INTRODUCTION: FROM EPISODIC TO CHRONIC MIGRAINE
Migraine is a debilitating headache disorder including both episodic and chronic forms. It is currently ranked by the World Health Organization as 19th among causes for years lived with disability. Because there are no biological markers for migraine, diagnosis is based on clinical history and the exclusion of other headache disorders (Defining the Differences Between Episodic Migraine and Chronic Migraine, 2011).
The definition of migraine from the second edition of the International Classification of Headache Disorders requires all of the following symptoms:
- Frequency of headaches which must occur on 15 or more days per month for at least 3 months of which at least 8 days with headaches fulfilling the criteria for migraine ;
- Untreated or unsuccessfully treated headache duration of 4 to 72 h;
- At least two of the following pain characteristics: unilateral, pulsating, moderate or severe intensity, or aggravated by routine physical activity;
- Association with at least one of the following symptoms: nausea/vomiting, photophobia, or phonophobia (Chronic migraine, 2006).
Chronic migraine constitutes migraine natural evolution from its episodic form. Episodic migraine (EM) is characterized by a frequency of attacks between 0 and 14 per month, while chronic migraine (CM) is characterized by 15 or more headache days per month. The prevalence rate of CM in general population is 2–4%: each year, approximately 2.5% of patients with episodic migraine (EM) develop new-onset CM. Because not all EM progress to CM, special attention should be paid in order to identify risk factors which might favor the migraine chronicization process and/or the outbreak of MOH (Tracing transformation: chronic migraine classification, progression, and epidemiology, 2009).
RISK FACTORS
We can distinguish two groups of risk factors:
- Non-modifiable risk factors: older age, female sex, caucasian race, worse socioeconomic status, low education level (Risk factors for headache chronification, 2008); it must also have to be included in this group the genetic factors since recent studies (Drug consumption in medication overuse headache is influenced by brain-derived neurotrophic factor Val66Met polymorphism, 2009) showed that a single-nucleotide polymorphism of BDNF gene, resulting in a Valine 66 to Methionine (Val66Met) is related with behavior disorders and substance abuse.
- Modifiable factors: attack frequency, obesity (Putative mechanisms of the relationship between obesity and migraine progression, 2008), medication overuse (A narrative review on the management of medication overuse headache: the steep road from experience to evidence, 2009), caffeine use/misuse (High dietary caffeine consumption is associated with a modest increase in headache prevalence: results from the Head-HUNT Study,2009), sleep disorders including snoring, obstructive sleep apnea, insomnia, hypersomnia (Associations between sleep disturbance and primary headaches: the third Nord-Trøndelag Health Study, 2010), stressful life events (Associations between headache and stress, alcohol drinking, exercise, sleep, and comorbid health conditions in a Japanese population, 2009) , specific psychological patterns including depression, anxiety, and personality disorders (Migraine and psychiatric comorbidity: a review of clinical findings, 2011), behavioral issues (Association between lifestyle factors and headache, 2011), and family history of mood disorders and substance use disorders such as alcohol and drugs (Family history for chronic headache and drug overuse as a risk factor for headache chronification, 2009).
Other risk factors currently being investigated include low serum vitamin D levels (The prevalence of headache may be related with the latitude: a possible role of Vitamin D insufficiency?, 2010) and gastroesophageal reflux disease (GERD prevalence in migraine patients and the implication for acute migraine treatment, 2009).
Regarding Medication Overuse, the frequent use (>15 times/month) of medication for the treatment of acute migraine attacks may cause MOH. This kind of headache can be caused by the intake of a combination of analgesics, opioids, ergot alkaloids and triptans. The delay between first intake and these attacks is shortest for triptans (1-2 years), longer for ergots (3-5 years) and longest (5-10 years) for analgesics.
The risk is progressively higher in those taking barbiturates, followed by opiates, triptans and NSAID. The latter, like NSAIDs and triptans, can induce progression in those with more than 10-14 headache days per month, but whether combined with barbiturates or caffeine, they can induce headache after a short period and with use of lower doses. MOH develops faster and in a much lower dose with triptans than ergot or simple analgesic alone(Medication Overuse Headache, 2001).
