Pregabalin Powerful Action, Uses, Dosage, Side effects and Top 10 Brands in Pakistan

Introduction

Pregabalin is a medication widely used to treat neuropathic pain, fibromyalgia, and generalized anxiety disorder. It is a prescription medication classified as an anticonvulsant or antiepileptic drug. It works by slowing down impulses in the brain that cause seizures and affecting chemicals in the brain that send pain signals across the nervous system. Structurally, pregabalin is similar to the neurotransmitter gamma-aminobutyric acid (GABA), but it does not bind directly to GABA receptors.

How Pregabalin Works

Pregabalin primarily works by binding to the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system. This action reduces the release of neurotransmitters such as glutamate, norepinephrine, and substance P, which are involved in pain transmission and seizure activity. By modulating these neurotransmitters, pregabalin helps to alleviate symptoms of neuropathic pain, control seizures, and reduce anxiety.

Pregabalin in Pakistan

In Pakistan, pregabalin is widely used to manage various medical conditions, including neuropathic pain, epilepsy, fibromyalgia, and generalized anxiety disorder (GAD). Available under various brand names, it is commonly prescribed by healthcare professionals due to its effectiveness in reducing pain and improving the quality of life for patients with chronic conditions.

Despite its benefits, the potential for misuse and dependence has led to strict regulations and prescription requirements in the country. Pharmacies require a valid prescription to dispense pregabalin, ensuring that its use is carefully monitored. The medication’s accessibility and efficacy make it a crucial component of pain management and neurological treatment in Pakistan, offering relief to countless patients.

Uses of Pregabalin

Pregabalin is prescribed by doctors for various medical conditions, including neuropathic pain, epilepsy, generalized anxiety disorder, and fibromyalgia, which are described below:

Neuropathic Pain

Pregabalin is commonly prescribed for neuropathic pain, which can result from conditions such as diabetes (diabetic neuropathy), shingles (postherpetic neuralgia), spinal cord injury, and peripheral nerve damage. Neuropathic pain is often chronic and can be debilitating, but it helps to reduce the intensity and frequency of pain episodes.

Fibromyalgia

Fibromyalgia is a chronic condition characterized by widespread musculoskeletal pain, fatigue, and tenderness in localized areas. Pregabalin is one of the few medications approved by the FDA for the treatment of fibromyalgia. It helps by reducing pain and improving sleep quality, which significantly enhances the quality of life for patients.

Epilepsy

Pregabalin is used as an adjunctive therapy for partial-onset seizures in adults with epilepsy. It is typically added to other antiepileptic medications when the primary treatment does not fully control seizures. It helps to decrease the frequency of seizures by stabilizing electrical activity in the brain.

Generalized Anxiety Disorder (GAD)

Pregabalin has also been approved for the treatment of generalized anxiety disorder (GAD) in several countries outside the United States. GAD is characterized by excessive, uncontrollable worry about various aspects of daily life. Pregabalin helps to alleviate anxiety symptoms by modulating neurotransmitter activity in the brain.

Pregabalin Uses in Urdu

پریگابالن مختلف طبی حالتوں کے لئے ڈاکٹروں کی طرف سے تجویز کیا جاتا ہے، جن میں نیوروپیتھک درد، مرگی، عمومی اضطرابی خرابی، اور فائبرومیالجیا شامل ہیں، جو نیچے بیان کی گئی ہیں

نیوروپیتھک درد

پریگابالن عام طور پر نیوروپیتھک درد کے لئے تجویز کیا جاتا ہے، جو ذیابیطس (ذیابیطسی نیوروپیتھی)، شنگلز (پوسٹ ہیرپٹک نیورالجیا)، ریڑھ کی ہڈی کی چوٹ، اور پیریفرل اعصاب کے نقصان جیسی حالتوں سے پیدا ہو سکتا ہے۔ نیوروپیتھک درد اکثر دائمی اور کمزور کرنے والا ہوتا ہے، لیکن پریگابالن درد کی شدت اور تعدد کو کم کرنے میں مدد کر سکتا ہے۔

