**5. Pharmacological options for headache treatment**

It is a well-known fact that prevention of a medical condition is usually the best approach because it tends to be easier, cheaper, and cost effective; hence the aim of primary headache treatment should be focused on such a target. However, at this moment, prevention strategies for primary headache are not 100% reliable and the failure rates are high [26] leading to the use of palliative measures in order to relieve patients' suffering derived mainly from migraine and tension-type headache.

In this regard, current pharmacological approaches include two major groups of action: pain relief and brain modulation, each one aimed to act on a particular stage. Although pain relief should be the last resort and be used only when modulation and prevention have failed, this is the main therapeutic approach in real life, treating the problem once it has fully showed up; the reason behind such behavior could be related to the ancient approach toward headache based on pain relief, used for decades when primary headache was not known as it is today and no other therapeutic option was available; and although there may be numerous and powerful effective pain killers and analgesics available, this option should be restricted only to cases where prevention has failed; always giving priority to novel, preventive therapies offering patients a better quality of life [27]. With the everyday increase in knowledge on primary headache pathophysiology, neurochemistry, and pain pathways, modern, current treatments of primary headaches intended to act as brain modulators have gained popularity because they are more expensive than conventional pain killers, such drugs are able to give patients a better quality of life, decreasing the negative impact of headache on both personal and work commitments [28]. Novel migraine and tension-type headache treatments exert their action in several ways but with a common goal: reduction of pain crisis by downregulating sensitized brain pathways, which usually act as a trigger or maintain the headache pain crisis, leading to an overall reduction of acute primary headache and thus a drop in the requirements for over-the-counter (OTC) painkillers and prescription analgesic use.

According to the U.S. Headache Consortium the scope of modern migraine treatment must be to:


could be possible to treat different primary headache types with a single drug working on key, shared points of the pain pathway [25]; however, more extensive research as well as a deeper understanding of different pain pathway integration is needed to achieve such goals; primary headache treatments still focus on two main targets: pain control and crisis prevention.

146 Pain Relief - From Analgesics to Alternative Therapies

**5. Pharmacological options for headache treatment**

**Figure 2.** Blood vessel innervation pattern and migraine associate pain pathways [22].

and tension-type headache.

It is a well-known fact that prevention of a medical condition is usually the best approach because it tends to be easier, cheaper, and cost effective; hence the aim of primary headache treatment should be focused on such a target. However, at this moment, prevention strategies for primary headache are not 100% reliable and the failure rates are high [26] leading to the use of palliative measures in order to relieve patients' suffering derived mainly from migraine


It is clear that the use of OTC painkillers and analgesics are a last resort and is considered to be a damage control strategy, leading the way not only to better control of the migraine but also to a reduction in headache medication overuse [30].

Hence, the aforementioned medications may be extrapolated for use with tension-type and cluster headaches due to them having similar pathological pathways and neurotransmitters shared by the three major causes of primary headache.

The modern approach toward current headache management is shown in **Figure 3**.

After careful analysis of **Figure 3**, one can deduce that primary headaches still remain a diagnostic and therapeutic challenge, where a misdiagnosis or improper drug selection could lead to treatment failure, with unexpected consequences not only by reducing the patient's quality of life but also due to the possible development of complications, thus it is mandatory to have a clear idea of available treatments and their mechanisms of action in order to properly select one or another option when necessary.

**Figure 3.** Assessment and management of patients with primary headaches [31].

### **5.1. Comparison of the mechanism of action of different primary headache treatments**

to treatment failure, with unexpected consequences not only by reducing the patient's quality of life but also due to the possible development of complications, thus it is mandatory to have a clear idea of available treatments and their mechanisms of action in order to properly select

one or another option when necessary.

148 Pain Relief - From Analgesics to Alternative Therapies

**Figure 3.** Assessment and management of patients with primary headaches [31].

Due to the complex underlying pathologic mechanisms regarding primary headaches, common pain pathways, as well as the different drugs types and mechanisms of action, it is best to evaluate the most effective treatment for a particular patient by using a comparison chart because even though general guidelines may be helpful, primary headache treatment still needs to be individualized and adapted to the particular requirements of each patient. Modern therapeutic options for primary headaches as well as their primary and complementary mechanisms of action and indications are summarized in **Table 1**.



