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Pharmacological Effects of Tricyclic Antidepressant Medications


Normally, strong pain is a symptom of pathology or tissue injury. Sharp pain is a physiological reaction performing a defensive function because it notifies about the development of pathological processes in tissues and promotes the development of complex adaptation reactions in the organism. The purpose of the treatment of strong pain is to eliminate the cause of pain or minimize its allogenic influence. The paper investigates the treatment of migraine pain with the help of tricyclic antidepressants and its nursing implications.

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Migraine Definition

Migraine is a chronic pain that has a pulsating character. It is usually one-sided, and the side of pain can vary with each attack. Children usually have one-sided headache localized in the frontal zone. In most cases, the first migraine attack occurs from ten to thirty years. Patients often report suffering from pain in the abdomen in childhood; approximately 25% of people were also reported vomiting and susceptibility to motion sickness at an early age. Approximately 60-75% of patients are women; in this case, migraine attacks occur before menstruation (Loder & Marcus, 2004).

Chronic or recurrent pain has multicomponent nature-based not only on pathophysiological but also interacted psychological and social factors. Chronic pain is also pathologic as it has a pathogenic influence on the organism and may cause interruptions in the work of the central nervous system, psychological and emotional deviation with possible damages of internal organs (Daniel, 2010).

Migraine is considered a disease with the primary pathological process in the somatic sphere and the secondary dysfunction in the peripheric and central nervous system. The key features of this type of pain include the duration for more than three months, an increase in the patient’s resistance to therapy, and the absence of a connection between determination and abolishment of the cause (Sacks, 1992).

In the past, migraine was considered a vessel disease. It was suggested that rapid expansion of the brain's vessels results in the irritation of receptors and thus infliction of pain. However, the latest researches have shown that migraine relates to deviations in the central nervous system. These deviations cause a chain of biochemical changes that influence the vessel system and cause the symptoms (Ford-Martin, 2008).

Every vessel is connected with nerves responsible for constriction and dilatation that depend on the needs of a certain organism. It is considered that breaks in the work of the central nervous system may cause pathologic impulsion and unnecessary stimulation of vessels. As a result, there appears migraine and other symptoms. There exists a chain of factors that may cause migraine: medicine and chemical substances; alcohol (in particular beer); sweet products; unhealthy lifestyle; the surrounding atmosphere, particularly smoke, different smells or glittering light (Ford-Martin, 2008).

Migraine spasm has four phases of development; however, some patients may not face all of them. Migraine typically consists of the prodromal phase, aura, the phase of a headache, and the postdrome phase. The prodromal phase occurs several hours or days before the spasm. There may appear such symptoms as irritation, depression, tiredness, general weakness, the feeling of cold, hyperactivity, a lack of attention concentration, and high sensibility towards light or sounds.

The phase of aura takes place from 20 to 60 minutes before the beginning of a migraine. It involves one or more deviation in the work of the organs of perception. Each of the symptoms develops gradually from five minutes to one hour. The most common ones are deviations of visual perception. The most important features of the phase of a headache are pain that lasts from four to seventy-two hours, pain in the front part of the head, sickness, and diarrhea.

The headache increases with physical activity. A person also experiences increased sensibility to light, sounds, smells, or touches. The postdrome phase is the period of recovery from spasms. During this period, people may feel tiredness and irritation, have difficulties with attention concentration, weakness of muscle tissue, hyperactivity, or euphoria (Davidoff, 2002).

Patients who suffer from migraine attacks can suddenly feel a headache of maximum intensity. The attack may take place in certain situations (for example, under the influence of physical stress) or without any apparent reason. To exclude the risk of subarachnoid hemorrhage, CT, MRI, or lumbar puncture may be recommended.

The investigations have shown that there exists a direct dependence between pain and depression. According to the researchers, depression develops in 30 to 87% of cases of migraine. On the one hand, depression is the key factor lowering the life quality of patients who suffer from migraine. On the other hand, patients who suffer from depression are more sensitive to pain.

At first, the use of antidepressants for migraine treatment aimed at producing a sedative effect and creating a favorable background for the main therapy. However, antidepressants also have an analgesic effect due to three mechanisms: the reduction of depression, increase of the influence of analgesics, and a personal analgesic influence that consists of the long-term prolongation of the synaptic activity of noradrenaline and serotonin.

Migraine is diagnosed relatively seldom. At the same time, it is difficult to develop the methods of treatment as they differ in each particular case. Sometimes, it is necessary to spend months choosing the necessary combination of medicine. As soon as the necessary treatment is chosen, the symptoms of migraine become moderate. However, nowadays there are no methods of treatment to guarantee an absolute recovery of the disease.

