [2] and thus, preventing the development of secondary disorders as well as finding novel treatments especially for those suffering with chronic headache are important to maintain workforce productivity and quality of life.

When headache frequency occurs for ≥15 days for over 3 consecutive months it fulfills the criteria for chronic headache as defined by International Classification of Headache Disorders (ICHD-3) [3]. Patients diagnosed with chronic headache and mostly chronic migraine (CM) often have a long history of unsuccessful preventive treatments in addition to a high incidence of comorbidities [4, 5] . Causes of headache chronification are not fully understood but in some patients, it has been linked to overuse of medications to abort the headache. In fact, overuse of medication has been reported in almost three-quarters of CM patients [6], suggesting that most headache patients may not be receiving a close follow up from their doctors.

The ICHD-3 defines medication overuse headache (MOH) as a secondary headache that develops from the use of (I) triptans, ergotamine, opioids, or combination-analgesics of two or more classes for at least 10 days a month for > 3 months, or (II) non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol for at least 15 days a month for > 3 months [3]. Women in their 40’s are three to four times more prevalent than men [6, 7], and that proportion fluctuates similar across countries [7].

MOH is often the result of the progression of long-standing chronic headache disorders, and mostly CM [8]. Whether MOH is a secondary headache originated by the condition of medication overuse (MO) or MO is a consequence of chronic headache disorders remains a matter of debate [9]. Therefore, in the present review, we will focus on the condition of medication overuse (MO) irrespective of the underlying headache.

Some risk factors have been associated with the expression of MO [10], including genetic predisposition, low education level, chronic gastrointestinal complaints, smoking, high caffeine intake, lack of physical activity, and psychiatric comorbidities, e.g. depression and anxiety [6]. Other health conditions that entail frequent use of analgesics, such as chronic pain, may also lead to MO [7]. Although it has been previously suggested that MO and addiction may share a common pathway [11], our aim herein is to provide a review from addiction point of view in order to clarify and identify other common features between MO and drug addiction.

Medications to abort headache attacks

They are generally separated in two classes, (I) specific medications, and (II) non-specific medications [12]. Specific medications include triptans and ergotamine, which are usually prescribed for migraine and cluster headaches. Their anti-migraine effects are mainly by actions on 5-HT1 receptors localized in the trigeminovascular system. Specifically, they inhibit the release of peripheral vasoactive peptides, such as substance P, neurokinin A and calcitonin gene-related peptide (CGRP) that lead to nociceptor activation and consequent trigeminal activation or vasoconstriction of meningeal blood vessels [13,14,15]. Non-specific medications comprise of various active compounds with different mechanism of actions. NSAIDs, aspirin, paracetamol, antiemetics, corticosteroids, and opiates can be prescribed to treat headache. In short, NSAIDs, aspirin, and paracetamol have actions on cyclooxygenase (COX) enzymes that convert the free essential fatty acids to prostanoids, which levels are found increased in inflamed tissue [16]. Blocking prostanoid biosynthesis prevents the neurogenic inflammation and the central sensitization of second-order trigeminal nociceptors that mediates allodynia during migraine attacks [16, 17]. Opioids, e.g. butorphanol, codeine, tramadol, and meperidine, bind to opioid receptors - μ (mu), κ (kappa), δ (delta), and nociceptin/orphanin FQ – that are found throughout the central nervous system, including in the brain regions recruited to pain signaling such as periacqueductal grey area (PAG), cerebral cortex, thalamus, nucleus raphe magnus, rostral ventral medulla, spinal cord dorsal horn, and brain stem [18, 19]. At the cellular level, opioids reduce the overall synaptic transmission as well as inhibit the GABAergic signaling in the brain stem, which results in the inhibition of the pain circuit signaling [18].

Specific and non-specific medications can both cause MO. Patients treated with triptans or opioids are more frequently reported with MO at a shorter time than those undertaking treatments with other medications [6, 20]. On average, triptans produce MO in approximately 1.7 years and opioids, in approximately 4.8 years [21]. NSAIDs and paracetamol exhibit the lowest risk for MO as it is less frequently reported [6, 22, 23]. Although triptans might lead to rapid development of MO its withdrawal is short and withdrawal symptoms diminish rapidly. Conversely, withdrawal from opioid overuse is complex and gradual as patients report strong withdrawal symptoms, requiring in-patient supervision in certain cases [6, 24]. In addition, opioids have high potential of abuse and consequently, a high risk to develop addiction when misused or taken for long periods. The United States have been facing a rise in opioid overdose over the past 30 years and the indiscriminate use of opioids is estimated to cause more than 15,000 deaths a year in that country [25,26,27]. Europe has also seen an increase in opioid prescriptions in recent years [28] and that brings along fears for an imminent opioid misuse in Europe. Nevertheless, opioids prescriptions are fully discouraged in Europe [29].

MO and drug addiction: the overlapping features

MO and drug addiction initiate from different contexts and reasons. Smoking and alcohol are normally used as recreational drugs, whereas headache patients seek medications in order to alleviate their feeling of pain [30,31,32]. Nevertheless, the regular use of drugs or other substances can facilitate the acquisition of Pavlovian learning that may instate a habit formation or even lead to the development of an incentive sensitization [33]. Takahashi et al. (2019) have demonstrated that Pavlovian learning and transfer do not correlate with addictive behaviors [34]. However, the drug associated cues might be able to modify how a particular drug that is regularly used is perceived (see Robinson and Berridge, 2008 for review). More details will be given below about this topic.

Drug addiction is a complex mental disorder that compromises all spheres of life, i.e. behavioral, cognitive, social, and emotional. It is a condition that is characterized by recurrent relapses and impaired inhibitory control over the drug taking and seeking [35]. However, the term “addiction” has been excluded from the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Instead, the substance use disorder has been adopted to characterize individuals with different levels of the disorder. In this present review, we will refer to ‘addiction’ to individuals showing severe substance use disorder as the International Classification of Diseases (ICD-10) still uses this term.

The development of drug addiction in individuals is associated with risk factors and some risks factors for MO and addiction may overlap. The risk factors for MO are genetic predisposition, low education level, smoking, and psychiatric disorders, mostly depression and anxiety.

Individuals who have a close relative with migraine are highly susceptible to develop migraine, and different gene loci have been linked to migraine susceptibility [36, 37]. In drug addiction, genetic predisposition is also considered a risk factor. However, the development of drug addiction is not strictly related to familiar history of the disease.

Another risk factor for MO, the low education level, could perhaps be associated with low income [38, 39]. Individuals that are exposed to frequent life threatening/stressing situations, i.e. hunger, violence, moral and physical abuses, especially at younger age, are often also exposed to bad life examples, which conscious or not, it can shape their way of making decisions. For instance, youth criminality and drug abuse are often associated. Several studies have shown that the early the start of drug use, the higher their risk to develop drug addiction. Additionally, other evidence demonstrates patients with MO have lower educational levels compared with those without MO [40], suggesting that socioeconomic factors are risk factor for both addiction and MO.

The other risk factor that may overlap between MO and addiction is some psychiatric disorders. In drug addiction, individuals living in a highly pressured environment and who suffer from high anxiety or severe depression often use drugs as an escape. Anxiety and depression are also associated with the development of MO in patients with headache [41, 42]. However, it is not yet clear whether MO patients with ritualized behaviors take medications for comforting reasons or as a matter of habit. More studies are warranted to clarify all those associations. Nevertheless, the risk factors combined might likely account for the alterations in cortical and subcortical regions that underpin the changes in neuro-circuitry of reward, motivation, memory, and judgment [35, 43], which in turn express as a pathology.