\*The model drug is shown as the main drug even when there are other molecules sharing the same mechanism of action (shown below the main category group in brackets).

\*\*Even when each one has good therapeutic effect using alone, recent investigations suggest that combination of fixed doses of paracetamol, NSAIDs, and caffeine is more effective that any single drug alone [54].

+Some studies show that the addition of metoclopramide to paracetamol potentiates its effects on migraine patients [49]. ++Despite the well-known analgesic effect of opiates, there is no strong clinical trials supporting their use in migraine, thus its use must be considered when all other available therapies have failed [55].

**Table 1.** Comparison of different primary headache available treatments.

Different options are available to stop migraine attacks: acute, symptomatic treatment. According to recent clinical evidence, the common approach to treating a migraine attack is based on early intervention when the pain is still mild, which can result in shortening the time to achieve a pain-free response. A proper clinical approach, individual considerations for each patient and a quick view of the guidelines may help to provide the best treatment for specific case [56].

#### **5.2. Acute, sporadic headache treatment**

Many people in the general population have experienced at least one headache crisis which is usually of no major concern since it may be treated with OTC painkillers with no further complications or sequelae. In fact, sporadic headaches need no medical attention and most cases are resolved by the patients themselves [57].

The most popular treatments for this type of acute, primary headache include paracetamol, when pain intensity is mild to moderate, and aspirin or any other NSAIDs such as ibuprofen, for high intensity headaches; it usually requires no more than a single dose to control the crisis [58]. From this perspective, acute sporadic headache treatment represents no problem at all since the risk of complications derived from treatment use and abuse are low or even null; however, many tension-type headaches begin as sporadic ones and with time they progress to a classic chronic cephalalgia. On the other hand, many undiagnosed migraine patients with low intensity crisis make it through the year with a very low frequency of intense attacks (less than one a month) and may handle their headache as a sporadic one with relative success in its initial stages [59] but sooner or later, a chronic pattern will develop, requiring medical assistance, with treatment optimization and monitoring in order to avoid headache treatment abuse-related problems. Since paracetamol, aspirin, ibuprofen, and various other OTC drugs are effective, safe treatments for acute headache crisis [60], there are no major concerns regarding the risks and so the use of such medication must not be discouraged because it is not a threat for patients; however, the underdiagnosis of migraine as well as tension-type headaches must be addressed. Many undiagnosed patients are left to deal with, on their own, against complex headaches which do require professional counseling in order to obtain proper relief and avoid headache overuse treatment-related problems, which are much more difficult to manage.

#### **5.3. Chronic headache treatment**

Different options are available to stop migraine attacks: acute, symptomatic treatment. According to recent clinical evidence, the common approach to treating a migraine attack is based on early intervention when the pain is still mild, which can result in shortening the time to achieve a pain-free response. A proper clinical approach, individual considerations for each patient and a quick view of the guidelines may help to provide the best treatment for specific case [56].

\*The model drug is shown as the main drug even when there are other molecules sharing the same mechanism of action

\*\*Even when each one has good therapeutic effect using alone, recent investigations suggest that combination of fixed

+Some studies show that the addition of metoclopramide to paracetamol potentiates its effects on migraine patients [49]. ++Despite the well-known analgesic effect of opiates, there is no strong clinical trials supporting their use in migraine,

**Drug\* Drug class Mechanism of action Indication**

**NSAIDs Primary:** COX-1 and COX-2 inhibition

> - Suppression of signal towards the dorsal horn from the peripheral nerves by blocking TRPA1-receptors (peripheral pain pathway blockage) [47] - Inhibition of the reuptake of the endogenous cannabinoid/ vanilloid anandamide by neurons down regulating TRPV1 nociceptor stimulation (central pain pathway blockage) [48]

**NSAIDs Primary:** COX-2 inhibition [50] **Tension-type headache**

opioids receptors, down regulating central pain stimuli transmission [53] **Tension-type headache**

**Tension-type Headache**

**Migraine** (Rescue) [49]

+

(Rescue) [46]

(Rescue) [51] **Migraine** (Rescue) [52]

**Migraine** (Rescue)++

(Rescue)

Many people in the general population have experienced at least one headache crisis which is usually of no major concern since it may be treated with OTC painkillers with no further complications or sequelae. In fact, sporadic headaches need no medical attention and most

The most popular treatments for this type of acute, primary headache include paracetamol, when pain intensity is mild to moderate, and aspirin or any other NSAIDs such as ibuprofen, for high intensity headaches; it usually requires no more than a single dose to control the crisis [58]. From this perspective, acute sporadic headache treatment represents no problem at all

**5.2. Acute, sporadic headache treatment**

(shown below the main category group in brackets).

