Combination Therapies In Migraine Treatment: Triptans And Nsaids

In these modern times, where there are so many new opportunities and responsibilities, all of us have experienced minor health issues like headaches. Most of us experience it due to lifestyle problems like lack of sleep, improper meal times, excessive screen time, poor posture, stress, dehydration, etc. Certain dietary factors also play a role in this, for example, taking caffeinated drinks at late hours can also trigger headaches.

However, if you get frequent headaches that do not subside by correcting the abovementioned factors, it is advisable to visit a doctor. This is because the headache might be a symptom of a serious underlying condition, such as migraine.

Migraines are not just simple headaches, but a way more complex type of condition. Before a migraine hits its full-blown headache stage, there are a lot of symptoms seen in a stage called the “premonitory stage”. As the name suggests, this stage gives a premonition of the headache. These symptoms include:

• Lethargy
• Frequent yawning
• Sensitivity to light and sound
• Thirst and cravings
• Fatigue
• Nausea

Also, just an hour or so before the migraine headache, some people may also get another warning sign called the “migraine aura”. A migraine aura can make a person see strange things, blind spots in vision, tingling sensation in the body or even trouble speaking.⁷ 

However, as dramatic as it sounds, it does not have to be. If you are ever experiencing any of the above symptoms, seeking help from a doctor can help you manage these symptoms and also prevent you from getting frequent migraine attacks. This article discusses in further detail, the treatment strategies currently used to manage migraine and also a potential combination therapy strategy that might be even more useful.

Introduction

Overview of migraine & its symptoms

Migraine is one of the most common neurological disorders which is accompanied by pounding headaches. These headaches are usually one-sided but can also spread all over the head, face and neck. Migraine is one of the 20 most disabling disorders in the world according to the World Health Organization.¹ A 1-year study of migraine prevalence in England tells us that about 5.85 million people in the age group of 16-65 years experience migraine attacks everyday.² 

Treatment

Common treatment strategies

Treatment strategies can be varied based on the severity of the headaches you are experiencing. For mild headaches, the doctor might prescribe you non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin, ibuprofen, or naproxen. More severe headaches are initially treated with a class of drugs called triptans. Examples of triptans include frovatriptan, sumatriptan or zolmitriptan. These medications can be taken as pills, shots, or nasal sprays. This is the first-line treatment for migraines.³ 

Second-line treatment includes the use of drugs like antiemetics like chlorpromazine, droperidol or metoclopramide if the patient is experiencing nausea. Opioids like codeine, tramadol, etc., have also shown effectiveness in migraine treatments, but are not recommended due to the high potential for addiction and drug abuse.³ Acetaminophen, frequently known as paracetamol, is also used to treat migraines quite often due to its easy availability as an over-the-counter (OTC) medicine.

Introduction to Combination Therapy

Combination therapy, by definition, means using multiple therapies or different classes of drugs to treat a single disease. Historically, combination therapy was used for severe conditions like infectious diseases or cancer.

Using a combination of different treatments has significantly improved patient outcomes in many disorders. A classic example of combination therapy is tuberculosis treatment.⁴ The combination of streptomycin, isoniazid, rifamycins along with rifampicin improved the effectiveness of treatment. Many cardiovascular diseases like hypertension are also treated using multiple classes of drugs.⁵ 

There are many benefits of combination therapy which justify its extensive use as a treatment strategy. These include:

• Improved treatment outcomes due to the synergistic actions of two or more drugs
• Reduced drug toxicity and adverse events as lower dosages of drugs are taken by patients
• Reduction in the emergence of drug resistance⁶ 

Mechanism of action 

Pathophysiology of Migraine

Pathophysiology of migraine is dependent on many factors involving the interaction between the nervous system and the circulatory system. Hence, it is also known as a neurovascular disorder. The exact pathophysiology of migraine is not fully understood yet, but one prevailing theory involves the major pain-signalling pathway of the brain, known as the “trigeminovascular system”.

Due to the release of certain inflammatory neurotransmitters and chemicals like prostaglandins, there is a dysfunction in the trigeminovascular system leading to dilation of the blood vessels. This activates the pain pathways in the brain, leading to a migraine attack.⁸ 

Triptans: serotonin receptor agonists 

Triptans are a common class of medications used to treat migraine headaches. They are also known as serotonin receptor agonists, as they have selective affinity for serotonergic receptors 5HT_1B, 5HT_1D and 5HT_1F.

These receptors are located on the blood vessels and nerve endings. When triptans, like sumatriptan, bind to 5HT_1B, they induce constriction of the dilated blood vessels. Binding to 5HT_1D inhibits the release of inflammatory neurotransmitters and hence prevents the activation of pain pathways, thereby subsiding the migraine headache.⁹ 

NSAIDs: non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs, often shortened to NSAIDs, are another common class of drugs used to treat migraine. They possess anti-inflammatory, analgesic (pain-relieving) and antipyretic (fever-reducing) properties. Their mechanism of action involves the inhibition of cyclooxygenase (COX) enzymes.

