Pregabalin - An Overview

Overview:

Patients with neuropathic pain originating from injured nerves in the arms, hands, fingers, legs, feet, or toes are prescribed Pregabalin capsules (oral solution or extended-release tablets), especially if they have diabetes. These drugs are also used to treat post therapeutic neuralgia (PHN), which is a condition marked by aching, burning, or stabbing pain that lasts for months or even years after a shingles epidemic.

Additionally, Pregabalin oral solution and pills are utilized to treat fibromyalgia, a chronic disorder that causes pain, muscle stiffness, discomfort, exhaustion, and sleep difficulties, as well as neuropathic pain that follows a spinal cord injury. Moreover, they are included in treatment plans in addition to other drugs to control particular kinds of seizures in adults and children one month of age and older. Pregabalin was approved by the US FDA (United States Food and Drug Administration) in 2004.

Drug Group:

Pregabalin belongs to the drug group of anticonvulsants.

Available Doses and Dosage Forms:

• Capsules: 25 mg (milligrams), 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg.

• Oral Solution: 20 mg/ml (milligrams per milliliter).

For Patients

What Is Epilepsy?

Recurrent seizures are an indicator of epilepsy, which is a brain disorder. A seizure is commonly characterized as a sudden change in behavior brought on by a temporary disruption in the brain's electrical activity. The brain constantly produces little electrical signals in a regular pattern. These impulses are carried by neurotransmitters, which are chemical messengers that allow the impulses to flow throughout the body and along neurons (brain nerve cells).

An imbalance in the electrical rhythms of the brain causes recurrent seizures in epilepsy. It is common for the electrical rhythms in the brain to become imbalanced in people with epilepsy. Recurrent seizures are the result of this imbalance. Sudden and synchronized bursts of electrical energy disrupt the normal, orderly pattern of electrical impulses during a seizure. These episodes might momentarily affect an individual's actions, sensations, or consciousness.

When a person has at least two seizures that are not related to a recognized medical condition, such as alcohol withdrawal or dangerously low blood sugar, they are usually diagnosed with epilepsy. To accurately diagnose epilepsy and develop a treatment plan, medical professionals must carefully review the patient's medical history and do diagnostic testing before confirming the diagnosis.

How Does Pregabalin Work?

Pregabalin reduces abnormal brain activity, lessens seizures, stops pain signals in the brain and spine, and reduces anxiety by preventing the release of hormones that make people feel worried.

What Are the Things to Inform the Doctor Before Taking Pregabalin?

When taking Pregabalin, inform the doctor about allergies, prescriptions, and medical history. The person should also avoid alcohol, watch out for drowsiness, and report any changes in mental health, suicidal thoughts, or strange actions.

How Is Pregabalin Administered?

Pregabalin is supplied as extended-release tablets, oral solutions, and capsules. Pregabalin capsules and oral solution should be taken twice or thrice daily, with or without food. Pregabalin extended-release tablets should be taken daily, preferably after an evening meal. The suggested dosage varies. Patients are urged to read the medication label carefully and to schedule appointments consistently. The extended-release tablets must be consumed whole, not broken, chewed, or crushed.

What Are the Side Effects of Pregabalin?

Patients using Pregabalin should notify their doctor immediately if they have any adverse effects that worsen or last longer than expected. Frequent adverse effects include:

• Tiredness.

• Vertigo (dizziness).

• Headaches.

• Dry mouth.

• Nausea, vomiting, constipation, gas, and bloating.

• Agitation.

• Difficulty in speaking.

• Memory problems and anxiety.

• There is a lack of coordination, balance issues, uncontrollable shaking or jerking of a body part, and muscle twitching (tightening).

• Weight gain.

• Increased hunger.

Individuals should be vigilant for potentially serious side effects of Pregabalin and seek immediate medical attention if they encounter symptoms such as the following.

• Bluish-tinged skin, lips, or fingernails.

• Pain in the chest, difficulty in breathing, wheezing, and shortness of breath.

• Confusion, extreme sleepiness.

• Blurred or double vision and changes in eyesight.

• Hives, rash, itching, blisters, swelling of the eyes, face, throat, mouth, lips, gums, tongue, head, neck, arms, hands, feet, ankles, or lower legs.