**Preventive and abortive treatments**

150 Pain Relief - From Analgesics to Alternative Therapies

**Rescue treatments (pain control)**

**Paracetamol\*\* Mild analgesic Primary:**

**Butorphanol Opiates Primary:** Binding to central

thus its use must be considered when all other available therapies have failed [55].

**Table 1.** Comparison of different primary headache available treatments.

doses of paracetamol, NSAIDs, and caffeine is more effective that any single drug alone [54].

**Acetylsalicylic acid - Aspirin-\*\***

**Ibuprofen\*\*** (Ketoprofen)

cases are resolved by the patients themselves [57].

It is clear that a common, acute headache crisis presents no danger neither for the patient nor public health; however, when headache crises become more frequent requiring regular self-medication, often with poor outcomes and when such crises are accompanied by other symptoms such as auras or nausea, it becomes compulsory on the part of the physician to evaluate the patient for more complex etiologies, more than just a sporadic headache, in this case, a thorough medical consultation is mandatory in order to properly assess the patient, providing a diagnosis and a treatment intended not only to relieve pain but also to prevent recurrences. As stated previously, a high percentage of migraine sufferers have had no formal diagnosis of the disease [61], while some others progress from acute crisis of the tension-type headache to a chronic pattern when sensitization pathways become activated [62]; in both cases, symptoms may develop so subtly that patients are not fully aware of the disease state and may remain on the same selfmedicating strategy for years despite the poor outcome. Even worse, this increases the chances of developing complications associated with improper management of chronic cephalea and treatment abuse. In this regard, the best strategy to conquer this problem is education. Beyond pharmacological treatment, it is important to inform the general public about primary headaches and how such entities may be easily confused with a banal headache and explain why their insidious evolution may render them undiagnosed for a long period of time; it is mandatory to educate patients about their diseases, giving emphasis to how important preventive medications are as primary therapy intended to reduce the likelihood of pain crises and increase their quality of life, leaving analgesics and OTC painkillers as a last resort when prevention has failed [63].

Implementation of education programs about headaches from school and on to the general public can be a key strategy to address the problem of underdiagnosis, misdiagnosis, and improper management of headaches [64]. The aim of such programs must be to encourage people to seek medical advice when certain headache patterns show up and this will help direct them to specialized physicians who will provide the appropriate care and counseling [65, 66]. Unfortunately, due to an increase in the access to over-the-counter treatments, low income, lack of medical secure coverage, and unawareness about migraine, tension-type headaches, and other primary cephalalgias, the trend is moving toward self-medication instead of professional counseling [67] which has led to the improper use or even abuse of headache medications; however, once a headache patient has reached regular medical care, efforts must be made in order to enhance doctor-patient communication and provide as much information as possible to the patient [68] since having an in-depth knowledge of these diseases will lead to better management [69]; once patients are aware of a medical condition such as primary headaches, they act as multipliers among their families, relatives, friends, and coworkers [70], making it easier to catch public interest on a public health problem like migraine and other primary headaches. It remains clear that education and information play a key role in addressing chronic primary headache; however, once a patient has grasped these important concepts and the physician has given a diagnosis, it is necessary to utilize the right tools in order to correctly estimate the impact of headache on their quality of life [71] and to choose the right treatment for each individual case; otherwise, using standardized protocols even in the medical community may present the danger of improper treatment and abuse of certain medications [72]. To accomplish such a delicate task, health care providers rely on many tools such as MIDAS (Migraine Disability Assessment Score) intended to objectively evaluate headache frequency, pain intensity, and associated symptoms so as to measure not only the impact of headache on quality of life but also to assess treatment outcomes leading to a personal, tailored treatment regimen for each patient [73]. Once the diagnosis has been achieved and the impact on both quality of life and productivity is assessed [74], the precise treatment can then be chosen for each patient. It is important to note that the main goal of chronic primary headache treatment is to lower as much as possible the number of pain crises (preventive treatment), the secondary objective is to end a possible a crisis once it has evolved and has been triggered (abortive treatment), and finally, rescue patients once a crisis has stopped (rescue treatment). Long-term treatment options for each step of therapy have widened, providing physicians with a variety of drugs acting on different key points in the pathological chain as seen in **Table 1**. Everyday there is the development of a more complex therapeutic arsenal against migraine as well as other primary headaches. Gaining the proper knowledge of all available treatment options may be a challenge to even the most expert specialists; thus, this report has rendered the task easier by providing an organized list of all available therapeutic options summarized in **Tables 2** and **3**.