Furthermore, it has been observed (Does chronic daily headache arise de novo in association with regular use of analgesics?, 2003) that chronic overuse of analgesics does not cause increased headache in nonmigraineurs. For example, a group of arthritis patients who were consuming fairly large amounts of analgesics regularly for arthritis did not show increased incidence of headache. The conclusion drawn from various clinical observations and studies is that medication overuse headache may be restricted to those who are already headache sufferers. The basis for this could either be genetic or the fact that migraine pain is more severe than joint pain. Different mechanisms probably contribute to the transition from the original headache to medication overuse headache. For instance, many patients report taking migraine drugs prophylactically because they are worrying about missing work (or, inevitably, the job) or missing an important social event. More importantly, patients often fear an imminent headache and take analgesics or specific migraine drugs prophylactically as they are often instructed by the physicians or by the instructions supplied with the medication to take the migraine drug as early as possible at the start of either the aura or the headache phase of a migraine attack.
DEFINITION OF MOH
Medication Overuse Headache (MOH) is a common and debilitating disorder, which is characterized by generation, perpetuation and persistence of intense chronic migraine caused by the frequent and excessive use of symptomatic drugs for at least 3 months, for a certain number of days per month. It is a clinical important entity which may complicate each type of headache and all the drugs employed for headache treatment can cause MOH. Classification criteria of abuse are related to the pharmaceutical class applied during acute treatment, namely of 15 days/month for analgesics and non-steroid anti-inflammatory drugs (NSAID), and 10 days/month for mixed drugs including triptans, ergotamines, opioids, and NSAID.
Several clinical characteristics are helpful in identifying the occurrence of analgesic rebound headache in patients with primary headache disorders. The following are the clinical features of MOH (Medication Overuse Headache, 2001):
- The headaches are refractory, daily, or nearly daily;
- The headaches occur in a patient with primary headache disorders who use immediate relief medications very frequently, often in excessive quantities;
- The headache itself varies in its severity, type, and location from time to time;
- The slightest physical or intellectual effort may bring on headache. In other words, the threshold for head pain appears to be low;
- Headaches are accompanied by asthenia, nausea and other gastrointestinal symptoms, restlessness, anxiety, irritability, memory problems, and difficulty in intellectual concentration and depression;
- Those consuming large quantities of ergot derivatives or triptans may exhibit cold extremities, tachycardia, paraesthesias, diminished pulse, hypertension, light-headedness, muscle pain of the extremities, weakness of the legs, and depression;
- There is evidence of tolerance to analgesics over time, with patients needing progressively larger doses;
- Withdrawal symptoms are observed when patients are taken off pain medications abruptly;
- Spontaneous improvement of headache occurs on discontinuing the medications;
- Concomitant prophylactic medications are relatively ineffective while the patients are consuming excess amounts of immediate relief medications.
EPIDEMIOLOGY
Among patients in headache clinics or centers of tertiary care, patients with MOH form the largest group along with migraine and tension-type headache. Up to 30% of patients in such centers in Europe, and more than 50% in the USA, present with MOH. It affects 1–4% of general population, with prevalence rates similar across different countries but with a higher preponderance in women than in men (Chronic migraine plus medication overuse headache: two entities or not?, 2011). It has been noted that the overuse of analgesics for chronic headache is not only prevalent in Europe and North America but also presents in Asian countries (Classification and clinical features of headache patients: an outpatient clinic study from China, 2011). Moreover, clinical evidences demonstrate that overuse associated with chronic forms of headache can occur even in childhood and early adolescence and not only in adults and elderly patients (Medication Overuse Headache in School-Aged Children: More Common Than Expected?, 2012).
PATHOPHYSIOLOGY
The way in which Medication Overuse transforms episodic migraine into chronic daily headache is still unknown but thanks to the improved neurophysiological and functional imaging techniques many studies has been made in the last decades in order to search for candidate brain areas involved in this process (Orbitofrontal cortex involvement in chronic analgesic-overuse headache evolving from episodic migraine, 2005). In this studies they measured glucose metabolism with 18-FDG PET in chronic migraineurs with analgesic overuse before and 3 weeks after medication withdrawal and compared the data with those of a control population.
These functional imaging studies in acute and chronic pain have demonstrated that multiple brain areas contribute to the various facets of pain processing and that they are interconnected within the pain network.
-Before withdrawal: bilateral thalamus, orbitofrontal cortex, anterior cingulate cortex, insula, ventral striatum, and right inferior parietal lobule were hypometabolic, while the cerebellar vermis was hypermetabolic.