In the behavioral aspect, sensitization is a feature found in both addiction and MO though expressed differently. In headache sensitization is expressed as allodynia, a feeling of pain that results from an innocuous stimulus such as light touch. Cutaneous allodynia is a marker of central sensitization and it involves actions of pro-nociceptive mediators, increasing nociceptor responses. Cutaneous allodynia is estimated to affect 50–80% of migraineurs and it has been suggested to predict migraine chronification [44]. In drug addiction sensitization is developed after repetitive, often intermittent, administration of substance of abuse, expressed by enhancement of locomotor activity in mice [45], or an increase in activity/energy level, mood, amount of speech, and eye-blink rates in humans [46]. The increase in the drug effects following repeated drug administration reflects the sensitization of the brain mesocorticolimbic systems [33, 45, 47, 48]. Moreover, a sensitization of the brain incentive systems can further engage the motivation for drugs and drug-cues, and that can lead to a pathological ‘wanting’ for drugs [33]. The dopaminergic system plays a role in both locomotor and incentive sensitization in drug addiction [49], and recently, dopamine (DA) has also been demonstrated in cutaneous allodynia [50]. A study evaluating the dynamics of endogenous DA neurotransmission in migraineurs has shown variations in DA receptor density during the migraine attack accompanied by allodynia [51]. Previous studies have also shown that migraineurs are hypersensitive to dopamine agonists [52] and dopamine D2 receptor antagonists can reduce both migraine frequency and severity [53]. Those studies have initiated several discussions among researchers with focus of DA actions on premonitory symptoms of migraine. That is fundamentally based on the fact that A11 hypothalamic neurons to trigeminal neurons are the sole source of dopaminergic neurons to the spinal cord [54]. However, the emotional valence of headache chronification should be taken into consideration as an important component in the development of MO. As demonstrated in previous studies with chronic back pain patients, DA can regulate sensory and affective dimensions of pain, and interestingly, the development of chronic pain is influenced by the striatum [55]. The striatum is a brain region strongly modulated by dopaminergic neurotransmission and it is essentially involved in some addictive behaviors, such as habit formation and drug seeking behavior (see [56, 57] for review). Further studies are still warranted to clarify the mechanisms in which dopamine engages in the chronification of migraine, however, there is a strong indication it might contribute to the expression of MO.

According to the incentive-sensitization theory, DA can modulate wanting to take the drug that is distinguished from liking the drug [58]. In other words, drug addicts can continue wanting the drug despite not liking it anymore due to lack of rewarding effects developed through pharmacological tolerance. Based on the theory, MO patients may similarly want to take analgesics despite the lack of pain relief effects. It is, therefore, a desire to continue administering analgesics that can be translated as psychological attachment. That attachment might motivate the MO patients to ritualistically take analgesics every morning despite lack of benefit or positive outcomes. Further studies are still needed to clarify whether those behaviors could progress to an obsessive behavior.

Based on the ability of DA in changing the perception of pain in chronic pain patients as well as in altering the motivation for reinforcing activities, it is very likely that the psychological attachment to the drug by MO patients is contributed or governed by DA.

Another common feature for both conditions is the relapse after drug withdrawal [59]. The relapse rate for MO patients is estimated to range between 25 and 35% within the first year [60, 61], whereas for drug addiction it can be over 65% in the first year [62, 63]. In drug addiction, factors such as drug-associated cues and/or stress can trigger craving and the drug seeking behavior. For MO, the type of primary headache and the class of the drug overused by the patient, i.e. opioids and barbiturates [64], the baseline headache frequency [65], and the number of previous preventive treatments [66] have all being associated as predictors to relapse. No factor has yet been identified or directly associated with relapse in MO.

Identification of early signs or symptoms of addictive behaviors in patients with MO are fundamental to break the cycle. Although it is challenging to distinguish patients with continuous or frequent headaches from MO [2, 6, 24] as headache characteristics change day-by-day [2], patients with MO generally have their headache symptoms ameliorated when medication is stopped, and withdrawal symptoms diminished [25, 26]. In addition, MO patients show behaviors such as typical fear of headache attacks - cephalalgiaphobia -, anticipatory anxiety, obsessional or ritualized drug-taking behaviors, psychological drug attachment, and abstinence symptoms after drug discontinuation [27]. The Severity of Dependence Scale (SDS) questionnaire provided by the World Health Organization (WHO) has been suggested to help in MO diagnosis [28]. Although SDS is a screening questionnaire for behavioral dependence, SDS scores are correlated with MO, and they also predicted the probability of successful withdrawal [29, 30]. A simplified summary of behaviors expressed by MO and drug addiction can be found in Fig. 1.

Fig. 1
figure 1

Simplified schematic of behaviors expressed by MO and drug addiction patients

Common systems in MO and drug addiction

The neuronal mechanisms of MO are not fully clear. However, some systems have been identified. Evidence from both animal and human studies suggests that MO patients have higher excitability of the nociceptive pathways during and between migraine attacks, leading to cutaneous allodynia [20]. Cutaneous allodynia reflects the central sensitization, and several studies support the role of pro-nociceptive substances in this phenomenon. Allodynia can also be caused by repeated administration of triptans, which have been demonstrated in experimental models. The chronic use of triptans can cause facilitation of descending pro-nociceptive pathways that consequently increase responsiveness to migraine triggers [67,68,69]. Pro-nociceptive substances such as CGRP and neuronal nitric oxide synthase (nNOS) in the dural afferent neurons of the trigeminal ganglion have shown to decrease the pain threshold that triggers migraine attacks [20]. Conversely, application of inflammatory mediators to the dura mater can cause responses to previously insensitive mechanical stimulation, additionally those mediators have also been linked to the sustained activation of trigeminal afferents [70, 71]. Previous studies assessing the effects of long-term treatments with triptans or morphine have shown an upregulation of CGRP or nNOS in the trigeminal dural afferents that persisted even after discontinuation of the treatment [20, 72, 73]. This imbalance of nociceptive substances in the dural afferent neurons has been suggested to be critical to the neuroadaptations that lower the threshold for migraine attack.

Another neurotransmitter that is certainly playing a role is 5-hydroxytryptamine (5-HT, serotonin). The specific antimigraine drugs are 5-HT1B/1D receptor agonists and, not surprising, the 5-HT system is dysfunctional in patients and animals chronically treated with non-specific medications, i.e. common analgesics [74]. Patients overusing analgesics have lower 5-HT levels, higher 5-HT uptake and higher 5-HT2A receptor density in blood platelets [75,76,77,78]. Drug withdrawal reversed those changes, which inversely correlated with the clinical improvement. Preclinical studies, however, have demonstrated different outcomes for short- or long-term treatments with analgesics. A 15 day-acetaminophen treatment in rats produced an increase in platelet 5-HT concentration, which was accompanied by downregulation of the 5-HT2A receptor and upregulation of the 5-HT transporter in the frontal cortex [79]. Conversely, a 30 day-acetaminophen treatment produced normalization of platelet 5-HT levels that correlated with reduction in analgesic effects [79]. Other studies have shown an upregulation of 5-HT2A receptor in the cerebral cortex and trigeminal ganglia following prolonged administration of acetaminophen, which also correlated with an increase in frequency of cortical spreading depression and higher potentiation of trigeminal nociception. Ketanserin, a 5-HT2A receptor antagonist, significantly attenuated those effects [80]. These studies suggest that, while the analgesic efficacy is correlated with an increase in platelet 5-HT levels, the normalization of platelet 5-HT levels as well as the changes in the 5-HT density after prolonged analgesic administration may be associated with increased headache frequency. A simplified summary of the effects of long-term administration of triptans or analgesics can be found in Fig. 2.