• Muscle pain, tenderness, soreness, or weakness (especially with fever).

Additionally, patients with diabetes should be particularly aware of their skin health, as Pregabalin has been connected with animal skin sores. Any unexpected side effects from taking Pregabalin should be immediately reported to the physician for additional assessment and advice.

Dietary Considerations:

People should stick to their regular diet unless their doctor instructs them to change or modify it.

Missed Dose:

People who take oral solutions or capsules of Pregabalin should take the missing dose as soon as possible if they realize it a few hours later. They should, however, disregard the missed dose and continue with their usual dosing regimen if the next scheduled dose is already almost due. The warning is repeated that it is not advisable to take two doses to make up for a missing one.

If an extended-release tablet dose is missed after dinner, the patient should take the missed dose with a snack before bed. If this is overlooked, take the dose the following day after breakfast. If the morning dose is missed, the patient should take it at their regular hour after dinner. Maintaining consistency with the usual dosing schedule and avoiding taking two doses simultaneously to make up for missed ones should be avoided.

Overdose:

Although there is little information available regarding Pregabalin overdoses, the largest accidental overdose recorded during clinical trials was 8000 mg, and it did not result in any serious problems. There is not a specific Pregabalin antidote in case of an overdose. While ensuring the airway is clean, techniques like stomach pumping or producing vomiting may be used to get rid of any medication that has not been absorbed. It is crucial to provide supportive care, which includes vital sign monitoring. If an overdose is suspected, get the most recent advice by contacting a poison control center. Hemodialysis has not been utilized much for Pregabalin overdoses. However, it might be considered if the patient has serious renal issues or is in poor health. Standard hemodialysis techniques can eliminate around half of the Pregabalin within four hours.

For Doctors:

Indication

• Addressing neuropathic discomfort due to diabetic peripheral neuropathy.

• Post therapeutic neuralgia management.

• Providing supplementary therapy for the treatment of partial onset seizures in individuals aged four years and older.

• Taking care of fibromyalgia.

• Managing the neuropathic pain brought on by a spinal cord injury.

Contraindication:

Pregabalin should not be supplied to persons with a confirmed hypersensitivity to Pregabalin or its components. There have been reports of angioedema and hypersensitivity events in patients receiving Pregabalin medication. As a result, caution is recommended, and those with a known hypersensitivity to the medication or any of its ingredients should consider other treatment choices.

Drug Abuse:

Pregabalin is categorized as a Schedule V restricted substance. It is important to closely evaluate patients for a history of drug abuse and keep an eye out for any indications of Pregabalin usage or abuse, such as tolerance building or drug-seeking behavior, even though it does not work on the same receptors as drugs of abuse.

• In a research conducted on recreational users, the subjective effects of Pregabalin (at a single dose of 450 mg) were assessed similarly to those of Diazepam, including "good drug effect," "high," and "liking."

• In clinical trials, euphoria was reported as a side effect by approximately four percent of patients treated with Pregabalin, compared to one percent of patients receiving a placebo. On the other hand, the percentage of patients who reported experiencing euphoria ranged from one percent to 12 percent.

• Regarding dependence, sudden withdrawal from Pregabalin in clinical trials resulted in symptoms such as headache, nausea, diarrhea, or sleeplessness, indicating a physical dependence.

• Reports from post marketing also referenced instances of anxiety and profuse perspiration. Healthcare providers should consider these things and use Pregabalin with caution.

Dose:

It is possible to take Pregabalin orally with or without food. As stated in the warnings, it is best to gradually lower the dosage of Pregabalin over a minimum of one week when stopping the medication. Given that renal excretion is the primary method of Pregabalin elimination, the dosage should be modified if an adult has reduced kidney function.

• Neuropathic Pain Associated With Diabetic Peripheral Neuropathy: For people with normal kidney function, Pregabalin is typically administered at three doses of 100 mg per day, or 300 mg total. Based on effectiveness and tolerance, the usual starting dose for treatment is 50 mg three times a day, 150 milligrams per day (mg/day). After a week, the dosage can be increased to 300 mg/day. A larger dose of 600 mg/day of the drug was examined; however, a definite effect and improved tolerability were observed. Since there could be negative consequences, it is usually advised not to take more than 300 mg daily.

