Introduction

Cervical Dystonia (CD) is a form of dystonia - a syndrome of sustained involuntary muscle spasms. Dystonia can target your whole body or just one part. CD, also known as spasmodic torticollis, affects the muscles of the neck, resulting in abnormal positions of the head. CD is a lifelong condition, with the most widely used therapy being intramuscular Botox injections. Oral drugs can be used either alone or in combination with other interventions. Surgery is reserved as a last resort when other treatments fail. 

Different oral medications have been proposed to be effective treatments for CD. This article will provide you with more information regarding their mechanisms, benefits and limitations as well as a glance at emerging therapies.^1,2,3

What is Cervical Dystonia?

People with dystonia are typically classified into two main groups: primary (idiopathic) and secondary (symptomatic). Individuals with primary dystonia do not have an identifiable underlying cause for their symptoms. In contrast, secondary dystonia may occur due to trauma, neurodegenerative disorders, or conditions linked to imbalances of neurotransmitters in the basal ganglia.⁴ 

The basal ganglia regulate the various muscle contractions needed to move the body. A dysregulated basal ganglia results in the wrong muscles contracting or muscles contracting when you do not intend to move, leading to uncontrollable twitching and tremors. These movements are referred to as dystonic episodes.⁵

In CD, the dystonic episodes are limited to the muscles of the neck. People with CD also report abnormal positioning of the head and neck or patterns of tilting or rotation. These movements result in symptoms of recurrent headaches, restricted motion and muscle spasms in patients with CD.⁶

CD can progress to involve other body parts such as the face, jaw and trunk. It can contribute to secondary issues such as the development of bone spurs in the spine. This narrows the spinal canal and results in compressed nerve endings, which can lead to patients suffering with tingling, numbness and weakness of their limbs. Outside of physical complications, patients with CD are at greater risk of suffering from depression and a significantly reduced quality of life.^7,8

Therefore, oral therapy in CD is focused not just on alleviating current symptoms but also on preventing long-term complications.

Oral medications used in CD

Levodopa

Levodopa (L-DOPA) is primarily used in people with secondary CD. As mentioned above, certain neurological disorders can cause the manifestation of CD; the most common of these is Segawa syndrome, a form of dopamine-responsive dystonia (DRD).⁹

People with DRD have a defect in the enzymes involved in the biosynthesis of dopamine, resulting in a deficiency. Dopamine is a key neurotransmitter involved in multiple physiological functions - one of which is motor control through its influence on the basal ganglia. The basal ganglia regulate the function of neurons that play a role in voluntary movement, so a lack of dopamine leads to tremors.⁴

Levodopa is converted into dopamine in the brain, effectively bypassing the defective enzyme pathway and increasing dopamine levels. This increase in dopamine results in a reduction of dystonic episodes.

Levodopa is combined with other medications such as Benserazide or Carbidopa. These medications reduce the breakdown of Levodopa in the bloodstream, thus it can get to the brain. They also reduce the side effects of Levodopa such as nausea, fatigue and dizziness.

Levodopa can further be administered with a medication called Entacapone. This inhibits the enzymes in the brain responsible for the breakdown of levodopa, thereby increasing its duration of action.

If you are prescribed Levodopa, the starting dosage is usually low, and it will be slowly increased until you notice a benefit.

People with DRD report excellent and sustained responses to Levodopa, and over time can typically stay on relatively low and stable doses into adulthood. The use of Levodopa is associated with symptoms of “dyskinesias”, which refers to jerky movements.^10,11 

You may encounter another occurrence with Levodopa known as “on/off” fluctuations. There could be times when your symptoms are effectively managed, termed the “on” phase, and other times when your symptoms reappear, known as the “off” phase. Generally, “off” periods develop slowly, but they can also appear abruptly.¹²

Tetrabenazine 

Tetrabenazine is a dopaminergic medication that affects dopamine release. Compared to Levodopa, which aims to enhance dopamine release, Tetrabenazine reduces dopamine levels in the brain by blocking a dopamine transporter. This mechanism is effective because dopamine interacts with both inhibitory and excitatory neurons in the brain. Elevated levels of dopamine can lead to hyperkinesis, which manifests as repetitive movements.^13,14 

It is generally well tolerated; however is associated with common side effects of drowsiness, insomnia and depression. The starting dosage is usually low, and it will be slowly increased until you notice a benefit.

Anticholinergics

The basal ganglia consist of a particular type of neuron known as cholinergic neurons. These neurons interact with the body by releasing acetylcholine, a neurotransmitter that attaches to acetylcholine receptors. Acetylcholine receptors are categorised into G-coupled muscarinic receptors (GPCRs) and G-coupled nicotinic receptors. Muscarinic receptors are found on the nerve endings of smooth muscle cells, secretory glands, and within the central nervous system (CNS).¹⁵ 

Anticholinergic medications function by blocking the binding of acetylcholine to its receptor sites. By attaching to nicotinic receptors on dopamine neurons within the basal ganglia, acetylcholine can stimulate the release of dopamine; thus, anticholinergics inhibit dopamine release, which can lessen dopamine-related dystonia, similar to the action of Tetrabenazine.