Fig. 2
figure 2

Simplified summary of changes produced by repeated administration of triptans or analgesics

As demonstrated above, several neuroadaptations occur over the course of headache chronification and regular analgesic administration. Certain behaviors from MO patients, such as ritualized drug taking and psychological attachment to the drug also suggest that other neurotransmitter systems are involved. As we hypothesized above, DA may be playing a role in MO. DA is critical to multiple brain functions as well as it modulates reward and reinforcement. To mention a few examples, DA neurotransmission is found altered in Parkinson’s disease, depression, drug addiction, and chronic pain. Studies in chronic back pain patients using PET neuroimaging have shown alterations in affective state regulated by DA [55, 81,82,83], confirming its modulation to pain sensitivity and perception in patients [84, 85]. MOH is a chronic pain condition and recent genetic association studies support dopaminergic alterations in MO. A case-control study has shown that the presence of a 19-bp insertion/ deletion polymorphism (rs72393728/ rs141116007) to the dopamine-beta-hydroxylase gene correlated with the development of MO in chronic migraine patients [8, 86]. Conversely, carriers of the rs7590387GG polymorphism in the receptor activity modifying 1 (RAMP1) locus are correlated with lower risk of episodic migraine transformation to MO [87]. In drug addiction, DA levels and receptor density fluctuate during the different stages of drug use, withdrawal, and abstinence [88,89,90]. Specifically, DA D2 receptor gene (DRD2) [91,92,93] and the allele 9 of DA transporter (DAT) [94,95,96,97] have been associated with the susceptibility to drug abuse. DaSilva et al. (2017) demonstrated imbalance of DA D2/D3 receptors during migraine attacks and neuroimaging studies have revealed dysfunctions in the mesocorticolimbic dopamine circuit in MO patients [98]. The above evidence supports our hypothesis of altered dopaminergic circuitry in contributing either to the expression of MO or to an increase in the risk for MO, or both.

In human subjects, neuroimaging studies have suggested similarities between MO and drug addiction. Structural brain MRI with morphometric measurements showed that patients with MO, compared with healthy controls, had an increased grey matter volume in the ventral striatum, an area implicated in reward behaviors and addiction [99]. Furthermore, when considering patients with CM, those with MO have decreased grey matter volume in the orbitofrontal cortex compared with those without MO; this finding is relevant because orbitofrontal cortex is part of the mesocorticolimbic system implied in addictive behaviors [100]. Functional magnetic resonance imaging (fMRI) uses blood-oxygenation-level-dependent (BOLD) signal to investigate regional changes in blood oxygenation patterns, providing an indirect measurement of brain connectivity. The available fMRI studies show that patients with MO, compared with episodic migraine, have altered connectivity in regions of the pain reward system, including the nucleus accumbens, putamen, caudate, hippocampus, periaqueductal gray, precuneus, and the insula, suggesting that MO might involve the same brain areas as drug addiction [101]. A simplified summary of findings from neuroimaging studies for MO and drug addiction can be found in Fig. 3.

Fig. 3
figure 3

Simplified neuroimaging findings that overlap for MO and drug addiction

Treatments of MO

While recently the combination of withdrawal and preventive medication was recommended as the most successful treatment of MOH [102], multiple studies have suggested withdrawal as the primary treatment of choice for MO [61, 103, 104]. Withdrawal does not only reduce the headache attacks, but also improve responsiveness to acute or prophylactic drugs [22, 61]. The most common symptoms experienced during withdrawal are initial worsening of headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, anxiety, and nervousness [6, 22]. They normally last between 2 to 10 days, and do not persist longer than 4 weeks [22, 105]. Furthermore, it is important to set the correct treatment expectations for the patients, i.e. make them aware of no-full ablation of their primary headache, to achieve treatment success [106].

In most cases, withdrawal can be established by outpatient management. For instance, patients overusing triptans have shorter withdrawal symptoms when compared to ergotamine-treated or NSAIDs-treated patients [6, 22]. However, inpatient treatment should be offered to complex cases such as patients overusing opioids or barbiturates, those who show psychological problems, severe medical comorbidities, failures from previous withdrawal treatments and/or those with severe withdrawal symptoms [22, 61]. Abrupt withdrawal without tapering is advisable for patients overusing simple analgesics, ergotamine, and triptans, while tapering is recommended for those under opioids or barbiturate treatments [22, 107].

Preventive medication such as monoclonal antibodies acting on the CGRP pathway [108,109,110,111] or Onabotulinum-toxin A [61, 112] can be prescribed prior to the withdrawal treatment [113, 114]. Interdisciplinary approaches with psychological counselling and behavioral interventions are beneficial [61, 115] for complex cases [22, 61, 105]. Psychotherapy combined with short-term pharmacotherapy appears to increase the success rate in preventing relapses rather than pharmacological interventions alone, i.e. tapering medications [116].

Furthermore, patient’s engagement and behavioral interventions are both necessary for successful treatment. Interventions such as cognitive behavior therapy, management of stress, relaxation training, biofeedback, management of comorbidities, enhancement of adherence and encouragement have proved to help in the recovery [117]. Self-help groups can additionally contribute to improve coping of cephalalgiaphobia in MO patients [118].

Considering that over a quarter of MO patients relapse within the first year [60, 61], a regular follow-up of the patients is recommended to reduce the risk to relapse during remission [61]. It is also important to identify and treat comorbidities, such as mood disorders, anxiety, concurrent use of psychoactive substances, psychological dependence, and pain catastrophizing, accordingly [42, 119]. If a MO patient shows any signs of addictive behaviors a psychiatrist specialized in addiction should be engaged to initiate other relevant treatments [120]. Opioids are among the most difficult drugs to withdraw [61, 120] and, therefore, psychiatrists could provide additional assistance and support to increase the success rate and prevent relapses. From a clinical point of view, remediation at this crucial point of unstable reversibility of MO requires efficient healthcare policies that include patients with chronic migraine complicated by MO in specific public health addiction rehabilitation programs (106).

Conclusions

Several studies support that MO shares certain behavioral, genetic, and neuronal pathways with drug addiction. DA might likely be involved in the pathophysiology of the secondary headache and though the mechanism is unclear, over the course of recurrent attacks and drug administration DA actions appear to increase in several brain regions. Consequently, DA could either lead to an increase in the risk for MO or to the manifestation of MO. Opioids prescription must be completely avoided considering its high potential of abuse and high economical and societal costs. Chronic headache patients holding similar risks to addiction should be followed up with more discretion to prevent the development of MO and addictive behaviors. Clinical interventions to those patients showing initial signs and symptoms of addiction should be performed promptly. While recently the combination of withdrawal and preventive medication was recommended as the most successful treatment of MOH, multiple studies have suggested withdrawal as the primary treatment of choice for MO. If relapse occurs repeated times and/or a patient has a complex case with addictive behaviors, a psychiatrist should be brought on board to take further measures. Combined psychological and pharmacological interventions can also increase the success rate for MO patients in remission. Further studies are still warranted to clarify the role of DA in MO, as well as to understand the molecular mechanisms of chronic use of medications in the development of the secondary headache disorder such as MO.

Availability of data and materials

Not applicable.