There are two subsets of COX enzymes, COX-1 and COX-2. Out of these, COX-1 is involved in homeostasis (regulation of normal bodily functions and systems) and COX-2 is involved in inflammatory pathways. NSAIDs bind to COX-2 and prevent the release of inflammatory molecules like prostaglandins and leukotrienes. It is in this way NSAIDs are effective in migraine therapy.¹⁰ 

Clinical evidence

Studies supporting the efficacy of combination therapy

There is ample evidence in the medical literature documenting the synergistic effects of using a combination therapy of triptans and NSAIDs for the treatment of migraine. A study in 2011 was conducted involving subjects who had migraines that largely impacted their daily lives.

Different groups among them were administered with a combination of sumatriptan (85mg) and naproxen (500mg), butalbital-containing medication (BCM - 50mg), paracetamol (325 mg) and caffeine (40mg), and the last group was administered a placebo treatment. The results showed that the sumatriptan-naproxen combination was more effective in migraine treatment with less rescue medication required.¹² 

Another study conducted in the UK in 2015 involved clinical trials using sumatriptan and naproxen. People were given a combination of sumatriptan and naproxen, sumatriptan alone, naproxen alone, and a placebo which contains neither of the drugs.

The key results showed that the combination therapy was superior to therapy using only one of the drugs, and beginning treatment early in patients with mild symptoms rendered them pain-free in two hours. Other symptoms of migraine were also better controlled in the combination therapy group than the other two groups.¹¹ 

In both studies, adverse events were recorded more in patients treated with only sumatriptan than in the combination group. No such events were recorded in naproxen-only and placebo patients.

Challenges and limitations

Potential drug interactions

Drug-NSAID interactions

Many drugs which are used to treat different conditions, when taken along with NSAIDs can lead to potential adverse reactions in the body. A few such interactions are mentioned below:

• Blood-thinning agents like warfarin when taken along with NSAIDs can cause excessive bleeding
• When taken along with diuretics or ACE inhibitors, NSAIDs increase the risk of kidney failure
• When NSAIDs are taken along with steroids like prednisolone, they can aggravate gastric ulcers¹³ 

Drug-triptan interactions

The major potential drug interaction with triptans is usually with ergot alkaloids (for example, dihydroergotamine and ergotamine). This is because triptans cause constriction of blood vessels, and when taken alongside ergot alkaloids, this constriction might increase to excessive levels.

This can cause several disruptions in the cardiovascular system. Triptans should not be taken with monoamine oxidase (MAOI) antidepressants (e.g. isocarboxazid, phenelzine, selegiline, and tranylcypromine) as the latter causes breakdown of many triptans like sumatriptan, rizatriptan and zolmitriptan.¹⁴ 

Future directions

Although the treatment strategies discussed in this article are quite effective for the majority of patients, there is always scope for further developments in this field. New approaches to migraine treatment are being researched. One of them is preventive therapy which focuses on the prevention of frequent migraine attacks. A special extract of the Petasites genus of flowers is being tested for migraine prevention. 

Another treatment approach in ongoing research involves calcitonin gene-related peptide antibodies (CGRP) receptor inhibitors. CGRP receptors play a role in the dilation of blood vessels in enhancing migraine attacks. Two inhibitors for this receptor, ubrogepant and rimegepant, have completed phase III studies and are now US FDA-approved for acute migraine treatment. However, ubrogepant is not yet approved for use in migraine treatment in the UK. Apart from these, certain monoclonal antibodies and neuromodulation are also under research for migraine therapy.¹⁵ 

FAQs

Which therapy is best for migraine?

Answer: Apart from pharmaceutical medications, there are many non-traditional methods to deal with migraine as well. Such options include meditation, yoga, acupuncture, and cognitive therapy. Recognising and avoiding your triggers for migraine headaches can also help prevent migraine attacks.

What are the 5C’s of migraine?

Answer: Certain foods and beverages are known to trigger migraine headaches. The 5C’s include:¹⁶ cheese, coffee (and other sources of caffeine), chocolate, cola, and citrus fruits like oranges, lime, etc. Avoiding these foods can help prevent frequent migraine attacks.

What is the 2-hour migraine medication?

Answer: Nurtec ODT is a placebo drug that patients can take to treat acute migraine headaches. This might relieve the pain in 2 hours.

Summary

• Migraine is not just a simple headache, but a complex disorder with many symptoms and triggers 
• Triptans and non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly used drug classes for migraine treatment. Even though they are effective in treatment when used alone, their combination at certain dosages has proven to produce better outcomes in some patients
• There are still adverse events seen in patients due to this therapy. Drug interactions and contraindications for these drugs reduce the efficacy of the treatment
• Further research is being conducted and will give rise to more successful treatment options for migraine patients that will help them manage their disorder in a better way