فائبرومیالجیا

فائبرومیالجیا ایک دائمی حالت ہے جو وسیع پیمانے پر عضلاتی درد، تھکاوٹ، اور مخصوص مقامات میں نرمی کی خصوصیت رکھتی ہے۔ فائبرومیالجیا کے علاج کے لئے پریگابالن ان چند دواؤں میں سے ایک ہے جو FDA کی طرف سے منظور شدہ ہیں۔ یہ درد کو کم کرنے اور نیند کے معیار کو بہتر بنانے میں مدد کرتی ہے، جو مریضوں کی زندگی کے معیار کو نمایاں طور پر بہتر بناتی ہے۔

مرگی

پریگابالن بالغوں میں جزوی دوروں کے لئے ضمنی علاج کے طور پر استعمال ہوتا ہے۔ یہ عام طور پر دیگر اینٹی ایپیلیپٹک دواؤں کے ساتھ شامل کیا جاتا ہے جب بنیادی علاج مکمل طور پر دوروں کو کنٹرول نہیں کرتا۔ یہ دماغ میں برقی سرگرمی کو مستحکم کرکے دوروں کی تعدد کو کم کرنے میں مدد کرتا ہے۔

عمومی اضطرابی خرابی (GAD)

پریگابالن کو متعدد ممالک میں عمومی اضطرابی خرابی (GAD) کے علاج کے لئے بھی منظور کیا گیا ہے۔ GAD کی خصوصیت غیر ضروری، ناقابل کنٹرول پریشانی ہوتی ہے جو روزمرہ کی زندگی کے مختلف پہلوؤں سے متعلق ہوتی ہے۔ پریگابالن دماغ میں نیورو ٹرانسمیٹر کی سرگرمی کو معتدل کرکے اضطراب کی علامات کو کم کرنے میں مدد کرتا ہے۔

Benefits

Key benefits of pregabalin include:

Effective Pain Relief

Pregabalin has been shown to provide significant pain relief for individuals with neuropathic pain and fibromyalgia. By targeting specific pathways involved in pain transmission, it can reduce both the intensity and frequency of pain episodes, improving patients’ overall quality of life.

Improved Sleep Quality

Many individuals with chronic pain or anxiety disorders also suffer from poor sleep quality. This drug helps to improve sleep by reducing pain and anxiety, allowing patients to achieve more restful and restorative sleep.

Reduced Anxiety Symptoms

For those with generalized anxiety disorder, It effectively reduces symptoms such as excessive worry, restlessness, and irritability. This can lead to improved daily functioning and a better overall sense of well-being.

Fewer Seizures

When used as an adjunctive therapy for epilepsy, pregabalin can help to reduce the frequency and severity of partial-onset seizures. This can make a significant difference in the lives of individuals with epilepsy, allowing them to lead more normal and less disrupted lives.

Approval and Usage in the United States

Pregabalin was approved for medical use in the United States in 2004, and it was developed as a successor to the related medication gabapentin. As of 2021, it is available as a generic medication and ranks as the 73rd most commonly prescribed medication in the United States, with over 8 million prescriptions.

Controlled Substance Classification

In the United States, pregabalin is classified as a Schedule V controlled substance under the Controlled Substances Act of 1970. This classification indicates that the drug has low abuse potential compared to substances in Schedules I-IV. However, there is still a potential for misuse, and reports have indicated the possibility of experiencing euphoria, improved happiness, excitement, calmness, and a “high” similar to marijuana with the use of pregabalin. Despite its low abuse potential, there is still a risk of developing dependence on pregabalin, and withdrawal symptoms may occur if the medication is abruptly discontinued.

Classification in the United Kingdom

In the UK, pregabalin is classified as a Class C controlled substance. This classification signifies that while Class C drugs are considered by the UK government to be the least harmful of the controlled substances, it is still illegal to possess, supply, or sell Class C drugs like pregabalin without a prescription. Additionally, specific requirements are needed on the prescription, such as clearly defining the dose.

Despite being seen as the least harmful by the UK government, possession of Class C drugs can lead to long prison sentences if found guilty in court. It’s important to note that pregabalin has the potential for misuse, as it has been reported to bring about an elevated mood in users but can also have serious side effects, especially when used in combination with other drugs.

Side Effects

Some reported side effects of pregabalin are categorized as common and serious side effects which are mentioned below:

Common Side Effects

Like all medications, pregabalin can cause side effects. The most common side effects include:

• Dizziness
• Sleepiness
• Dry mouth
• Edema (swelling) in the hands and feet
• Blurred vision
• Weight gain

These side effects are usually mild and tend to decrease over time as the body adjusts to the medication.

