Clonidine For Migraine Prophylaxis: Essay On Mechanism, Dosage, And Side Effects.

Write the development of clonidine in prophylaxis of migraine.

Introduction and Physiology of Migraine

Migraine is a term which is commonly used to describe mild to severe headache. Due to the physiological changes in the brain, a pain starts to develop which causes migraine associated headaches and other symptoms. Studies show that migraine headaches have a positive relation with light, sound and smell. Excessive light, certain disturbing sounds and foul and repugnant smells often increases the intensity of migraine (1). The probable symptoms include vomiting or nausea. Some patients complain that they experience pain on just one side of the brain while pain on both sides of the brain are also reported. The migraine associated pain is often reported as a throbbing or pounding pain. Designating all types and forms of headaches as migraine is not appropriate because there is another form of headache which is associated with tension and it occurs due to muscle contraction of the neck, face and scalp (2).

Boehringer Ingelheim Pharma decided to discover a peripherally active adrenergic compound for nasal decongestion in the form of nose drops and task was given to to chemist named Helmut Stahle. It was believed that decongestive agents are derived from imidazoline structure. He ended up discovering Clonidine by introducing chlorine atoms as substituents in the 2- and 6- positions of the phenyl ring. It was found out that clonidine has more antihypertensive activity than decongestant (5).

Clonidine is indicated in lowering blood pressure, used in the prophylaxis of vascular migraine headaches, treatment of severe dysmenorrhea, management of vasomotor symptoms associated with menopause, in conjunction with benzodiazepines for the treatment of alcohol withdrawal, to manage nicotine dependence, use in the treatment of open-angle and secondary glaucoma and attention-deficit hyperactivity (ADHD) is also treated (6).           

Clonidine acts by stimulation of the centrally active alpha 2A subtype of alpha adrenergic receptors in the brainstem, causing decrease in sympathetic outflow of central nervous system. Clonidine is imidazole derivative and metabolized by cytochrome P450 (CYP). Clonidine is therapeutically active in lowering blood pressure in conjunction with other drugs. Clonidine is also used in other conditions like neuropathy, smoking and alcohol cessation, attention deficit syndrome, vascular headache, menopausal symptoms, diabetic diarrhoea, and restless leg disorder. Clonidine was first approved in US in 1974 and still widely used for various indications. Mostly clonidine is indicated in hypertension, but sometime also used for cancer pain management, attention deficit syndrome and menopausal flushing in some parts of the world. In NHS clonidine is mainly used for hypertension and menopausal flushing.  Unlicensed use of clonidine includes Tourette syndrome, sedation, migraine, and to alleviate symptoms of alcohol, nicotine and narcotic withdrawal. Clonidine available in tablet (25mcg, 100mcg) and injection (150mcg). Clonidine dose in adults is 50-100mcg three times daily, and can be increased steadily 2^nd or 3^rd day until control achieved. Main side effects are sedation, fatigue, bradycardia, dry mouth, headache, dizziness, postural hypotension, male impotence and gastrointestinal tract disturbance. (1)

Discovery of Clonidine and Its Indications

Clonidine tablet has duration of action of 3-5 hours and half-life of 12-16 hours and can be prolonged to 41 hours in severed impaired renal function. Normally clonidine prescribed after dinner or bedtime because of its sedating effects. Clonidine primarily activates presynaptic auto receptors in locus coeruleus and reduces norepinephrine release. Reduction in plasma levels of norepinephrine links with its antihypertensive effect. In USA clonidine extended release tablet used as adjunctive therapy in children for attention deficit hyperactivity disorder. Sudden withdrawal can rebound hypertension due to rebound in sympathetic outflow. That’s why clonidine therapy needs to be gradually tapered to discontinue in easing rebound side effects.  (2) Sudden withdrawal in patients on high doses of Clonidine may results in agitation, restlessness, palpitation, tremor, nervousness, abdominal symptoms and headache. Catapres (Clonidine) tablet contains lactose monohydrate and patient who got galactose intolerance, should avoid this medicine. Clonidine and its metabolites are extensively excreted in urine, and dosage should be adjusted according to response and it can show variability in patients with renal insufficiency. About 70% of Clonidine excreted in urine as unchanged parent drug and 20% excreted with faeces of administered drug. In patients using contact lenses, clonidine can cause decreased lacrimation. Clonidine is available Catapres tablet and injection as brand by Boehringer Ingelheim, and various generics also available in the market. (3)

Clonidine was first seen in to use in the year 1966. Firstly, the drug was developed in the treatment of hypersensitivity and was traded under the name of Catapres. Initially clonidine was widely used in the treatment of nicotine, opium and alcohol withdrawal syndromes. Tourette’s syndrome and attention-deficit/hyperactivity disorder (ADHD). Later, U.S Food and drug administration allowed clonidine to be used in the treatment of high blood pressure. Clonidine was also found to act specifically to act on nerve cells of the brain that helped in lowering the blood pressure (3).

