**7. Underlying pathways for headache chronification following treatment abuse**

It is a well-known fact that chronic exposure to pain treatment [92] as well suffering from chronic pain, especially chronic headache, increase the risk of chronic pain development due to "*reduced endogenous inhibition of pain, implying that an individual's processing of pain-related information changes with the onset of the syndrome*" [93]; however, the underlying mechanisms behind it still remain partially unknown.

Among the painful syndromes, chronic headache is one of those most commonly associated with long lasting analgesic consumption, termed medication overuse headache (MOH) when it occurs, a pathological entity "defined by the International Headache Society as a headache induced by the overuse of analgesics, triptans, or other acute headache compounds whose detailed pathophysiology is still unknown" [94]. Current knowledge indicates that it can take up to 25 years for a chronic pain condition to develop after the use of chronic analgesics MOH [95] with strong evidence to support that chronic use of analgesics is a good predictor of an increased occurrence of both migraine and nonmigrainous headaches within the next 11 years, with a combined risk ratio of 19.6%, which is extremely high when compared to only 3.1% for patients who do not overuse analgesic treatments [96]. But analgesics are not the only medications involved in MOH, ergots and triptans also play a key role in MOH, with a shorter interval between initial treatment and development of induced chronic headache. "*The delay between first intake and these attacks is the shortest for triptans (1–2 years), longer for ergots (3–5 years)*" [97] and the longest for analgesics as it was previously mentioned. In this regard, the risk of induced chronic headache is lower for triptans (i.e., sumatriptan) than for ergotamine [98], which is good news for patients since triptans are the drug of choice before ergotamine. The problem when trying to establish a prevention/treatment strategy for drug-induced headache as well as MOH arises from the fact that different drugs are involved in their development; hence, there is no single way to explain the related mechanisms or physiopathology. Even more complex is the attempt to establish the diagnosis of MOH or drug-induced headache since most of the time the clinical profile of the primary entity is the same as the induced one, making it very difficult to establish a difference among them and even worse, to determine when the primary headache has ended and MOH appeared. A single approach to establish such differences is symptom improvement with treatment withdrawal [99]; the headache was drug induced and not of a primary origin and once the trigger (the drug) has ceased, symptoms should improve.

**Figure 4** shows a schema of what happens during drug-induced headache and how the diagnosis may be addressed regardless of the underlying molecular mechanisms.

**Figure 4.** Drug-induced headache vicious circle [100].

stages, their chronic, unsupervised use and abuse tends to lead toward pain chronification; increasing the number of pain crises, intensity of pain, and resistance to regular analgesic dosing. Moreover, relapsing after medication withdrawal is still a major issue regarding both preventive and rescue primary headache treatments [90]. How many patients progress toward chronification will vary depending on the abused medication, according to Bigal "*available data suggest that opioids induce migraine chronification (progression), and the effect is dose dependent (critical dose around 8 days of exposure per month) and more pronounced in men. Barbiturates also induce migraine progression, and the effect is dose dependent (critical dose around 5 days of exposure per month) and more pronounced in women. Triptans induce migraine progression only in those with high migraine frequency at baseline (10–14 days per month), but not overall. NSAIDs protect against migraine progression unless individuals have 10 or more headache days per month (when they become inducers, rather than protective). Finally, caffeine-containing over-thecounter products increase risk of progression*" [91], thus each available drug used must be monitored individually in order to avoid overuse and abuse-related complications. Why and how primary headaches progress to chronification because of treatment abuse is still partially

**7. Underlying pathways for headache chronification following** 

It is a well-known fact that chronic exposure to pain treatment [92] as well suffering from chronic pain, especially chronic headache, increase the risk of chronic pain development due to "*reduced endogenous inhibition of pain, implying that an individual's processing of pain-related information changes with the onset of the syndrome*" [93]; however, the underlying mechanisms

Among the painful syndromes, chronic headache is one of those most commonly associated with long lasting analgesic consumption, termed medication overuse headache (MOH) when it occurs, a pathological entity "defined by the International Headache Society as a headache induced by the overuse of analgesics, triptans, or other acute headache compounds whose detailed pathophysiology is still unknown" [94]. Current knowledge indicates that it can take up to 25 years for a chronic pain condition to develop after the use of chronic analgesics MOH [95] with strong evidence to support that chronic use of analgesics is a good predictor of an increased occurrence of both migraine and nonmigrainous headaches within the next 11 years, with a combined risk ratio of 19.6%, which is extremely high when compared to only 3.1% for patients who do not overuse analgesic treatments [96]. But analgesics are not the only medications involved in MOH, ergots and triptans also play a key role in MOH, with a shorter interval between initial treatment and development of induced chronic headache. "*The delay between first intake and these attacks is the shortest for triptans (1–2 years), longer for ergots (3–5 years)*" [97] and the longest for analgesics as it was previously mentioned. In this regard, the risk of induced chronic headache is lower for triptans (i.e., sumatriptan) than for ergotamine [98], which is good news for patients since triptans are the drug of choice before ergotamine. The problem when trying to establish a prevention/treatment strategy for drug-induced headache

unknown and a field of very active research.