Change history

Abbreviations

5-HT:

5-hydroxytriptamine (serotonin)

CGRP:

calcitonin gene-related peptide

CM:

chronic migraine

COX:

cyclooxygenase

DA:

dopamine

DRD2:

dopamine receptor D2

GABA:

gamma-aminobutyric acid

ICHD:

International Classification of Headache Disorders

MO:

medication overuse

MOH:

medication overuse headache

nNOS:

neural nitric oxide synthase

NSAIDs:

non-steroidal anti-inflammatory drugs

PAG:

periaqueductal grey (area)

RAMP1:

receptor activity modifying protein 1

References

  1. G.B.D.H (2018) Global, regional, and national burden of migraine and tension-type headache, 1990–2016: A systematic analysis for the global burden of disease study 2016. Lancet Neurol 17(11):954–976. https://doi.org/10.1016/S1474-4422(18)30322-3

    Article  Google Scholar 

  2. Steiner TJ et al (2020) Migraine remains second among the world's causes of disability, and first among young women: findings from GBD2019. J Headache Pain 21(1):137. https://doi.org/10.1186/s10194-020-01208-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia, 2018. 38(1): p. 1–211 DOI: https://doi.org/10.1177/0333102417738202

  4. May A, Schulte LH (2016) Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol 12(8):455–464. https://doi.org/10.1038/nrneurol.2016.93

    Article  CAS  PubMed  Google Scholar 

  5. Negro A, Rocchietti-March M, Fiorillo M, Martelletti P (2011) Chronic migraine: current concepts and ongoing treatments. Eur Rev Med Pharmacol Sci 15(12):1401–1420

    CAS  PubMed  Google Scholar 

  6. Wakerley BR (2019) Medication-overuse headache. Pract Neurol 19(5):399–403. https://doi.org/10.1136/practneurol-2018-002048

    Article  PubMed  Google Scholar 

  7. Russell MB (2019) Epidemiology and management of medication-overuse headache in the general population. Neurol Sci 40(Suppl 1):23–26. https://doi.org/10.1007/s10072-019-03812-8

    Article  PubMed  Google Scholar 

  8. Martelletti P (2018) The journey from genetic predisposition to medication overuse headache to its acquisition as sequela of chronic migraine. J Headache Pain 19(1):2. https://doi.org/10.1186/s10194-017-0830-2

    Article  PubMed  PubMed Central  Google Scholar 

  9. Vandenbussche N, Laterza D, Lisicki M, Lloyd J, Lupi C, Tischler H, Toom K, Vandervorst F, Quintana S, Paemeleire K, Katsarava Z (2018) Medication-overuse headache: a widely recognized entity amidst ongoing debate. J Headache Pain 19(1):50. https://doi.org/10.1186/s10194-018-0875-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Diener HC, Holle D, Solbach K, Gaul C (2016) Medication-overuse headache: risk factors, pathophysiology and management. Nat Rev Neurol 12(10):575–583. https://doi.org/10.1038/nrneurol.2016.124

    Article  PubMed  Google Scholar 

  11. Calabresi P, Cupini LM (2005) Medication-overuse headache: similarities with drug addiction. Trends Pharmacol Sci 26(2):62–68. https://doi.org/10.1016/j.tips.2004.12.008

    Article  CAS  PubMed  Google Scholar 

  12. Ong JJY, De Felice M (2018) Migraine treatment: current acute medications and their potential mechanisms of action. Neurotherapeutics 15(2):274–290. https://doi.org/10.1007/s13311-017-0592-1

    Article  CAS  PubMed  Google Scholar 

  13. Ahn AH, Basbaum AI (2005) Where do triptans act in the treatment of migraine? Pain 115(1–2):1–4. https://doi.org/10.1016/j.pain.2005.03.008

    Article  PubMed  PubMed Central  Google Scholar 

  14. Tfelt-Hansen P et al (2000) Ergotamine in the acute treatment of migraine: a review and European consensus. Brain 123(Pt 1):9–18. https://doi.org/10.1093/brain/123.1.9

    Article  PubMed  Google Scholar 

  15. Tfelt-Hansen P (2020) Pharmacological strategies to treat attacks of episodic migraine in adults. Expert Opin Pharmacother 22(3):1–12. https://doi.org/10.1080/14656566.2020.1828347

    Article  CAS  Google Scholar 

  16. Silberstein SD, Stirpe JC (2014) COX inhibitors for the treatment of migraine. Expert Opin Pharmacother 15(13):1863–1874. https://doi.org/10.1517/14656566.2014.937704

    Article  CAS  PubMed  Google Scholar 

  17. Graham GG, Scott KF (2003) Mechanisms of action of paracetamol and related analgesics. Inflammopharmacology 11(4):401–413. https://doi.org/10.1163/156856003322699573

    Article  CAS  PubMed  Google Scholar 

  18. Inturrisi CE (2002) Clinical pharmacology of opioids for pain. Clin J Pain 18(4 Suppl):S3–S13. https://doi.org/10.1097/00002508-200207001-00002

  19. Toll L, Bruchas MR, Calo' G, Cox BM, Zaveri NT (2016) Nociceptin/Orphanin FQ receptor structure, signaling, ligands, functions, and interactions with opioid systems. Pharmacol Rev 68(2):419–457. https://doi.org/10.1124/pr.114.009209

    Article  PubMed  PubMed Central  Google Scholar 

  20. De Felice M, Ossipov MH, Porreca F (2011) Update on medication-overuse headache. Curr Pain Headache Rep 15(1):79–83. https://doi.org/10.1007/s11916-010-0155-1

    Article  PubMed  PubMed Central  Google Scholar 

  21. Limmroth V, Katsarava Z, Fritsche G, Przywara S, Diener HC (2002) Features of medication overuse headache following overuse of different acute headache drugs. Neurology 59(7):1011–1014. https://doi.org/10.1212/wnl.59.7.1011

    Article  CAS  PubMed  Google Scholar 

  22. Evers S, Marziniak M (2010) Clinical features, pathophysiology, and treatment of medication-overuse headache. Lancet Neurol 9(4):391–401. https://doi.org/10.1016/S1474-4422(10)70008-9

    Article  PubMed  Google Scholar 

  23. Scher AI, Lipton RB, Stewart WF, Bigal M (2010) Patterns of medication use by chronic and episodic headache sufferers in the general population: results from the frequent headache epidemiology study. Cephalalgia 30(3):321–328. https://doi.org/10.1111/j.1468-2982.2009.01913.x

    Article  CAS  PubMed  Google Scholar 

  24. Katsarava Z, Diener HC, Limmroth V (2001) Medication overuse headache: a focus on analgesics, ergot alkaloids and triptans. Drug Saf 24(12):921–927. https://doi.org/10.2165/00002018-200124120-00005

    Article  CAS  PubMed  Google Scholar 

  25. van Amsterdam J, van den Brink W (2015) The misuse of prescription opioids: a threat for Europe? Curr Drug Abuse Rev 8(1):3–14. https://doi.org/10.2174/187447370801150611184218

    Article  PubMed  Google Scholar 

  26. Weisberg DF, Becker WC, Fiellin DA, Stannard C (2014) Prescription opioid misuse in the United States and the United Kingdom: cautionary lessons. Int J Drug Policy 25(6):1124–1130. https://doi.org/10.1016/j.drugpo.2014.07.009

    Article  PubMed  Google Scholar 

  27. Soelberg CD, Brown RE Jr, du Vivier D, Meyer JE, Ramachandran BK (2017) The US opioid crisis: current federal and state legal issues. Anesth Analg 125(5):1675–1681. https://doi.org/10.1213/ANE.0000000000002403

    Article  PubMed  Google Scholar 

  28. Kalkman GA, Kramers C, van Dongen RT, van den Brink W, Schellekens A (2019) Trends in use and misuse of opioids in the Netherlands: a retrospective, multi-source database study. Lancet Public Health 4(10):e498–e505. https://doi.org/10.1016/S2468-2667(19)30128-8