A clinical was conducted in which consolidated the development of clonidine in the prophylaxis of migraine. In the trial clonidine was given in the dose of 25 micro grams thrice per day which reduced the mean number of migraine attacks from 3.94 to 2.26 a month. However, after increasing the dosage to 50 micro grams, the mean number of migraine attack reduced from 4 to 1.88 during the treatment process. In the 25 micro gram dosage, 44% of the patients shows reduced attacks, while it was unchanged in the 46% of the patients and the remaining 10% showed increased attacks. In the 50 micro gram dosage group, 58% of the patients reported reduced attacks and in the 40% of the patients, there was no change. While in the remaining 1%, there was increased incidence of attacks. Also the duration of the attacks was considered for the 2 types of doses. In the 25 microgram dosage, the duration of pain reduced in the 38% of the patients, while unchanged in the 60% and elevated in the remaining 2%. The same way in the 50 microgram clonidine dosage, the duration of pain reduced in the 52% of the patients, while it remained unchanged for the 46% patients, and in 2% the effects got elevated. However, the increased dosage showed some side effects, like the sedation and nausea, the effects of increased dosage of clonidine resulted in sedation of the 22% of the patients. Thus, this trial can be considered important in the prophylaxis of migraine with the effective dosage of clonidine (7).  

Thus, clonidine development can be related to the prophylaxis of migraine because the causes of migraine are dependent on the levels of serotonin, which regulate pain in the nervous system. Migraines are also caused due to the several changes in the brainstem and due to the interactions with trigeminal nerve. When the level of serotonin in the brain drops, this triggers the trigeminal nerve to produce neuropeptides that move to the outer portion of the brain (meninges) and cause the migraine pain (4). Hypertension and migraine have a positive correlation, which means due to an increase in hypertension, the migraine pain also increases. Clonidine is an imidazole derivative which has its wide usage in the treatment of hypertension. several studies have shown that clonidine taken in low doses can effectively reduce the hypertension and subsequently reduces migraine. Figure 1 shows how Clonidine activates the alpha-adrenoreceptors in brain, which reduces the sympathetic outflow of the CNS (central nervous system) and peripheral resistance, heart rate and renal vascular pressure and blood pressure (5).

Figure 1: Clonidine acting pathway [Source: (6)]

Therefore, from the above disclosure it can be concluded that migraine pain is a serious health issue which if not controlled medically can impair the normal everyday work and concentration. While there are several medications that are available in the market, among them clonidine is considered the best medication. Clonidine when taken in small doses can help in the treatment of migraine because clonidine directly acts on the central nervous system and brain cells which effectively reduces the incidence of hypertension which is considered as the main cause of migraine pain.

References

1. Nihgov. [Online]. Available from: .https://livertox.nih.gov/Clonidine.htm [Accessed 7 December 2017].
2. Sciencedirectcom.[Online].Availablefrom: https://www.sciencedirect.com/science/article/pii/B9780080552323614953 [Accessed 7 December 2017)
3. Medicinesorguk. [Online]. Available from: 3.https://beta.medicines.org.uk/emc/product/2200 [Accessed 7 December 2017].
4. Drugscom. [Online]. Available from: https://www.drugs.com/pro/clonidine.html [Accessed 7 December 2017].
5. StaÈhle, H. A historical perspective: development of clonidine. BaillieÁ re's Best Practice and research. 2000;14(2): 237±246.
6. Drugbankca. [Online]. Available from: https://www.drugbank.ca/indications/DBCOND0029450 [Accessed 7 December 2017].
7. Goadsby PJ, Sprenger T. Current practice and future directions in the prevention and acute management of migraine. The Lancet Neurology. 2010 Mar 31;9(3):285-98.