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At the same time, it is possible to carry out the preventive treatment of migraine. For patients who have frequent spasms, it is necessary to undergo preventive therapy along with the main course of treatment. The aim of preventive therapy is to reduce the number of migraine cases and the strength of pain as well as improve living standards. Patients who suffer from complex forms of migraine and have neurological symptoms should be the first candidates for preventive therapy. For such patients, even a single episode of migraine is the reason for recommending the therapy (Bernstein & McArdle, 2008).

When planning the process of therapy, it is necessary to take into consideration the existing pathologies such as depression, overweight, bronchial asthma, pregnancy planning, etc. Each type of medication has some side effects that should be taken into consideration before its application. Preventive medication includes beta-blockers, tricyclic antidepressants, anticonvulsants, etc. This medication is designed for the treatment of other diseases; however, their application as a means of preventive therapy had an empiric effect.

Tricyclic Antidepressants

Tricyclic antidepressants are considered more effective for the prevention of everyday migraine-like pain than beta-blockers, which have a better influence on classical migraine. However, sometimes tricyclic antidepressants are also beneficial for prophylactic treatment of classical migraine. At the same time, it is necessary that future nurses take into consideration both benefits and limitations of treatment.

Tricyclic antidepressants received their name because of their tricyclic structure. The mechanism of influence of tricyclic antidepressants is connected with the inhibition of monoamine neurotransmitter reuptake by presynaptic nerve ending, which results in the accumulation of neurotransmitters in the synaptic cleft and activation of synaptic transmission. Tricyclic antidepressants, as a rule, reduce the capture of neurotransmitter amines (norepinephrine, serotonin, and dopamine) that cause their ability to prevent migraine and tension headaches.

The nociceptive impulses transmission requires the involvement of ascending afferent somatosensory, spinothalamic pathways, which pass through the rear of the dorsal horn of the spinal cord. These impulses are modulated through the nociceptive activation of descending inhibitory pathways originating from the gray matter of the brain. Both serotonin and norepinephrine are involved in the descending inhibitory mechanisms and neurochemical changes and contribute to the changes in the spinal cord.

These changes may facilitate the release of the neurotransmitter that increases nociceptive transmission as well as influence the effects of endogenous endorphins. The analgesic effect of antidepressants is a result of the internal analgesic properties of the molecules of antidepressants. It is related to the indirect effect of antidepressants on pain resulting in the reduction of overall depression or the creation of the feeling of sedation.

The common feature of tricyclic antidepressants is their inhibitory effect on the repeated uptake of norepinephrine and serotonin as well as its antihistamine effects. This variety of effects is also expressed in a sufficiently large number of side effects that occur in the course of therapy with these drugs. Therefore, it is difficult to choose the recommended dose that would relieve the symptoms of migraine and would not cause significant side effects.


Tricyclic antidepressants have a complex pharmacological mechanism of influence. These drugs inhibit the reuptake of 5-HT and noradrenaline in the nerve endings and have an anticholinergic and sedative effect. At the same time, they have the features of beta-blockers. The recommended starting dose is 25-50 mg of amitriptyline at night. Generally, this dose is well tolerated. Gradually, the dose can be increased by 25-50 mg once in one or two weeks. The maximum dose of amitriptyline is 300 mg/day. The required dose is determined by the therapeutic effect, namely the prevention of migraines and the severity of side effects. The therapeutic effect of amitriptyline as well as propranolol results not only from the concentration of the drug in the blood but also depends on the reaction of idiosyncrasies (DeMaagd, 2008).

If during amitriptyline treatment the patient continues suffering from headaches but does not develop any side effects, it is recommended to continue increasing the dose. When reaching a dose of 200 mg per day, it is necessary to determine drug concentration. If the total level of amitriptyline and nortriptyline exceeds 300 mg, the dose should be reduced. Usually, the daily dose is divided into several stages: half for the night and the other one during the daytime (DeMaagd, 2008).

The possible side effects of tricyclic antidepressants include sedation and anticholinergic effects (dry mouth, constipation, difficulties with urinating, and disturbance of accommodation). In 2-5% of cases, anxiety, and psychological stimulation in the form of insomnia may also take place. There may also be cases of tardive dyskinesia after the long-term use of tricyclic antidepressants. Additionally, the cases of sudden death associated with taking amitriptyline and imipramine sometimes occur. Very rarely, these drugs may cause severe heart rhythm disorders (DeMaagd, 2008).