\*Other NSAIDs are useful as well.

has led to the improper use or even abuse of headache medications; however, once a headache patient has reached regular medical care, efforts must be made in order to enhance doctor-patient communication and provide as much information as possible to the patient [68] since having an in-depth knowledge of these diseases will lead to better management [69]; once patients are aware of a medical condition such as primary headaches, they act as multipliers among their families, relatives, friends, and coworkers [70], making it easier to catch public interest on a public health problem like migraine and other primary headaches. It remains clear that education and information play a key role in addressing chronic primary headache; however, once a patient has grasped these important concepts and the physician has given a diagnosis, it is necessary to utilize the right tools in order to correctly estimate the impact of headache on their quality of life [71] and to choose the right treatment for each individual case; otherwise, using standardized protocols even in the medical community may present the danger of improper treatment and abuse of certain medications [72]. To accomplish such a delicate task, health care providers rely on many tools such as MIDAS (Migraine Disability Assessment Score) intended to objectively evaluate headache frequency, pain intensity, and associated symptoms so as to measure not only the impact of headache on quality of life but also to assess treatment outcomes leading to a personal, tailored treatment regimen for each patient [73]. Once the diagnosis has been achieved and the impact on both quality of life and productivity is assessed [74], the precise treatment can then be chosen for each patient. It is important to note that the main goal of chronic primary headache treatment is to lower as much as possible the number of pain crises (preventive treatment), the secondary objective is to end a possible a crisis once it has evolved and has been triggered (abortive treatment), and finally, rescue patients once a crisis has stopped (rescue treatment). Long-term treatment options for each step of therapy have widened, providing physicians with a variety of drugs acting on different key points in the pathological chain as seen in **Table 1**. Everyday there is the development of a more complex therapeutic arsenal against migraine as well as other primary headaches. Gaining the proper knowledge of all available treatment options may be a challenge to even the most expert specialists; thus, this report has rendered the task easier by providing an

organized list of all available therapeutic options summarized in **Tables 2** and **3**.

**Onabotulinum toxin A** Yes Injection Dose: Varies (FDA official dose is 155 units

**Topiramate** Yes Oral Total dose varies from 25 or 50 mg/day up to

**Valproic or divalproex sodium** Yes Oral Usual dose: 500–1000 mg/day in divided doses

via 31 injections every 3 months)

400 mg/day

**Drug name FDA-approved Formulation Dosage**

**Propranolol** Yes Oral 60–120 mg/day **Metoprolol** No Oral 25–100 mg/day **Atenolol** No Oral 25–50 mg/day **Nebivolol** No Oral 2.5–10 mg/day

**First-line preventive medications for migraine**

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**Anticonvulsants**

**B-blockers**

**Table 2.** First-line migraine preventive medications.


Table reproduced and adapted from the original source [76].

\*Polypharmacy also is commonly used as second-line treatment of migraine (i.e., amitriptyline with propranolol or amitriptyline with valproic acid).