Very few of this class of drug can achieve the intended effect due to low bioavailability. However, Benztropine and Trihexyphenidyl from this class of medication stand out as exceptions, as they can cross the blood-brain barrier and exert their effects in the CNS. These medications are administered orally, which makes them easier to take and allows for systemic absorption. Consequently, their effects can be experienced throughout various bodily systems where cholinergic receptors are present. This effect is utilised in the treatment of different types of dystonia that affect multiple muscles and regions.¹⁶

However, there are also limitations to this class. Firstly, they must be taken as part of a complex treatment regimen, which can be unfavourable for patients who struggle with pill burden. There is a huge range of anticholinergic side effects, such as:

• Dry mouth
• Visual disturbances
• Bowel problems
• Increased confusion

This especially affects tolerability in older adults or patients with cognitive problems.¹⁷

Benzodiazepines

Benzodiazepines primarily act by enhancing the effects of the neurotransmitter gamma-aminobutyric Acid (GABA), which is inhibitory. Benzodiazepines exert their effects on GABA receptors in the CNS, enhancing the effects of GABA, resulting in a reduction of muscle excitability often associated with dystonia. There is a wide range of drugs in this class, and Diazepam and Clonazepam are the two most commonly used, given their long half-lives and duration of action. They are also beneficial for their effect on reducing anxiety, which can sometimes exacerbate symptoms of dystonia.^10,18

As a class, benzodiazepines are used as a short-term treatment, preferably as they carry a risk of dependence, withdrawal and sedation. 

Baclofen 

Baclofen attaches to GABA receptors in the CNS, and through this mechanism, it imitates GABA's effects to decrease muscle excitability and encourage muscle relaxation. The dose of Baclofen can be titrated till benefit is observed. Common side effects of Baclofen include hallucinations, confusion and mental changes. These are more likely to occur in elderly patients.^18,19

Choosing the right medication for you

When selecting the right medication for you, it is important to consider various factors. For example, in elderly patients, medications such as anticholinergics are less preferred due to their risk of anticholinergic side effects. 

On the other hand, Levodopa would be preferred for patients with DRD. People experiencing dyskinesia symptoms are recommended to steer clear of medications like Tetrabenzene, as they could worsen these symptoms. In the end, treatment options should be tailored to fit the specific requirements of each patient.

Emerging therapies 

Research is now exploring gene-targeted therapies, which would target the underlying diseases responsible for CD. Certain studies are looking into the possibility of eliminating mutated genes to enhance normal cellular functions. However, gene therapies are often expensive and less accessible than oral therapies, raising questions about their benefit as well as ethical concerns.

There are also research studies exploring the effects of novel drugs such as Zonisamide in the potential for treating CD. Zonisamide is already utilised as an anticonvulsant for patients with epilepsy due to its effect on reducing repetitive firing of neurons, and therefore reducing seizure activity. It has also been found to enhance GABA function outside of its anticonvulsant mechanisms.^20,21,22 

Summary

Cervical Dystonia (CD) is a condition characterised by involuntary muscle spasms, mainly affecting the neck and causing abnormal head positions. It is a lifelong issue, typically treated with Botox injections, oral medications, or surgery as a last option. Dystonia is classified into two types: primary, with no known cause, and secondary, which is linked to trauma or neurological disorders. The disorder affects the basal ganglia, leading to improper muscle contractions and uncontrollable movements called dystonic episodes. In CD, symptoms include abnormal head positioning, headaches, restricted neck motion, and muscle spasms. CD may worsen over time, potentially impacting other body parts and causing complications like bone spurs, which can compress nerves.

Patients are also at a higher risk for depression and may face a reduced quality of life. Oral treatment aims to relieve symptoms and prevent long-term issues. Levodopa (L-DOPA) is a key oral medication for individuals with secondary chorea dystonia (CD), particularly those with dopamine-responsive dystonia (DRD) like Segawa syndrome. It increases dopamine levels in the brain, helping to reduce dystonic episodes caused by dopamine deficiency. Levodopa is often paired with Benserazide or Carbidopa to enhance its effectiveness and minimise side effects like nausea and dizziness. It can also be combined with Entacapone to prolong its action. Patients typically start with a low dose that is gradually increased, and many experience good long-term results, although some may develop "dyskinesias" and experience "on/off" symptom fluctuations.

Tetrabenazine decreases dopamine levels and is effective in mitigating hyperkinesis, but may cause side effects like drowsiness and depression. Anticholinergics, like Benztropine and Trihexyphenidyl, block acetylcholine receptors to reduce dopamine-related symptoms but can have significant side effects. Benzodiazepines, such as Diazepam and Clonazepam, enhance GABA effects to reduce muscle excitability and anxiety but are recommended for short-term use due to the risk of dependence. Baclofen also mimics GABA to promote muscle relaxation but may confuse, especially in older patients. Drug choices should be tailored to individual patient needs, considering risks and benefits. Research is ongoing into gene-targeted therapies and novel medications like Zonisamide, which has potential for treating CD.