• Post-herpetic Neuralgia: For people with good renal function (creatinine clearance of at least 60 mL/min), Pregabalin is normally administered at 75 to 150 mg twice a day or 50 to 100 mg three times a day for a total of 150 to 300 mg/day. The treatment usually starts at 75 mg twice or 50 mg thrice daily (150 mg/day). Depending on efficacy and tolerance, dosages can be increased to 300 mg/day in as little as one week. The dose may be increased to 300 mg twice a day or 200 mg three times a day (600 mg/day) if the patient can tolerate it and the pain relief is still unsatisfactory after two to four weeks at 300 mg/day. Nevertheless, because of possible adverse effects, patients with persistent pain who are coping well with the lower dose should only take more than 300 mg/day.

• Fibromyalgia: It is advised to take 300 to 450 mg of Pregabalin every day to treat fibromyalgia. The starting dose is 75 mg twice daily (150 mg/day). If it is well tolerated, increase the dose to 150 mg twice daily (300 mg/day) in less than a week. A further increase of 225 mg twice daily (450 mg/day) is possible if 300 mg/day is insufficient. A study using 600 mg/day of Pregabalin found no discernible additional benefit and poorer tolerance. Taking more than 450 mg daily is generally not advised due to possible adverse effects.

• Neuropathic Pain Associated with Spinal Cord Injury: The recommended daily dose of Pregabalin for the treatment of neuropathic pain related to injuries to the spinal cord is 150 to 600 mg. If tolerated, increase the dose to 150 mg twice daily (300 mg/day) after a week from a starting dose of 75 mg twice daily (150 mg/day). If the patient tolerates Pregabalin and the dosage of 150 mg twice daily is insufficient to relieve pain after two to three weeks, the dosage may be increased to 300 mg twice daily.

• Adjunctive Therapy for Partial Onset Seizures: The suggested Pregabalin dosage for adults and kids four years of age and above is listed below. Oral administration of the entire daily dosage should be split into two or three doses. Dosing for pediatric patients is determined by body weight; doses can be increased or decreased based on tolerance and clinical response, usually once a week.

  • Adults (17 Years of Age and Above): The recommended daily dose is 150 mg, with a maximum of 600 mg.

  • Children Who Weigh 30 Kg or More: They should start off taking 2.5 mg/kg daily, and the dose should not exceed 600 mg.

  • For Children 11 Kg to Less Than 30 Kg: The daily dose should start at 3.5 mg/kg/day and not exceed 14 mg/kg/day.

What Are the Pharmacological Aspects of Pregabalin?

Description

• Chemical Structure: (S)-3-(aminomethyl)-5-methylhexanoic acid.

• Molecular Formula: C8H17NO2.

• Molecular Weight: 159.23.

• Appearance: Crystalline solid that is white to off-white.

• Solubility: The material dissolves readily in water and in aqueous solutions that are basic or acidic.

Mechanism of Action

• Pregabalin operates in the central nervous system by binding tightly to a specific location termed the alpha2-delta subunit, which is part of voltage-gated calcium channels. Though its precise mechanism of action is still unknown, this binding aids in pain reduction and seizure prevention.

• Pregabalin shares structural similarities with the neurotransmitter gamma-aminobutyric acid (GABA); however, it does not bind to GABA receptors directly or normally influence GABA-related functions. Moreover, it does not affect noradrenaline, serotonin, dopamine, or other neurotransmitter systems.

• Pregabalin has been shown to reduce the release of pain-related neurotransmitters in the spinal cord in nerve injury models, potentially by altering calcium channels. Additionally, it might interfere with specific brain circuits that control how pain is transmitted.

• Pregabalin does not affect opiate receptors, sodium channels, or inflammatory enzyme activity. It does not block noradrenaline, serotonin, or dopamine reuptake and stays inactive at these neurotransmitter receptors.

Pharmacokinetics: Pregabalin has a half-life of approximately six hours after oral administration, and the kidneys mostly excrete it.

• Absorption and Distribution

  • The peak concentration of Pregabalin in the blood occurs approximately 1.5 hours after a person takes the capsules without food. Regardless of dosage, pregabalin is constantly bioavailable. The medication takes 24 to 48 hours to establish a stable state in the body with frequent administration.