158 Pain Relief - From Analgesics to Alternative Therapies

behind it still remain partially unknown.

**treatment abuse**

Of note, opioids have been found to be one of the most problematic drugs found to induce chronic headache, regardless of the purpose of their use whether it be chronic headache or any other chronic pain condition such as back pain, oncologic pain, and so on. The underlying mechanism seems to be "*the activation of toll-like receptor-4 on glial cells, resulting in a pro- inflammatory state that manifests clinically as increased pain*" [101], such activation may explain not only the development of MOH but also of the transformation to migraine [102].

Another hypothesis sustained by preclinical research is the presence of neuroadaptive changes related to chronic use of opiates; such changes "*include increased expression of calcitonin gene-related peptide (CGRP) in trigeminal primary afferent neurons. Centrally, they include increased excitatory neurotransmission at the level of the dorsal horn and nucleus caudalis. Critically, these neuroadaptive changes persist for long periods of time and the evoked release of CGRP is enhanced following morphine pretreatment* [103]*; all these changes lead to Induced Hyperalgesia* [101, 104] *and thus Headache Chronification*."

But opiates are not the only molecules associated with MOH, there is also strong evidence suggesting that combined analgesics as well as joined ergotamine-caffeine preparations may induce a metabolic decrease in several brain areas, especially the orbitofrontal cortex leading to a decrease in intrinsic pain downregulation circuits and the development of chronic headaches such as MOH and modified migraine (MM) [105]. Such metabolic changes may be associated with the sensitization of the trigeminal and somatic nociceptive systems; another possible path leading to MOH was demonstrated by Ayzenberg et al. on triptaninduced MOH [106].

Furthermore, the mechanisms stated earlier may be connected to others both centrally and peripherally by a complex net of interactions currently unknown but feasible such as "*upregulation of calcitonin gene–related peptide, substance P, and nitric oxide synthase in trigeminal ganglia; expansion of receptive field and decreased nociceptive threshold of central trigeminal neurons; decrease in diffuse noxious inhibitory control; and increased susceptibility to develop cortical spreading depression (CSD). These changes indicate an increase in excitability of cortical and trigeminal neurons. The neuronal hyperexcitability may be the result of derangement of a central, possibly serotonin (5-HT) dependent, modulating control system. Experiments with animals with low 5-HT showed that the processes of CSD and trigeminal nociception are enhanced in this condition*" [107] as it has been demonstrated by Bongsebandhu et al. in animal models.

The available information clearly supports the theory that analgesics and painkillers play an active role in the chronification of headache, which is a real concern for the medical community considering the high number of available over-the-counter analgesics. Furthermore, primary therapies such as triptans are also involved in MOH development after chronic use and there is even weaker evidence to explain the underlying pathways that cause this occurrence. At the moment the most probable mechanism of triptaninduced MOH is "*induction of neural adaptations that result in a state of latent sensitization, which might increase sensitivity to migraine triggers"* [108], in addition, *"triptan administration promotes increased expression of neuronal nitric oxide synthase in dural afferents, which is critical for enhanced sensitivity to environmental stress, which is a biological basis for increased frequency of headache following*" [109].

Certainly, current knowledge regarding MOH and other types of headache chronification caused by the use of therapy is still lacking although the results from many research reports are available. However, until a deeper scientific understanding is available regarding this relatively new entity, it becomes necessary to improve the diagnostic criteria and methods, enhance treatment protocols, and provide proper monitoring not only to chronic primary headache patients but also to each one suffering from a chronic pain condition.

Until a more precise and wider scope of information is available, prevention remains the best, most cost-effective option used to prevent headache treatment abuse-related complications. When the disorder of MOH and drug-induced headache presents, the main treatment must be treatment withdrawal and even then the discussion on what is the best withdrawal method (stationary vs. ambulatory) still remains inconclusive [110]; as a preventive strategy, drug combinations must be avoided as much as possible and high-risk patients who develop MOH must be regularly evaluated to ensure that no late complications are showing up during long-term treatment.