Serious Side Effects

While serious side effects are less common, they can occur. Patients should be aware of the following and seek medical attention if they experience:

• Severe allergic reactions (rash, itching, swelling, severe dizziness, difficulty breathing)
• Suicidal thoughts or behaviour
• Unusual changes in mood or behaviour
• Muscle pain, tenderness, or weakness (especially if accompanied by fever and dark urine)
• Vision changes or loss of vision

Long-Term Effects

The long-term use of this drug leads to dependence or tolerance, especially if used in higher doses. Patients should follow their doctor’s instructions carefully and not exceed the prescribed dosage to minimize the risk of dependence.

Dosage and Administration

Initial Dosage

The initial dosage of pregabalin varies depending on the condition being treated. For neuropathic pain and fibromyalgia, the typical starting dose is 150 mg per day, divided into two or three doses. For epilepsy, the starting dose is usually 75 mg twice daily.

Adjusting the Dosage

The dosage of pregabalin may be adjusted based on the patient’s response to the medication and the presence of any side effects. The maximum recommended dose is 600 mg per day, but most patients achieve effective symptom control at lower doses.

How to Take Pregabalin

Pregabalin can be taken with or without food. It should be swallowed whole with water and not crushed or chewed. Consistency is key, so it’s important to take the medication at the same time(s) each day to maintain steady levels in the bloodstream.

Pharmacokinetics:

Absorption

Pregabalin is absorbed in the intestines through an active transport process involving the large neutral amino acid transporter 1 (LAT1, SLC7A5), which also transports amino acids like L-leucine and L-phenylalanine. This transporter handles very few drugs, fewer than ten. Unlike gabapentin, which relies solely on LAT1 for transport, pregabalin uses LAT1 along with other carriers. Gabapentin’s absorption is dose-dependent due to the easy saturation of LAT1, resulting in decreased bioavailability and delayed peak levels at higher doses. In contrast, pregabalin exhibits linear pharmacokinetics and does not experience saturation of absorption.

Its oral bioavailability is consistently high, at or above 90%, across its clinical dose range (75 to 600 mg/day). Food does not significantly impact pregabalin’s bioavailability, although it can delay absorption and reduce peak levels. On an empty stomach, It is quickly absorbed, reaching peak levels (Tmax) in less than or equal to one hour at doses of 300 mg or less. When taken with food, absorption is delayed, and peak levels are significantly reduced, with Tmax values shifting from 0.6 hours (fasted state) to 3.2 hours (fed state), and peak concentration (Cmax) reduced by 25-31%.

Distribution

Pregabalin crosses the blood-brain barrier, entering the central nervous system. However, due to its low lipophilicity, it requires active transport across the barrier. LAT1, which is highly expressed at the blood-brain barrier, facilitates this transport. Pregabalin has also been shown to cross the placenta and is present in the milk of lactating rats. In humans, the volume of distribution for an orally administered dose of pregabalin is approximately 0.56 L/kg, and it binds minimally to plasma proteins (less than 1%).

Metabolism

Pregabalin undergoes minimal to no metabolism in the body. Studies using nuclear medicine techniques indicate that about 98% of the administered pregabalin is recovered unchanged in the urine. The primary metabolite of pregabalin is N-methyl pregabalin. This minimal metabolism makes pregabalin generally safe for patients with liver cirrhosis.

Elimination

It is primarily eliminated by the kidneys in its unchanged form. It has a relatively short elimination half-life of about 6.3 hours, necessitating administration two to three times daily to maintain therapeutic levels. The renal clearance rate of pregabalin is 73 mL/minute.

Pregnancy and Breastfeeding

Pregabalin should be used during pregnancy only if the potential benefits outweigh the risks. There is limited data on its safety in pregnant women, and it can cause harm to the developing fetus. Pregabalin can also pass into breast milk, so breastfeeding while taking the medication is not recommended.

Drug Interactions

Pregabalin can interact with other medications, including:

• Opioid painkillers (e.g., oxycodone, hydrocodone)
• Sedatives and tranquilizers (e.g., lorazepam, diazepam)
• Other antiepileptic drugs (e.g., gabapentin, valproate)

These interactions can increase the risk of side effects such as drowsiness, dizziness, and respiratory depression. It’s important to inform your healthcare provider of all medications and supplements you are taking.