  • When Pregabalin is taken with meals, the absorption rate may decrease, resulting in a peak concentration approximately three hours after consumption. Nevertheless, the overall amount absorbed stays the same and is not affected by Pregabalin taken with or without food.

  • Administered orally, Pregabalin has a distribution volume of approximately 0.5 liters per kilogram and does not bind to blood proteins. The blood-brain barrier is crossed through a particular transport system. Pregabalin has been shown in animal experiments to cross the blood-brain barrier, reach the placenta of pregnant rats, and be found in the milk of nursing rats despite the lack of direct human data.

• Metabolism and Elimination

  • Pregabalin is not significantly metabolized by the bodies of those who take it. Ninety percent of the medicine administered is excreted in the urine unaltered. The N-methylated derivative is a minor byproduct that accounts for only 0.9 percent of the ejected material. Pregabalin does not change shape in experiments conducted on animals.

  • The kidneys are the main organs in the body that remove Pregabalin; in individuals with typical renal function, its half-life is an average of 6.3 hours. In young, healthy people, the estimated renal clearance (the rate at which the kidneys eliminate it) is between 67.0 and 80.9 mL/min (milliliter per minute). Pregabalin does not bind to blood proteins. Hence, this clearance rate indicates that the kidneys are involved in its reabsorption.

Warnings and Precautions:

• Angioedema: Warn patients that taking Pregabalin can result in severe facial, mouth, and neck edema that could impair their breathing. Tell them to stop taking Pregabalin and get help immediately if they experience any of these symptoms.

• Hypersensitivity Reactions: Advise patients that Pregabalin may cause hypersensitivity reactions, such as breathing difficulties, blisters, hives, or wheezing. Tell them to stop taking Pregabalin and to get medical attention immediately once they experience these symptoms.

• Higher Chance of Adverse Reactions Upon Abrupt or Quick Cessation: Tell patients to take Pregabalin according to the recommended schedule. Abrupt or fast withdrawal can induce symptoms like insomnia, headache, nausea, anxiety, perspiration, or diarrhea, as well as an increase in seizures in people with seizure disorders.

• Suicidal Behavior and Ideation: The risk of suicidal thoughts and behaviors may be increased by drugs such as Pregabalin, which patients, caregivers, and families should be informed of. They should look for indications of sadness, strange mood swings, or suicidal thoughts, and they should report any troubling behaviors to medical professionals right once.

• Edema and Weight Gain: Inform patients that taking Pregabalin could cause weight gain, edema, or fluid retention. Exercise caution when taking Pregabalin and a Thiazolidinedione antidiabetic medication at the same time, as this combination may intensify side effects and raise the risk of heart failure, especially in people who already have heart problems.

• Dizziness and Drowsiness - Inform patients that Pregabalin may result in other CNS (central nervous system) symptoms, such as impaired vision, sleeplessness, and dizziness. Therefore, counsel patients against using heavy machinery, driving, or partaking in other risky activities until they have had enough Pregabalin experience to determine whether it negatively impacts their mental, visual, or motor functioning.

• Tumorigenic Potential: Hemangiosarcoma, a kind of cancer, was shown to occur with an incredibly high frequency in mice used in typical preclinical in vivo trials of the drug Pregabalin. This discovery has unclear therapeutic implications since premarketing development does not allow for a direct evaluation of its ability to cause cancers in humans.

• Ophthalmological Effects: Inform patients that using Pregabalin could result in vision problems. Patients should contact their doctor if they have any changes in their vision.

• Decreased Platelet Count: A decrease in platelet count is associated with Pregabalin medication; the mean maximal decline was 20 × 10^3/µL (microliter), while in placebo patients, it was 11 × 10^3/µL. In controlled trials, a single Pregabalin-treated subject developed severe thrombocytopenia (platelet count fewer than 20 × 10^3/µL). In contrast, three percent of patients saw a potentially clinically relevant platelet reduction (20 % below the baseline and less than 150 × 10^3/µL). Pregabalin did not demonstrate a correlation with an elevated incidence of bleeding-related adverse effects, even despite the platelet reduction.