    Article  PubMed  Google Scholar 

  29. Steiner TJ, Jensen R, Katsarava Z, Linde M, MacGregor EA, Osipova V, Paemeleire K, Olesen J, Peters M, Martelletti P (2019) Aids to management of headache disorders in primary care (2nd edition) : on behalf of the European Headache Federation and Lifting The Burden: the Global Campaign against Headache. J Headache Pain 20(1):57. https://doi.org/10.1186/s10194-018-0899-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Van Etten ML, Anthony JC (1999) Comparative epidemiology of initial drug opportunities and transitions to first use: marijuana, cocaine, hallucinogens and heroin. Drug Alcohol Depend 54(2):117–125. https://doi.org/10.1016/s0376-8716(98)00151-3

    Article  PubMed  Google Scholar 

  31. DuPont RL, Han B, Shea CL, Madras BK (2018) Drug use among youth: national survey data support a common liability of all drug use. Prev Med 113:68–73. https://doi.org/10.1016/j.ypmed.2018.05.015

    Article  PubMed  Google Scholar 

  32. Delgado-Lobete, L., Montes-Montes R., Vila-Paz A., Cruz-Valiño J.M., Gándara-Gafo B., Talavera-Valverde M.Á., Santos-del-Riego S., Individual and Environmental Factors Associated with Tobacco Smoking, Alcohol Abuse and Illegal Drug Consumption in University Students: A Mediating Analysis. Int J Environ Res Public Health, 2020. 17(9) DOI: https://doi.org/10.3390/ijerph17093019, 17, 9

  33. Robinson TE, Berridge KC (2008) Review. The incentive sensitization theory of addiction: some current issues. Philos Trans R Soc Lond Ser B Biol Sci 363(1507):3137–3146. https://doi.org/10.1098/rstb.2008.0093

    Article  Google Scholar 

  34. Takahashi TT, Vengeliene V, Enkel T, Reithofer S, Spanagel R (2019) Pavlovian to instrumental transfer responses do not correlate with addiction-like behavior in rats. Front Behav Neurosci 13:129. https://doi.org/10.3389/fnbeh.2019.00129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Association, A.P., Diagnostic and statistical manual of mental disorders, 5th Edition. 2013, DOI: https://doi.org/10.1176/appi.books.9780890425596

  36. de Boer I, van den Maagdenberg A, Terwindt GM (2019) Advance in genetics of migraine. Curr Opin Neurol 32(3):413–421. https://doi.org/10.1097/WCO.0000000000000687

    Article  PubMed  PubMed Central  Google Scholar 

  37. Sutherland HG, Albury CL, Griffiths LR (2019) Advances in genetics of migraine. J Headache Pain 20(1):72. https://doi.org/10.1186/s10194-019-1017-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Westergaard ML, Glümer C, Hansen EH, Jensen RH (2014) Prevalence of chronic headache with and without medication overuse: associations with socioeconomic position and physical and mental health status. Pain 155(10):2005–2013. https://doi.org/10.1016/j.pain.2014.07.002

    Article  PubMed  Google Scholar 

  39. Jonsson P, Linde M, Hensing G, Hedenrud T (2012) Sociodemographic differences in medication use, health-care contacts and sickness absence among individuals with medication-overuse headache. J Headache Pain 13(4):281–290. https://doi.org/10.1007/s10194-012-0432-y

    Article  PubMed  PubMed Central  Google Scholar 

  40. Atasoy HT, Unal AE, Atasoy N, Emre U, Sumer M (2005) Low income and education levels may cause medication overuse and chronicity in migraine patients. Headache 45(1):25–31. https://doi.org/10.1111/j.1526-4610.2005.05006.x

    Article  PubMed  Google Scholar 

  41. Atasoy HT, Atasoy N, Unal AE, Emre U, Sumer M (2005) Psychiatric comorbidity in medication overuse headache patients with pre-existing headache type of episodic tension-type headache. Eur J Pain 9(3):285–291. https://doi.org/10.1016/j.ejpain.2004.07.006

    Article  PubMed  Google Scholar 

  42. Radat F, Creac'h C, Swendsen JD, Lafittau M, Irachabal S, Dousset V, Henry P (2005) Psychiatric comorbidity in the evolution from migraine to medication overuse headache. Cephalalgia 25(7):519–522. https://doi.org/10.1111/j.1468-2982.2005.00910.x

    Article  CAS  PubMed  Google Scholar 

  43. Everitt B (1997) Craving cocaine cues: cognitive neuroscience meets drug addiction research. Trends Cogn Sci 1(1):1–2. https://doi.org/10.1016/S1364-6613(97)01009-7

    Article  CAS  PubMed  Google Scholar 

  44. Louter MA, Bosker JE, van Oosterhout WPJ, van Zwet EW, Zitman FG, Ferrari MD, Terwindt GM (2013) Cutaneous allodynia as a predictor of migraine chronification. Brain 136(11):3489–3496. https://doi.org/10.1093/brain/awt251

    Article  PubMed  Google Scholar 

  45. Camarini R, Pautassi RM (2016) Behavioral sensitization to ethanol: neural basis and factors that influence its acquisition and expression. Brain Res Bull 125:53–78. https://doi.org/10.1016/j.brainresbull.2016.04.006

    Article  CAS  PubMed  Google Scholar 

  46. Strakowski SM, Sax KW, Setters MJ, Keck PE Jr (1996) Enhanced response to repeated d-amphetamine challenge: evidence for behavioral sensitization in humans. Biol Psychiatry 40(9):872–880. https://doi.org/10.1016/0006-3223(95)00497-1

    Article  CAS  PubMed  Google Scholar 

  47. Kalivas PW, Duffy P (1988) Effects of daily cocaine and morphine treatment on somatodendritic and terminal field dopamine release. J Neurochem 50(5):1498–1504. https://doi.org/10.1111/j.1471-4159.1988.tb03036.x

    Article  CAS  PubMed  Google Scholar 

  48. Kuczenski R, Segal D (1989) Concomitant characterization of behavioral and striatal neurotransmitter response to amphetamine using in vivo microdialysis. J Neurosci 9(6):2051–2065. https://doi.org/10.1523/jneurosci.09-06-02051.1989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Leyton M (2007) Conditioned and sensitized responses to stimulant drugs in humans. Prog Neuro-Psychopharmacol Biol Psychiatry 31(8):1601–1613. https://doi.org/10.1016/j.pnpbp.2007.08.027

    Article  CAS  Google Scholar 

  50. Sugiyama E, Kondo T, Kuzumaki N, Honda K, Yamanaka A, Narita M, Suematsu M, Sugiura Y (2019) Mechanical allodynia induced by optogenetic sensory nerve excitation activates dopamine signaling and metabolism in medial nucleus accumbens. Neurochem Int 129:104494. https://doi.org/10.1016/j.neuint.2019.104494

    Article  CAS  PubMed  Google Scholar 

  51. DaSilva AF, Nascimento TD, Jassar H, Heffernan J, Toback RL, Lucas S, DosSantos MF, Bellile EL, Boonstra PS, Taylor JMG, Casey KL, Koeppe RA, Smith YR, Zubieta JK (2017) Dopamine D2/D3 imbalance during migraine attack and allodynia in vivo. Neurology 88(17):1634–1641. https://doi.org/10.1212/wnl.0000000000003861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Peroutka SJ, Wilhoit T, Jones K (1997) Clinical susceptibility to migraine with aura is modified by dopamine D<sub>2</sub> receptor (DRD2) <em>Nco</em> I alleles. Neurology 49(1):201–206. https://doi.org/10.1212/wnl.49.1.201