-After withdrawal: all dysmetabolic areas recovered to almost normal glucose uptake, except the OFC where a further metabolic decrease was found. Medication overuse headache is thus associated with reversible metabolic changes in pain processing structures like other chronic pain disorders, but also with persistent orbitofrontal hypofunction. The orbitofrontal cortex hypofunction is known to occur in drug dependence and could predispose subgroups of migraineurs to recurrent analgesic overuse.
This finding of an abnormal glucose metabolism before medication withdrawal in areas belonging to the pain network is in line with several imaging studies performed in other pain disorders. In fact, these areas are involved in various aspects of pain processing: respectively in sensory discrimination, cognitive and attentional dimensions, emotional dimensions and unpleasantness. In most studies is underlined how changes predominate in the right-sided posterior parietal cortex, which has been attributed to the role of the right hemisphere in the emotional aspects of pain and behaviour and was also found during cluster headache attacks.
As regards the cerebellar vermis, it can be noticed an increased glucose metabolism in MOH before, and normalization of metabolism after analgesic withdrawal. Although typically activated in chronic ongoing neuropathic pain and in experimental acute phasic pain, the involvement of the cerebellar vermis was more recently emphasized in cognitive processing and suspected in drug addiction. The cerebellum could thus play a crucial role in MOH because it is involved both in pain processing and drug dependence.
The changes observed in OFC metabolism could specifically be related to drug dependence in MOH. There is indeed convincing evidence from FDG-PET, behavioral and pharmacological studies that the OFC plays a crucial role in drive and compulsive behavior and that its abnormal activation within the striato-thalamo-orbitofrontal circuit underlies the maladaptive behavior of substance abuse, including expectancy, craving and impaired decision making (Orbitofrontal Cortex and Human Drug Abuse: Functional Imaging, 2004).
Considering the available data on metabolic changes and role of the OFC in substance abuse, it can be speculated that the OFC hypometabolism found in analgesic-abusing migraineurs 3 weeks after withdrawal is related to their dependence on the analgesic compound and that its persistence will predispose them to relapsing drug overuse, as it has been confirmed by many clinical findings.
Indeed, persistence of OFC hypometabolism for several months after withdrawal is well known in substance abusers, including in alcoholics. It is thought to be responsible for reactivation of compulsive drug intake after prolonged periods of drug abstinence as a result of activation of reward circuits (nucleus accumbens, amygdala) by exposure either to the drug or to drug-conditioned stimuli.
Whether the OFC hypoactivity is secondary to the protracted drug self-administration or favoured by a genetic vulnerability to substance is still an unsolved question, but recent studies are supporting the hypothesis of a genetic correlation between some specific genetic polymorphisms and the amount of drug consumption in MOH patients (Drug consumption in medication overuse headache is influenced by brain-derived neurotrophic factor Val66Met polymorphism, 2009 and Role of 2 common variants of 5HT2A gene in medication overuse headache, 2010).
The image below shows the anatomical structures probably involved in the progression from migraine to MOH Medication-overuse headache: similarities with drug addiction, 2005.
(a) The trigger for migraine is neurogenic inflammation and the activation of the trigeminal neuron.
(b) The stimulus propagates in several brainstem nuclei: the trigeminal nucleus caudalis, the dorsal raphe nucleus, the locus coeruleus and the periacqueductal grey.
© From these nuclei, noradrenergic (NA) and 5-HT inputs project to the thalamus and cortex for sensory integration.
(d) Frequent migraine episodes coupled to an excessive use of symptomatic headache medication might lead to the transformation of migraine to medication-overuse headache.
(e) This transformation might involve a process of central sensitization that is mainly triggered by increased release of dopamine (DA) from a brainstem mesencephalic area such as the ventral tegmental area projecting to both cortical (prefrontal and limbic areas) and subcortical (ventral striatum) structures.
(f) Following the process of sensitization the maintenance of the habit to overuse drugs might be sustained by the increased release of DA in the dorsal striatum from neurons of the substantia nigra.
(g) GABAergic inputs from the striatum integrate with other sensory inputs in the thalamus.
MOLECULAR MECHANISM OF MOH SENSITIZATION
The image below shows the presumed cellular and molecular mechanisms potentially involved in the process of sensitization in medication overuse headache. Cortical glutamatergic and mesencephalic dopaminergic inputs converge on the postsynaptic striatal neuron by activating their respective receptors. 5-HT released from presynaptic neurons acts on 5-HT receptors on the presynaptic dopaminergic terminal to control the release of dopamine or activates its receptors on the postsynaptic cell. It is postulated that repeated exposure to the same substance sensitises the central receptors or reduce threshold of activation. Frequent intake of triptans may lead to down-regulation of 5-HT receptors and change central inhibitory pathways in some triggering areas of CNS (bilateral thalamus, anterior cingulated gyrus, inferior parietal lobe, cerebellar vermis and orbitofrontal cortex).
