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Question:

Write about the development of clonidine for prophylaxis against migraine.

Answer:

Introduction

Migraine refers to mild to severe headaches.

The neurological changes in brain cause migraine headaches.

Studies have shown that migraine headaches can be linked to light, sound and smell.

Migraine intensity is often increased by exposure to too much light, noises that are disturbing or foul-smelling and other unpleasant sounds (1).

There are two possible symptoms: nausea and vomiting.

Some people complain of experiencing pain only on one side of the head, but others experience both.

Many people describe migraine pain as a pounding or throbbing pain.

All types of headaches should not be considered migraines. Instead, there is another type of headache called tension headache. It occurs due to muscle contracture in the neck, face, and scalp (2).

Boehringer Ingelheim Pharma wanted to discover a peripherally activated adrenergic substance for nasal decongestion. The task was assigned to Helmut Stahle, a chemist.

It was believed that decongestive agent are derived form the imidazoline structural.

Clonidine was created by adding chlorine atoms as substitutes in the 2-, 6- and 7 positions of the Phenyl ring.

Clonidine was more effective than decongestant 5 (5) in antihypertensive activities.

Clonidine is used to lower blood pressure.

Clonidine works by stimulating the centrally activated alpha 2A subtype, alpha adrenergic receivers in brainstem. This results in decreased sympathetic outflow in central nervous system.

Clonidine is an imidazole derivative that is metabolized using cytochrome P450.

Clonidine has therapeutic properties in lowering blood pressure when used with other drugs.

Clonidine can be used to treat other conditions such as neuropathy and smoking cessation.

Clonidine first became available in the USA in 1974.

Clonidine is mainly used for hypertension. It can also be used for cancer pain management and attention deficit syndrome.

Clonidine is mostly used in the NHS to treat hypertension and menopausal symptoms.

Tourette syndrome, sedation and migraine are all possible uses of unlicensed clonidine. Also, it can be used to relieve withdrawal symptoms such as alcoholism, nicotine addiction, and narcotic dependence.

Clonidine can be purchased in tablets (25mcg), 100mcg and injections (150mcg).

Adults should take 50-100mcg daily. This can be increased gradually the 2nd and 3rd days until you achieve control.

The main side effects of Clonidine include fatigue, bradycardia and dry mouth.

Clonidine tablets are available in a three-hour duration of action and a half life of 12-16hrs. They can also be extended to 41 hours if severe renal impairment is present.

Clonidine tablets are usually taken before or after bedtime due to its sedating effects.

Clonidine activates presynaptic receptors in locus correus and reduces norepinephrine.

The antihypertensive properties of clonidine are linked to its ability to lower plasma levels.

Clonidine extended release tablet in USA is used as adjunctive therapy in children with attention deficit hyperactivity disorders.

Sudden withdrawal may cause rebound hypertension, which is due to a rebound of sympathetic outflow.

To reduce the rebound side effects, clonidine treatment should be slowly tapered.

Sudden withdrawal of Clonidine from patients taking high doses can cause agitation and restlessness.

Galactose intolerance is a concern as Catapres (Clonidine tablets) contains lactose monohydrate.

Clonidine, along with its metabolites, is extensively excreted in the urine. The dosage should be adjusted based on response. There can also be variability in renal function in patients with kidney disease.

Clonidine excreted as unchanged parent drug in 70% and 20% as faeces from administered drug in 20% of urine.

Patients who use contact lenses may experience decreased lacrimation due to clonidine.

Clonidine is also available as Catapres tablet or injection under the brand Boehringer Ingelheim. Other generics are also available.

Clonidine first came into use in 1966.

The drug was initially developed to treat hypersensitivity. Catapres was the trade name.

Clonidine was first widely used for the treatment of withdrawal symptoms such as nicotine, opium, and alcohol withdrawal.

Clonidine was eventually approved by the U.S Food & drug Administration to be used for high blood pressure.

Clonidine was also shown to be able to lower blood pressure by specifically targeting nerve cells of brain (3).

In a clinical trial, clonidine was demonstrated to be effective in the prevention of migraine attacks.

The trial involved 25 micrograms of clonidine given three times daily. This decreased the number of migraine attacks to 2.26 per month.

After increasing the dose to 50 micrograms, the average number of migraine attacks dropped from 4. to 1.88.

44% of patients experienced fewer attacks with the 25 microgram dosage. 46% had increased attacks while the remaining 10% suffered from more severe attacks.

The 50 microgram dosage group had 58% patients reporting reduced attacks while 40% of the patients saw no difference.

In the remaining 1%, attacks were more common.

Both doses were evaluated for their duration.

The duration of pain was reduced in patients who took 25 micrograms of clonidine. This effect was not seen in 60% of patients. However, it was higher in those who took 60%.

Similar results were seen with 50 micrograms of Clonidine. In 52% of patients, the pain duration decreased, but it was unchanged in 46%. The effect on 2% patients was also reduced.

However, increased clonidine dosage had side effects like nausea and sedation. Sedation was experienced by 22% of the patients.

The trial could be used to prophylactically migraine by clonidine at an effective dosage (7).

Clonidine development can be linked to migraine prophylaxis because migraine is caused by changes in the levels of serotonin. Serotonin regulates pain in our nervous system.

The brainstem changes and interactions with the trigeminal nerve can also cause migraines.

A drop in serotonin levels causes the trigeminal neuro to produce neuropeptides which travel to the outer portions of the brain (meninges). This triggers migraine pain.

There is a positive correlation between hypertension and migraine. This means that migraine pain will increase if there is more hypertension.

Clonidine is an imidazole derivative that can be used to treat hypertension.

Clonidine, taken in low doses, can be effective in reducing hypertension. This has been confirmed by numerous studies.

Given the above disclosure, migraine pain is a serious medical condition that if not managed medically can affect your daily life and cause concentration problems.

There are many medications on the market but clonidine is the best.

Clonidine can be used in small doses to treat migraines. It directly affects the central nervous systems and brain cells, which reduces hypertension.

References

StaEhle H. Historical perspective: Clonidine’s development.

BaillieA re: Best Practice and research.

Sprenger T. The current practice and future directions in migraine prevention and management.

The Lancet Neurology.

2010 Mar 31, 2009;9(3):285–98.