    Article  CAS  PubMed  Google Scholar 

  53. Wöber C, Brücke T, Wöber-Bingöl C, Asenbaum S, Wessely P, Podreka I (1994) Dopamine D2 receptor blockade and Antimigraine action of Flunarizine. Cephalalgia 14(3):235–240. https://doi.org/10.1046/j.1468-2982.1994.014003235.x

    Article  PubMed  Google Scholar 

  54. Akerman S, Goadsby P (2007) Dopamine and migraine: biology and clinical implications. Cephalalgia 27(11):1308–1314. https://doi.org/10.1111/j.1468-2982.2007.01478.x

    Article  CAS  PubMed  Google Scholar 

  55. Martikainen IK, Nuechterlein EB, Pecina M, Love TM, Cummiford CM, Green CR, Stohler CS, Zubieta JK (2015) Chronic Back pain is associated with alterations in dopamine neurotransmission in the ventral striatum. J Neurosci 35(27):9957–9965. https://doi.org/10.1523/JNEUROSCI.4605-14.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Everitt BJ, Robbins TW (2005) Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 8(11):1481–1489. https://doi.org/10.1038/nn1579

    Article  CAS  PubMed  Google Scholar 

  57. Everitt BJ, Robbins TW (2016) Drug addiction: updating actions to habits to compulsions ten years on. Annu Rev Psychol 67(1):23–50. https://doi.org/10.1146/annurev-psych-122414-033457

    Article  PubMed  Google Scholar 

  58. Berridge KC, Robinson TE (2016) Liking, wanting, and the incentive-sensitization theory of addiction. Am Psychol 71(8):670–679. https://doi.org/10.1037/amp0000059

    Article  PubMed  PubMed Central  Google Scholar 

  59. Hyman SE, Malenka RC (2001) Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci 2(10):695–703. https://doi.org/10.1038/35094560

    Article  CAS  PubMed  Google Scholar 

  60. Chiang C-C, Schwedt TJ, Wang SJ, Dodick DW (2016) Treatment of medication-overuse headache: a systematic review. Cephalalgia 36(4):371–386. https://doi.org/10.1177/0333102415593088

    Article  PubMed  Google Scholar 

  61. Diener HC, Dodick D, Evers S, Holle D, Jensen RH, Lipton RB, Porreca F, Silberstein S, Schwedt T (2019) Pathophysiology, prevention, and treatment of medication overuse headache. Lancet Neurol 18(9):891–902. https://doi.org/10.1016/S1474-4422(19)30146-2

    Article  PubMed  Google Scholar 

  62. Hunt WA, Bespalec DA (1974) Relapse rates after treatment for heroin addiction. J Commun Psychol 2(1):85–87. https://doi.org/10.1002/1520-6629(197401)2:1<85::AID-JCOP2290020130>3.0.CO;2-B

    Article  Google Scholar 

  63. Hunt WA, General WR (1973) Relapse rates after treatment for alcoholism. J Commun Psychol 1(1):66–68. https://doi.org/10.1002/1520-6629(197301)1:1<66::AID-JCOP2290010119>3.0.CO;2-R

    Article  Google Scholar 

  64. Katsarava Z, Muessig M, Dzagnidze A, Fritsche G, Diener HC, Limmroth V (2005) Medication overuse headache: rates and predictors for relapse in a 4-year prospective study. Cephalalgia 25(1):12–15. https://doi.org/10.1111/j.1468-2982.2004.00789.x

    Article  CAS  PubMed  Google Scholar 

  65. Raggi A, Giovannetti AM, Leonardi M, Sansone E, Schiavolin S, Curone M, Grazzi L, Usai S, D'Amico D (2017) Predictors of 12-months relapse after withdrawal treatment in hospitalized patients with chronic migraine associated with medication overuse: a longitudinal observational study. Headache 57(1):60–70. https://doi.org/10.1111/head.12979

    Article  PubMed  Google Scholar 

  66. Rossi P, Faroni J, Nappi G (2008) Medication overuse headache: predictors and rates of relapse in migraine patients with low medical needs. A 1-year prospective study. Cephalalgia 28(11):1196–1200. https://doi.org/10.1111/j.1468-2982.2008.01659.x

    Article  CAS  PubMed  Google Scholar 

  67. Becerra L, Bishop J, Barmettler G, Xie Y, Navratilova E, Porreca F, Borsook D (2016) Triptans disrupt brain networks and promote stress-induced CSD-like responses in cortical and subcortical areas. J Neurophysiol 115(1):208–217. https://doi.org/10.1152/jn.00632.2015

    Article  CAS  PubMed  Google Scholar 

  68. De Felice M, Ossipov MH, Porreca F (2011) Persistent medication-induced neural adaptations, descending facilitation, and medication overuse headache. Curr Opin Neurol 24(3):193–196. https://doi.org/10.1097/WCO.0b013e328346af25

    Article  PubMed  PubMed Central  Google Scholar 

  69. De Felice M et al (2010) Triptan-induced enhancement of neuronal nitric oxide synthase in trigeminal ganglion dural afferents underlies increased responsiveness to potential migraine triggers. Brain 133(Pt 8):2475–2488. https://doi.org/10.1093/brain/awq159

    Article  PubMed  PubMed Central  Google Scholar 

  70. Burstein R (2001) Deconstructing migraine headache into peripheral and central sensitization. Pain 89(2–3):107–110. https://doi.org/10.1016/s0304-3959(00)00478-4

    Article  CAS  PubMed  Google Scholar 

  71. Strassman AM, Raymond SA, Burstein R (1996) Sensitization of meningeal sensory neurons and the origin of headaches. Nature 384(6609):560–564. https://doi.org/10.1038/384560a0

    Article  CAS  PubMed  Google Scholar 

  72. De Felice M et al (2010) Triptan-induced latent sensitization: a possible basis for medication overuse headache. Ann Neurol 67(3):325–337. https://doi.org/10.1002/ana.21897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gardell, L.R., et al., Sustained morphine exposure induces a spinal dynorphin-dependent enhancement of excitatory transmitter release from primary afferent fibers. J Neurosci, 2002. 22(15): p. 6747–6755 DOI: 20026648

  74. Bongsebandhu-phubhakdi S, Srikiatkhachorn A (2012) Pathophysiology of medication-overuse headache: implications from animal studies. Curr Pain Headache Rep 16(1):110–115. https://doi.org/10.1007/s11916-011-0234-y

    Article  PubMed  Google Scholar 

  75. Ayzenberg I, Oberman M, Leineweber K, Franke L, Yoon MS, Diener HC, Katsarava Z (2008) Increased activity of serotonin uptake in platelets in medication overuse headache following regular intake of analgesics and triptans. J Headache Pain 9(2):109–112. https://doi.org/10.1007/s10194-008-0019-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hering R, Glover V, Pattichis K, Catarci T, Steiner TJ (1993) 5HT in migraine patients with medication-induced headache. Cephalalgia 13(6):410–412. https://doi.org/10.1046/j.1468-2982.1993.1306410.x

    Article  CAS  PubMed  Google Scholar 

  77. Srikiatkhachorn A, Anthony M (1996) Platelet serotonin in patients with analgesic-induced headache. Cephalalgia 16(6):423–426. https://doi.org/10.1046/j.1468-2982.1996.1606423.x

  78. Srikiatkhachorn A, Puangniyom S, Govitrapong P (1998) Plasticity of 5-HT serotonin receptor in patients with analgesic-induced transformed migraine. Headache 38(7):534–539. https://doi.org/10.1046/j.1526-4610.1998.3807534.x