Activation of high-voltage-activated Ca2+ channels of various subtypes (N, P/Q and L) on presynaptic terminals regulates transmitter release from these terminals and activation of these channels on the postsynaptic cell leads to an increase in the intracellular levels of Ca2+, which are also regulated by ligand-gated Ca2+ channels controlled by either glutamate receptors (AMPA and NMDA) or dopamine D2-like receptors. The level of intracellular Ca2+ is of crucial importance for the regulation of protein kinase C (PKC) activity. Conversely, the activity of protein kinase A (PKA) is modulated by dopamine D1-like receptors and by 5-HT receptors. Nitric oxide (NO) activates protein kinase G (PKG), which interacts with PKA. Both PKC and PKA converge to regulate the mitogen-activated protein kinase (MAPK) cascade. MAPK leads to activation of nuclear transcription factors, triggering the transcription of immediate-early genes and late-response genes. Thus, the central sensitization could be considered an activity-dependent functional plasticity that results from activation of different intracellular kinase cascades (Medication-overuse headache: similarities with drug addiction, 2005).
PROPOSAL OF THERAPY
The first step in the management of CM complicated by medication overuse must be the withdrawal of the overused drugs and a detoxification treatment (Chronic migraine plus medication overuse headache: two entities or not?, 2011). The headache experts agree that withdrawal of the overused medication should be the first priority in all cases as preventive treatment can only be fully effective after the overused medication is stopped. The withdrawal also limits progression to chronic state, positively impact on pain coping behaviour and maximise response to acute treatment.
There is lack of consensus as to how (abrupt or gradual), where (in-patient or out-patient) and when (before or after preventive treatment) to detoxify. Opiates and those with barbiturates and caffeine must be withdrawn gradually due to unpleasant withdrawal effects while other analgesics can be stopped abruptly.
The duration of rebound symptoms is shortest with triptans (4 days) longer with ergot (6.7 days) and longest with NSAIDs (9.5 days).
It has been observed that discontinuation of the acute medication can result in worsening of the pre-existing headache, associated with nausea, vomiting, arterial hypotension, tachycardia, sleep disturbances, restlessness, anxiety, nervousness and rebound headache. Seizures or hallucinations, although rare, are observed in patients who overuse barbiturates containing anti-migraine drugs. These symptoms generally last between 2 and 10 days, but can persist for up to 4 weeks. Withdrawal symptoms are usually relieved by further intake of the overused medication, but this could also lead to perpetuation of the overuse. The psychotropic side-effects of analgesic or migraine drugs such as sedation or mild euphoria and their stimulating action may lead to drug dependency. Barbiturates, codeine, other opioids and caffeine are the most likely substances to have this effect. Caffeine increases vigilance, relieves fatigue, and improves performance and mood. The typical symptoms of caffeine withdrawal such as irritability, nervousness, restlessness, and especially “caffeine withdrawal headache”, which may last for several days, encourage the patients to continue their abuse (Medication-overuse headache: a worldwide problem, Diener and Limmroth, 2004).
As regards the place where patients have to be detoxified, a direct comparison between inpatient and outpatient withdrawal treatment shows that both methods lead to a significant reduction of headache days/month and migraine disability after 12 months, without superiority of one method. Since the outpatient withdrawal approach is less expensive than the inpatient approach, and it is as successful in motivated patients, it is the preferred choice in many cases. Nevertheless, a substantial difference between Europe and the United States must be underlined. In Europe barbiturates in pain medication are banned and basically no one prescribes opioids for the treatment of headache whereas in the United States, barbiturates and opioids are the leading drugs that are overused. In patients who overuse these 2 kinds of drugs, it is advisable to provide the withdrawal treatment on an inpatient basis because the relapse rate is very high if withdrawal treatment is done on an outpatient basis (Chronic daily headaches, Fayyaz et al, 2012).
In the graphic below we can observe the course of headache intensity (top) and percentage of patients with headache (bottom) during 14 days of withdrawal therapy after medication overuse.
As it was said before, the first steps in the management of CM complicated by medication overuse must be the withdrawal of the overused drugs and a detoxification treatment. This is necessary in order to stop the chronic headache and mostly to improve the answer to the second step of the management, represented by re-prophylaxis with preventive medications that must be started immediately after the detoxification.