Pre-existing Medical Conditions

Patients with certain medical conditions should use pregabalin with caution, including those with:

• Kidney disease (dosage adjustments may be necessary)
• Heart failure (risk of edema may be increased)
• History of substance abuse (risk of dependence on pregabalin)

The Genesis of Pregabalin: A Breakthrough in Epilepsy Treatment

Synthesis and Invention

Pregabalin, synthesized in 1990, emerged as a potential anticonvulsant, owing to the pioneering work of medicinal chemist Richard Bruce Silverman at Northwestern University in Evanston, Illinois. Renowned for his expertise, Silverman identified pregabalin as a promising candidate for combating epileptic seizures.

Collaborative Discovery

During the years 1988 to 1990, Ryszard Andruszkiewicz, a visiting research fellow, worked under Silverman’s guidance, synthesizing a series of molecules at Silverman’s request. Among them, one molecule stood out for its potential. This molecule was meticulously crafted for efficient transport into the brain, where it could activate L-glutamic acid decarboxylase, an enzyme crucial for enhancing the production of the inhibitory neurotransmitter GABA, to curb convulsions.

Pharmaceutical Testing and Approval

Recognizing the significance of their discovery, Silverman and his team sent the set of molecules, including pregabalin, to Parke-Davis Pharmaceuticals for extensive testing. Subsequently, pregabalin garnered approval in the European Union in 2004. The United States FDA granted its approval in December 2004 for the treatment of epilepsy, diabetic neuropathic pain, and postherpetic neuralgia. Pregabalin made its debut in the US market under the brand name Lyrica in the fall of 2005.

Advancements and Limitations

In 2017, the FDA expanded its approval to include pregabalin extended-release Lyrica CR for managing neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. However, unlike the immediate-release formulation, Lyrica CR was not approved for managing fibromyalgia or as add-on therapy for adults with partial-onset seizures. This progression underscores the transformative journey of scientific discoveries into impactful medicines, facilitated by collaboration between academia and pharmaceutical enterprises.

Chemistry

The chemical structure of pregabalin reveals its close relationship to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Pregabalin is described as a 3-substituted derivative and a γ-amino acid, specifically (S)-(+)-3-isobutyl-GABA. It also bears a resemblance to the α-amino acids L-leucine and L-isoleucine, which may be more relevant to its pharmacodynamics than its structural similarity to GABA.

Additionally, despite being a GABA analog, pregabalin does not directly bind to GABA or benzodiazepine receptors. Instead, it has been found to produce a dose-dependent increase in the brain expression of L-glutamic acid decarboxylase (GAD), the enzyme responsible for synthesizing GABA. This suggests that pregabalin may have some indirect GABAergic effects by increasing GABA levels in the brain. However, the primary mechanism of action for pregabalin’s anticonvulsant, analgesic, and anxiolytic effects is the inhibition of 2-containing voltage-dependent calcium channels (VDCCs).

Brands

• Pregy is manufactured by the leading multinational pharma Sami Pharmaceuticals.
• GABICA is manufactured by GETZ PHARMA PAKISTAN (PVT) LTD.
• Pfizer Pharmaceuticals manufactures Lyrica.
• HIGH NOON LABORATORIES LTD produces HILIN.
• PRELIN is manufactured by MARTIN DOW PHARMACEUTICALS (PAK) LTD.
• CARAWAY PHARMACEUTICALS produces REGAB.
• ATCO LABORATORIES LIMITED manufactures SYNGAB.
• WILSHIRE LABORATORIES (PVT) LTD produces XAAR.
• ZEEGAP is manufactured by HILTON PHARMA (PVT) LIMITED.
• Sun Pharma Laboratories Ltd manufactures Neugaba.

Conclusion

Pregabalin is a versatile medication that provides effective relief for a variety of conditions, including neuropathic pain, fibromyalgia, epilepsy, and generalized anxiety disorder. While it has a range of benefits, it also comes with potential side effects and risks that should be carefully considered. By understanding how pregabalin works, its uses, benefits, and potential drawbacks, patients and healthcare providers can make informed decisions about its use in managing chronic pain and other conditions.