• PR-Interval Prolongation: An association between Pregabalin and an extension of the PR interval, a component of the heart's electrical activity, was discovered when examining ECG data from persons taking Pregabalin. The PR interval increased by three to six milliseconds with Pregabalin doses of 300 mg/day or more. No significant number of subjects saw significant increases in PR intervals or a higher risk of serious heart block reactions due to this alteration. According to subgroup studies, those using additional medications that lengthen the PR interval or those who had a longer PR interval initially did not exhibit an elevated risk. It is important to remember that the results of these analyses are not definitive because of the small number of patients in these categories.

Specific Considerations:

• Pregnancy

  • Pregabalin administration at high doses was associated with an increased risk of embryonic abnormalities, skeletal deformities, and developmental difficulties in rats and rabbits. However, research on pregnant women is yet lacking. The dosages administered to the animals were far greater than those suggested for humans.

  • For instance, when high dosages of the drug were given to pregnant rats, the progeny displayed altered skulls, lower body weight, and skeletal problems. At the highest dosage, there were more abnormalities and a lower fetal body weight in pregnant rabbits. Higher doses had detrimental effects on the growth and survival of the offspring, and when the female rats were evaluated as adults, they displayed neurobehavioral abnormalities and problems with reproduction. This study involved female rats during the whole gestation and lactation period.

• Nursing Mother

  • Breast milk from a nursing mother who uses Pregabalin may contain trace quantities of the drug. According to a study on nursing women, Pregabalin levels in breast milk were around 76 percent of those in the mother's blood. An infant could receive seven percent of the mother's daily dose of Pregabalin through breast milk.

  • It is noteworthy that the study did not look at the effects of Pregabalin on breastfed infants or how it impacts milk production. Although clinical data in older people is equivocal on this danger, animal research points to a possible risk of tumorigenicity, which is the growth of tumors with Pregabalin exposure through breast milk.

• Pediatric Population

  • The safety and efficacy of using Pregabalin to treat neuropathic pain in children patients suffering from illnesses such as diabetic peripheral neuropathy, postherpetic neuralgia, and spinal cord injury have not been shown.

  • A 15-week Pregabalin trial for fibromyalgia in youth aged 12 to 17 revealed some reduction in pain intensity when compared to a placebo, but the results were not statistically significant. Fatigue, headaches, nausea, dizziness, and increased weight were among the common adverse symptoms seen in teenagers.

  • A 12-week trial showed that Pregabalin, especially at 10 mg/kg/day, more effectively decreased partial onset seizures than a placebo in pediatric patients aged 4 to less than 17. However, the lower dosage of 2.5 mg/kg/day did not result in a statistically significant change. Increased weight, increased appetite, and sleeplessness were common adverse effects.

• Geriatric Population

  • There were no significant variations comparing individuals 65 years of age and older in terms of safety or effectiveness and younger patients for neuropathic pain related to diabetic peripheral neuropathy and post therpetic neuralgia.

  • Although there was little data available for older people with epilepsy, there were no overall differences in safety or effectiveness. Though the general adverse reaction profile for patients 65 and older was similar in fibromyalgia trials, this age group was more likely to have particular neurological side effects such as dizziness, impaired vision, and balance problems. Given that the kidneys are the primary organs responsible for eliminating Pregabalin, senior patients with reduced renal function should exercise caution and consider adjusting their dosage due to the possibility of hazardous responses.

• Renal Impairment - Since the kidneys are primarily responsible for removing Pregabalin, adult patients with kidney problems may consider adjusting their dosage. Pregabalin usage in kids with compromised renal function has not been investigated. This emphasizes the significance of using Pregabalin with caution and making the appropriate dosage modifications, especially for people who have renal problems.

Clinical Studies

Pregabalin (150 to 600 mg/day) was found to considerably reduce neuropathic pain in older individuals (greater than 65 years of age), with improvements in pain matching those seen in younger patients. In elderly individuals with neuropathic pain, titrating Pregabalin to the lowest effective dose should provide for efficient pain management while reducing adverse events. Pregabalin is a valuable treatment choice for older individuals with neuropathic pain because it does not have any known drug-drug interactions, which is relevant considering the usage of various medications in this population.