    Article  CAS  PubMed  Google Scholar 

  79. Srikiatkhachorn A, Tarasub N, Govitrapong P (2000) Effect of chronic analgesic exposure on the central serotonin system: a possible mechanism of analgesic abuse headache. Headache 40(5):343–350. https://doi.org/10.1046/j.1526-4610.2000.00052.x

    Article  CAS  PubMed  Google Scholar 

  80. Supornsilpchai W, le Grand SM, Srikiatkhachorn A (2010) Involvement of pro-nociceptive 5-HT2A receptor in the pathogenesis of medication-overuse headache. Headache 50(2):185–197. https://doi.org/10.1111/j.1526-4610.2009.01591.x

    Article  PubMed  Google Scholar 

  81. Loggia ML, Berna C, Kim J, Cahalan CM, Gollub RL, Wasan AD, Harris RE, Edwards RR, Napadow V (2014) Disrupted brain circuitry for pain-related reward/punishment in fibromyalgia. Arthritis Rheumatol 66(1):203–212. https://doi.org/10.1002/art.38191

    Article  PubMed  PubMed Central  Google Scholar 

  82. Wood PB, Schweinhardt P, Jaeger E, Dagher A, Hakyemez H, Rabiner EA, Bushnell MC, Chizh BA (2007) Fibromyalgia patients show an abnormal dopamine response to pain. Eur J Neurosci 25(12):3576–3582. https://doi.org/10.1111/j.1460-9568.2007.05623.x

    Article  PubMed  Google Scholar 

  83. Anselmi B, Baldi E, Casacci F, Salmon S (1980) Endogenous opioids in cerebrospinal fluid and blood in idiopathic headache sufferers. Headache 20(6):294–299. https://doi.org/10.1111/j.1526-4610.1980.hed2006294.x

    Article  CAS  PubMed  Google Scholar 

  84. Baliki MN, Geha PY, Fields HL, Apkarian AV (2010) Predicting value of pain and analgesia: nucleus accumbens response to noxious stimuli changes in the presence of chronic pain. Neuron 66(1):149–160. https://doi.org/10.1016/j.neuron.2010.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Jarcho JM, Mayer EA, Jiang ZK, Feier NA, London ED (2012) Pain, affective symptoms, and cognitive deficits in patients with cerebral dopamine dysfunction. Pain 153(4):744–754. https://doi.org/10.1016/j.pain.2012.01.002

    Article  CAS  PubMed  Google Scholar 

  86. Barbanti P, Guadagni F, de Marchis ML, Ialongo C, Egeo G, Fofi L, Aurilia C, Lovero D, Della-Morte D, Ferroni P, Palmirotta R (2019) Dopamine-beta-hydroxylase 19-bp insertion/deletion polymorphism affects medication overuse in patients with chronic migraine. Neurol Sci 40(8):1717–1724. https://doi.org/10.1007/s10072-019-03865-9

    Article  PubMed  Google Scholar 

  87. Cargnin S, Pautasso C, Viana M, Sances G, Mittino D, Cantello R, Tassorelli C, Nappi G, Terrazzino S (2015) Association of RAMP1 rs7590387 with the risk of migraine transformation into medication overuse headache. Headache 55(5):658–668. https://doi.org/10.1111/head.12559

    Article  PubMed  Google Scholar 

  88. Koob GF, Le Moal M (1997) Drug abuse: hedonic homeostatic dysregulation. Science 278(5335):52–58. https://doi.org/10.1126/science.278.5335.52

    Article  CAS  PubMed  Google Scholar 

  89. Koob GF, Le Moal M (2001) Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24(2):97–129. https://doi.org/10.1016/S0893-133X(00)00195-0

    Article  CAS  PubMed  Google Scholar 

  90. Volkow ND, Fowler JS, Wang GJ (1999) Imaging studies on the role of dopamine in cocaine reinforcement and addiction in humans. J Psychopharmacol 13(4):337–345. https://doi.org/10.1177/026988119901300406

    Article  CAS  PubMed  Google Scholar 

  91. Blum K, Sheridan PJ, Wood RC, Braverman ER, Chen TJH, Comings DE (1995) Dopamine D2 receptor gene variants: association and linkage studies in impulsive-addictive-compulsive behaviour. Pharmacogenet Genomics 5(3):121–141. https://doi.org/10.1097/00008571-199506000-00001

    Article  CAS  Google Scholar 

  92. Clarke, T.-K., et al., The Dopamine Receptor D2 (DRD2) SNP rs1076560 is Associated with Opioid Addiction. Annals of Human Genetics, 2014. 78(1): p. 33–39 DOI: https://doi.org/10.1111/ahg.12046

  93. Groman, S.M. and J.D. Jentsch, Cognitive control and the dopamine D2-like receptor: a dimensional understanding of addiction. Depression Anxiety, 2012. 29(4): p. 295–306 DOI: https://doi.org/https://doi.org/10.1002/da.20897

  94. Jorm AF, Henderson AS, Jacomb PA, Christensen H, Korten AE, Rodgers B, Tan X, Easteal S (2000) Association of smoking and personality with a polymorphism of the dopamine transporter gene: results from a community survey. Am J Med Genet 96(3):331–334. https://doi.org/10.1002/1096-8628(20000612)96:3<331::aid-ajmg19>3.0.co;2-0

    Article  CAS  PubMed  Google Scholar 

  95. Laine TP, Ahonen A, Räsänen P, Tiihonen J (2001) Dopamine transporter density and novelty seeking among alcoholics. J Addict Dis 20(4):91–96. https://doi.org/10.1300/j069v20n04_08

    Article  CAS  PubMed  Google Scholar 

  96. Lerman C, Caporaso NE, Audrain J, Main D, Bowman ED, Lockshin B, Boyd NR, Shields PG (1999) Evidence suggesting the role of specific genetic factors in cigarette smoking. Health Psychol 18(1):14–20. https://doi.org/10.1037/0278-6133.18.1.14

    Article  CAS  PubMed  Google Scholar 

  97. Schmidt LG, Harms H, Kuhn S, Rommelspacher H, Sander T (1998) Modification of alcohol withdrawal by the A9 allele of the dopamine transporter gene. Am J Psychiatry 155(4):474–478. https://doi.org/10.1176/ajp.155.4.474

    Article  CAS  PubMed  Google Scholar 

  98. Ferraro, S., et al., In Medication-Overuse Headache, fMRI Shows Long-Lasting Dysfunction in Midbrain Areas. Headache, 2012. 52(10): p. 1520–1534 DOI: https://doi.org/https://doi.org/10.1111/j.1526-4610.2012.02276.x

  99. Riederer F, Marti M, Luechinger R, Lanzenberger R, von Meyenburg J, Gantenbein AR, Pirrotta R, Gaul C, Kollias S, Sándor PS (2012) Grey matter changes associated with medication-overuse headache: correlations with disease related disability and anxiety. World J Biol Psychiatry 13(7):517–525. https://doi.org/10.3109/15622975.2012.665175

    Article  PubMed  Google Scholar 

  100. Lai TH, Chou KH, Fuh JL, Lee PL, Kung YC, Lin CP, Wang SJ (2016) Gray matter changes related to medication overuse in patients with chronic migraine. Cephalalgia 36(14):1324–1333. https://doi.org/10.1177/0333102416630593

    Article  PubMed  Google Scholar 

  101. Chong CD, Schwedt TJ, Hougaard A (2019) Brain functional connectivity in headache disorders: a narrative review of MRI investigations. J Cereb Blood Flow Metab 39(4):650–669. https://doi.org/10.1177/0271678X17740794