Decades of research on the individual clinical features of CDH (Chronic Daily Headache) sufferers, and on their response to the medications currently available, have demonstrated the existence of a subgroup of patients with a CDH which appeared to be resistant to treatment, as physicians working in headache clinics or centers of tertiary care can confim.
A recent randomized, double blind, active-controlled, crossover study, made on thirty MOH patient enrolled at the University of Modena’s Interdepartmental Centre for Research on Headache and Drug Abuse, demonstrated Nabilone’s efficacy and safety in reducing pain and frequency of headache, the number of analgesic intake and in increasing the quality of life on patients with long-standing intractable MOH (Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial, 2012).
Nabilone is a synthetic cannabinoid CB1-receptor agonist (licensed in Canada since 1981 for chemotherapy-induced vomiting and nausea); it is well-tolerated and has a good safety profile.
The study shows that Nabilone is more effective than Ibuprofen in reducing pain intensity and daily analgesic intake (p < 0.05); moreover, Nabilone seems to be the only drug able to reduce the level of medication dependence (−41 %, p < 0.01) and to improve the quality of life (p < 0.05). Side effects were uncommon, mild and disappeared when Nabilone was discontinued.
The main limits of this research are the small sample size and the short duration of the study. However, these results were obtained in a selected chronic headache population considered a representative sample of the most severe MOH patients who failed to respond to all available pharmacological treatments. Even though more studies would have to be carried out to confirm this discovery, this is the first randomized controlled trial demonstrating the benefits of Nabilone on headache, analgesic consumption and the quality of life in patients with intractable MOH.
Finally, it has been proved that the oral administration of cannabinoid drugs has a poorer bioavailability than when these drugs are administered by inhalation. An oromucosal spray of THC was one way of releasing active principle into the central nervous system, however, the rapid administration of cannabinoid drugs had different effects to those observed with slow absorption: the reward system is activated by a rapid rise in cannabinoids concentration, such as to obtain a significant euphoric effect, the main cause of dependence. This way, the oral cannabinoids administration avoids concentration peaks and with chronic administration, the individual differences in bioavailability are overcome. The use of Nabilone, a cannabinoid1-receptor agonist, would therefore appear reasonable in the treatment of MOH for which central mechanisms are hypothesised in the maintenance of chronic head pain due to medication overuse.
CONSIDERATIONS ON NABILONE’S EFFICACY
The requirements for understanding Nabilone efficacy in the treatment of MOH are the discoveries made in the last two decades in the field of Cannabinoids added to recent studies made on Nabilone in the treatment of chemotherapy-induced nausea and vomiting (A review of Nabilone in the treatment of chemotherapy-induced nausea and vomiting, 2008).
Since the definitive identification of cannabinoid (CB) receptors in humans, a better understanding of the science behind the effects of exogenous cannabinoids has emerged. Two CB receptors have been identified in humans (CB1 and CB2) which are recognized exclusively by cannabinoids (International Union of Pharmacology. XXVII. Classification of cannabinoid receptors, 2002). The CB1 receptor is present in high densities in areas of the central nervous system (CNS), and it is the interaction between Nabilone and this receptor and its signaling pathways that appears to be responsible for the antiemetic effects of the agent.
Endocannabinoids (endogenous cannabinoid ligands that act on CB receptors) exert complex effects, including the modulation of neurotransmitters known to be involved in CINV and probably in the MOH. More specifically, endocannabinoids activate the pre-synaptic CB1 receptor, inhibiting release of both excitatory and inhibitory neurotransmitters in the CNS and peripheral nervous system (glutamate and GABA respectively). In fact, these endogenous ligands for the cannabinoid CB1 receptor fulfill an essential role in the brain as retrograde synaptic messengers, in a number of structures including the hippocampus, cerebellum and the limbic and mesocortical systems. This essential discovery provides a cellular basis for the ubiquitous role of the endocannabinoids and their receptors (Endocannabinoid system: An overview of its potential in current medical practice, 2009).
The following image shows the mechanism of action of Cannabinoids: the innate cannabinoid system inhibits release of neurotransmitters via a multi-step retrograde signaling pathway. Nabilone mimics the action of endocannabinoids via direct activation of CB1 receptors: this way it could exert its function of neuromodulator, down-regulating 5HT and dopamine receptors and therefore preventing the increase of calcium concentration and the subsequent starting of the signal pathway.