The only drug in the group of tricyclic antidepressants that has a negative impact on the cardiac function is doxepin. It should not be prescribed to patients who are over 50 years old and suffer from heart disease or have a high risk of its development. In certain cases, it is possible to use a combination of 75-150 mg amitriptyline with 80-160 mg propranolol per day to prevent headaches. However, in these cases, the risk of addiction significantly increases (Jackson et al., 2010).

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Pharmacologically cyproheptadine has a tricyclic structure, but its primary influence is antihistaminic. Tests have shown that it is effective in preventing migraines, reducing the number of attacks by more than 50% in 45-50% of cases. The possible side effects are the same as that of amitriptyline, but they are generally less developed. An effective therapeutic dose of cyproheptadine is 12-24 mg per day. When prescribing more than 40 mg, there usually develop side effects that require dose reduction (Jackson et al., 2010).

Valproic Acid

The effectiveness of valproic acid in the preventive treatment of migraine was first discovered in 1987. Investigations have confirmed these findings, determining that the frequency of headaches decreased by half in approximately 50% of cases for the patients who were taking the drug. The valproic acid and its salts are tolerated well by patients. However, some forms of medication may cause stomach irritation. The main side effects of valproate, in addition to those mentioned above, include weight gain, tremor, and the loss of hair.

These symptoms are reversible and do no longer take place after the completion of treatment. The valproic acid alters carnitine metabolism, causing liver dysfunction, which, in turn, leads to an increase in the ammonia concentration in the blood. The risk of liver toxicity is higher when prescribing the combination of several drugs. Moreover, it is higher for children when compared with adults. In some cases, valproate leads to inhibition of bone marrow hematopoiesis (Jackson et al., 2010).


Methysergide is the serotonin receptor blocker that to a certain extent blocks noradrenaline receptors. It serves as an effective means for the prevention of migraine, reducing seizure frequency by more than 50% in 50-60% of cases. However, it has a variety of side effects that hinder the effectiveness of this drug. The main adverse effects are nausea and abdominal cramps, occurring in at least 10-20% of cases. Apart from that, there often takes place side effects associated with vascular spasm: the coldness of hands and feet, polyneuropathy, and limb swelling. There may also appear mental problems such as the dissociation of thinking, anxiety, nervousness, and hallucinations (Jackson et al., 2010).

The patients who received methysergide treatment for a long time (more than two years) may suffer from inflammatory fibrosis in the retroperitoneal space, lungs, or myocardium. Usually, these complications are observed in cases when patients have been continuously consuming methysergide for two to five years. For patients who received methysergide treatment for more than six months, it is recommended to do a pause for at least one month.

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The five drugs described above (propranolol, amitriptyline, cyproheptadine, methysergide, and valproic acid) are the most effective means for the preventive treatment of migraine, which are able to reduce the number of migraine attacks by at least 50%. The data obtained in the studies showed that for 58% of patients in the group taking methysergide, 55% in the group taking amitriptyline, 51% in the group taking propranolol, and 48% in the group taking cyproheptadine, the number of migraine attacks was reduced by approximately 50%. It should be taken into consideration that there is no direct relationship between the dose of the medication and the produced effect (Jackson et al., 2010).

The range of therapeutic doses of tricyclic antidepressants is quite wide, so the selection of dosage in each case requires an individual approach. Amitriptyline and doxepin produce a sedative effect. It is necessary to take into consideration that for patients who suffer from depression, it may be necessary to prescribe higher doses of these drugs. It is recommended to start with small doses of tricyclic antidepressants before going to bed, except for protriptyline, which should be taken in the morning after waking up. If the sedative effect of the drugs is too strong, it is possible to switch from tertiary amines (amitriptyline, doxepin) to secondary amines (nortriptyline, protriptyline).


Migraine is a disease characterized by a strong headache. The disease flow may encompass four stages: prodromal phase, aura, the phase of a headache, and the postdrome phase. At the same time, there exist different forms of the disease characterized by specific stages and symptoms. Nowadays, migraine pain may be successfully relieved with the help of antidepressants. At first, antidepressants were used to provide a sedative effect and to create the background for main treatment; however, they ultimately became one of the most efficient means in the struggle with migraine.

The most frequently prescribed tricyclic antidepressants include propranolol, amitriptyline, cyproheptadine, methysergide, and valproic acid. These drugs allow reducing the number of attacks by 50% in more than half of the cases. However, these medications may have multiple side effects that have to be taken into consideration during the course of treatment.

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