**Table 3.** Second line migraine preventive medications.

With the above information in mind it makes it easier to decide what the best options are for each patient; however, migraine treatment as well as the treatment for chronic tension-type and other primary cephaleas must be chosen considering each particular patient condition, available treatments at their location, exposure to triggers, and so on [77]. Usually this type of initial approach is enough to achieve adequate control of symptoms but if unsuccessful, it becomes mandatory to prioritize which attributes from each drug are better for a particular patient in order to choose the best mix of pharmacologic therapy [78]. In this regard, when precise medical treatment has been chosen, it is very important to measure its impact [79], not doing so could run the risk of the patient receiving a useless treatment over a long period of time leading to further problems regarding that particular treatment as well as future therapies. In this sense, it is also important to address the patient's expectations of the treatment in order to be able to provide not only a good outcome but also to gauge what the patient is expecting from treatment regarding tolerability, effectiveness, side effects, and other aspects of therapy; otherwise, there is a high risk of noncompliance which may lead patients toward self-medication and all the implied risk attributed to it. In addition, it is necessary to be aware of the adverse effects because even though the therapeutic action is good enough to improve the quality of life, the development of adverse side effects may lead to therapy discontinuation. A summary of the main adverse side effects associated with the main treatment categories are summarized in **Tables 4**–**6**.


**Table 4.** Side effects of main first-line migraine abortive drugs.

It remains clear that proper treatment selection, impact evaluation, and limiting the side effects are all challenging tasks requiring highly specialized medical staff with adequate experience; otherwise, the outcome may not be satisfactory leading to possible therapy discontinuation, self-medication, and the use of alternative treatments whose effectiveness and safety may not be well known. Unfortunately, there are still many cases worldwide of misdiagnosis, erroneous management, and self-medication due to lack of specialized medical assistance. All these factors are a "recipe for disaster" since many headache rescue treatments are available over the counter and thousands, perhaps millions of people try to fight alone against migraine, tension-type headache, and other primary cephaleas, lacking proper advice, leading to one of the worst complications of primary cephalalgias: drug overuse and abuse.


Table reproduced and adapted from the original source [80].

\*Other SSRIs include citalopram, escitalopram, fluvoxamine, paroxetine, sertraline.

\*\*GI, gastrointestinal.

With the above information in mind it makes it easier to decide what the best options are for each patient; however, migraine treatment as well as the treatment for chronic tension-type and other primary cephaleas must be chosen considering each particular patient condition, available treatments at their location, exposure to triggers, and so on [77]. Usually this type of initial approach is enough to achieve adequate control of symptoms but if unsuccessful, it becomes mandatory to prioritize which attributes from each drug are better for a particular patient in order to choose the best mix of pharmacologic therapy [78]. In this regard, when precise medical treatment has been chosen, it is very important to measure its impact [79], not doing so could run the risk of the patient receiving a useless treatment over a long period of time leading to further problems regarding that particular treatment as well as future therapies. In this sense, it is also important to address the patient's expectations of the treatment in order to be able to provide not only a good outcome but also to gauge what the patient is expecting from treatment regarding tolerability, effectiveness, side effects, and other aspects of therapy; otherwise, there is a high risk of noncompliance which may lead patients toward self-medication and all the implied risk attributed to it. In addition, it is necessary to be aware of the adverse effects because even though the therapeutic action is good enough to improve the quality of life, the development of adverse side effects may lead to therapy discontinuation. A summary of the main adverse side effects associated with the main treatment catego-

It remains clear that proper treatment selection, impact evaluation, and limiting the side effects are all challenging tasks requiring highly specialized medical staff with adequate experience; otherwise, the outcome may not be satisfactory leading to possible therapy discontinuation,

Nausea, numbness of fingers and toes

**common side effects may include:**

**Side effects for all the triptans are similar This class of drugs is well tolerated but the more** 

Nausea, headache, sleepiness, dry mouth, dizziness, fatigue, hot/cold sensations, chest pain, and flushing Other potential side effects that rarely occur include: Head, jaw, chest and arm discomfort/tightening/tingling; throat discomfort, muscle cramps, and flushing

ries are summarized in **Tables 4**–**6**.

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**Drug name Possible side effects**

**Medications for abortive therapy**

Dihydroergotamine mesylate

Sumatriptan succinate\*

Almotriptan malate\*× Frovatriptan succinate+ Eletriptan hydrobromide\*

×FDA approved for teens ages 12–18.

Table reproduced and adapted from the original source [80].

**Table 4.** Side effects of main first-line migraine abortive drugs.

**Ergot**

**Triptans**

Zolmitriptan\* Rizatriptan\* Naratriptan+

\*Short-acting. +Long-acting.

\*\*\*EKG, electrocardiogram.

**Table 5.** Side effects of main first-line migraine preventive drugs.


**Table 6.** Side effects of main migraine rescue drugs.