    Article  PubMed  Google Scholar 

  102. Fumal A, Laureys S, di Clemente L, Boly M, Bohotin V, Vandenheede M, Coppola G, Salmon E, Kupers R, Schoenen J (2006) Orbitofrontal cortex involvement in chronic analgesic-overuse headache evolving from episodic migraine. Brain 129(Pt 2):543–550. https://doi.org/10.1093/brain/awh691

    Article  PubMed  Google Scholar 

  103. Carlsen LN, Munksgaard SB, Jensen RH, Bendtsen L (2018) Complete detoxification is the most effective treatment of medication-overuse headache: a randomized controlled open-label trial. Cephalalgia 38(2):225–236. https://doi.org/10.1177/0333102417737779

    Article  PubMed  Google Scholar 

  104. Engelstoft IMS, Carlsen LN, Munksgaard SB, Nielsen M, Jensen RH, Bendtsen L (2019) Complete withdrawal is the most feasible treatment for medication-overuse headache: a randomized controlled open-label trial. Eur J Pain 23(6):1162–1170. https://doi.org/10.1002/ejp.1383

    Article  PubMed  Google Scholar 

  105. Evers S, Jensen R, S. European Federation Of neurological (2011) Treatment of medication overuse headache--guideline of the EFNS headache panel. Eur J Neurol 18(9):1115–1121. https://doi.org/10.1111/j.1468-1331.2011.03497.x

    Article  CAS  PubMed  Google Scholar 

  106. de Goffau MJ, Klaver ARE, Willemsen MG, Bindels PJE, Verhagen AP (2017) The effectiveness of treatments for patients with medication overuse headache: a systematic review and meta-analysis. J Pain 18(6):615–627. https://doi.org/10.1016/j.jpain.2016.12.005

    Article  CAS  PubMed  Google Scholar 

  107. Diener HC, Antonaci F, Braschinsky M, Evers S, Jensen R, Lainez M, Kristoffersen ES, Tassorelli C, Ryliskiene K, Petersen JA (2020) European academy of neurology guideline on the management of medication-overuse headache. Eur J Neurol 27(7):1102–1116. https://doi.org/10.1111/ene.14268

    Article  CAS  PubMed  Google Scholar 

  108. Tiseo C, Ornello R, Pistoia F, Sacco S (2019) How to integrate monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor in daily clinical practice. J Headache Pain 20(1):49. https://doi.org/10.1186/s10194-019-1000-5

    Article  PubMed  PubMed Central  Google Scholar 

  109. Tepper SJ, Diener HC, Ashina M, Brandes JL, Friedman DI, Reuter U, Cheng S, Nilsen J, Leonardi DK, Lenz RA, Mikol DD (2019) Erenumab in chronic migraine with medication overuse: subgroup analysis of a randomized trial. Neurology 92(20):e2309–e2320. https://doi.org/10.1212/WNL.0000000000007497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Dodick DW, Doty EG, Aurora SK, Ruff DD, Stauffer VL, Jedynak J, Dong Y, Pearlman EM (2020) Medication overuse in a subgroup analysis of phase 3 placebo-controlled studies of galcanezumab in the prevention of episodic and chronic migraine. Cephalalgia:333102420966658. https://doi.org/10.1177/0333102420966658

  111. Silberstein SD, Cohen JM, Seminerio MJ, Yang R, Ashina S, Katsarava Z (2020) The impact of fremanezumab on medication overuse in patients with chronic migraine: subgroup analysis of the HALO CM study. J Headache Pain 21(1):114. https://doi.org/10.1186/s10194-020-01173-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Pijpers JA, Kies DA, Louter MA, van Zwet EW, Ferrari MD, Terwindt GM (2019) Acute withdrawal and botulinum toxin a in chronic migraine with medication overuse: a double-blind randomized controlled trial. Brain 142(5):1203–1214. https://doi.org/10.1093/brain/awz052

    Article  PubMed  PubMed Central  Google Scholar 

  113. Hagen K, Albretsen C, Vilming ST, Salvesen R, Grøning M, Helde G, Gravdahl G, Zwart JA, Stovner LJ (2009) Management of medication overuse headache: 1-year randomized multicentre open-label trial. Cephalalgia 29(2):221–232. https://doi.org/10.1111/j.1468-2982.2008.01711.x

    Article  CAS  PubMed  Google Scholar 

  114. Negro A, Curto M, Lionetto L, Guerzoni S, Pini LA, Martelletti P (2017) A critical evaluation on MOH current treatments. Curr Treat Options Neurol 19(9):32. https://doi.org/10.1007/s11940-017-0465-2

    Article  PubMed  Google Scholar 

  115. Grazzi L, Bussone G (2011) What future for treatment of chronic migraine with medication overuse? Neurol Sci 32(Suppl 1):S19–S22. https://doi.org/10.1007/s10072-011-0553-0

    Article  PubMed  Google Scholar 

  116. Grazzi L, Andrasik F, D'Amico D, Leone M, Usai S, Kass SJ, Bussone G (2002) Behavioral and pharmacologic treatment of transformed migraine with analgesic overuse: outcome at 3 years. Headache 42(6):483–490. https://doi.org/10.1046/j.1526-4610.2002.02123.x

    Article  PubMed  Google Scholar 

  117. Andrasik F, Buse DC, Grazzi L (2009) Behavioral medicine for migraine and medication overuse headache. Curr Pain Headache Rep 13(3):241–248. https://doi.org/10.1007/s11916-009-0041-x

    Article  PubMed  Google Scholar 

  118. Sancisi E, Rausa M, Zanigni S, Cevoli S, Pala AN, Nicodemo M, Grimaldi D, Montagna P, Cortelli P, Pierangeli G (2009) Self-help group and medication overuse headache: preliminary data. Neurol Sci 30(6):459–463. https://doi.org/10.1007/s10072-009-0131-x

    Article  PubMed  Google Scholar 

  119. Radat F, Chanraud S, di Scala G, Dousset V, Allard M (2013) Psychological and neuropsychological correlates of dependence-related behaviour in medication overuse headaches: a one year follow-up study. J Headache Pain 14(1):59. https://doi.org/10.1186/1129-2377-14-59

    Article  PubMed  PubMed Central  Google Scholar 

  120. Volkow ND, Boyle M (2018) Neuroscience of addiction: relevance to prevention and treatment. Am J Psychiatry 175(8):729–740. https://doi.org/10.1176/appi.ajp.2018.17101174

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The European Headache Federation and the Department of Clinical and Molecular Medicine, Sapienza University of Rome, are gratefully acknowledged for supporting this work.

Funding

This work was supported by the European Headache Federation.

Author information

Authors and Affiliations

Authors

Consortia

Contributions

TTT and RO designed the outline, wrote the manuscript, corrected, formatted and led the review. MA and SV collaborated to the ‘Background’ section; LP and SDM to the ‘Medication to abort headache attacks’ subsection; DDL, VS, AVD, MF, MG, and CMDM to the ‘MO and drug addiction: the overlapping features’ section; GQ and AT to the ‘Common systems in MO and drug addiction’ subsection; CD and EC to the ‘Treatments of MO’ section; AMvdB and PM initiated the organization of the manuscript, and revised and corrected the manuscript; all authors reviewed the manuscript. The author(s) read and approved the final manuscript.

Corresponding author

Correspondence to Tatiane Teru Takahashi.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Takahashi, T.T., Ornello, R., Quatrosi, G. et al. Medication overuse and drug addiction: a narrative review from addiction perspective. J Headache Pain 22, 32 (2021). https://doi.org/10.1186/s10194-021-01224-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s10194-021-01224-8

Keywords