Neuropathy

Definition:is a collection of disorders that occurs when nerves of the peripheral nervous system (the part of the nervous system outside of the brain and spinal cord) are damaged. The condition is generally referred to as peripheral neuropathy, and it is most commonly due to damage to nerve axons. Neuropathy usually causes pain and numbness in the hands and feet. It can result from traumatic injuries, infections, metabolic disorders, and exposure to toxins. One of the most common causes of neuropathy is diabetes.

Neuropathy can affect nerves that control muscle movement (motor nerves) and those that detect sensations such as coldness or pain (sensory nerves). In some cases - autonomic neuropathy - it can affect internal organs, such as the heart, blood vessels, bladder,orintestines. Pain from peripheral neuropathy is often described as a tingling or burning sensation. There is no specific length of time that the pain exists, but symptoms often improve with time - especially if the neuropathy has an underlying condition that can be cured. The condition is often associated with poor nutrition, a number of diseases, and pressure or trauma, but many cases have no known reason (called idiopathic neuropathy).

In the United States, about 20 million people suffer from neuropathy. Over half of diabetes patients also suffer from the condition.

How is neuropathy classified?

Peripheral neuropathy can be broadly classified into the following categories: Mononeuropathy - involvement of a single nerve. Examples include carpal

tunnel syndrome, ulnar nerve palsy, radial nerve palsy, and peroneal nerve palsy.

Multiple mononeuropathy - two or more nerves individually affected.

Polyneuropathy - generalized involvement of peripheral nerves. Examples include diabetic neuropathy and Guillain-Barre syndrome.

Neurophathies may also be categorized based on a functional classification (motor, sensory, autonomic, or mixed) or the type of onset (acute - hours or days, subacute - weeks or months, or chronic - months or years).

The most common form of neuropathy is (symmetrical) peripheral polyneuropathy, which mainly affects the feet and legs on both sides of the body.

What causes neuropathy?

About 30% of neuropathy cases are considered idiopathic, which means they are of unknown cause. Another 30% of neuropathies are due to diabetes. In fact, about 50% of people with diabetes develop some type of neuropathy. The remaining cases of neuropathy, called acquired neuropathies, have several possible causes, including:

Trauma or pressure on nerves, often from a cast or crutch or repetitive motion such as typing on a keyboard

Nutritional problems and vitamin deficiencies, often from a lack of B vitamins

Alcoholism , often through poor dietary habits and vitamin deficiencies

Autoimmune diseases, such as lupus, rheumatoid arthritis, and Guillain-Barre syndrome

Tumors, which often press up against nerves

Other diseases and infections, such as kidney disease, liver disease, Lyme disease, HIV/AIDS, or an underactive thyroid (hypothyroidism)

Inherited disorders (hereditary neuropathies), such as Charcot-Marie-Tooth disease and amyloid polyneuropathy

Poison exposure, from toxins such as heavy metals, and certain medications and cancer treatments

Who gets neuropathy?

Risk factors for peripheral neuropathy include several conditions and behaviors. People with diabetes who poorly control their blood sugar levels are very likely to suffer from some neuropathy. Autoimmune diseases such as lupus and rheumatoid arthritis also increase one's chance of developing a neuropathy. People who have received organ transplants, AIDS patients, and others who have had some type of immune system suppression have a higher risk of neuropathy. In addition, those who abuse alcohol or have vitamin deficiencies (especially B vitamins) are at an increased risk. Neuropathy is also more likely to occur in people with kidney, liver or thyroid disorders.

The effects of neuropathy

Below are some of the ways neuropathy can affect the various parts of your body and the treatments available.

Skin

You may be less able to feel heat, cold, or pain. It can lead to pain and numbness or tingling in the hands, legs or feet. If you lose sensation in your feet you may not realise that you have trodden on something sharp or that the ground is hot if you walk barefoot.

You should be checked for this kind of neuropathy at your annual diabetes review. They should look for damage to your skin, test that you can sense gentle touch and vibration and check your blood flow.

Treatment: Paracetamol can help with this kind of discomfort. Your doctor can prescribe other tablets if this does not work. Keep a record of whether the painkiller is effective so your doctor knows whether to change the dose or medication. You may be referred to a pain clinic for specialist advice.

Muscles

Your muscles could become weak, which may be painful, and can cause muscle wasting in the thigh (although you may recover over time). If the nerves that supply the muscles in your feet are affected and you also have sensory neuropathy, the weakened muscles cannot stop the bones breaking when stressed. Because you may not feel the damage being done, your foot may become misshapen. This is called Charcot foot and you will need to see a podiatrist for

treatment. Calluses and ulcers may form when bony protrusions rub inside the shoes and these could become infected.

Treatment: If you have Charcot foot you may be given specially made shoes or insoles, moulded to shape, to remove pressure from the fragile bones. It is important to protect your foot from further damage by resting it. Your foot may be put into a cast or splint and you may be given crutches to use or even a wheelchair. If your foot has healed into a poor shape then you may need an operation to remodel the bones.

Stomach and intestines

The movement of food through the gut can become slow when your stomach takes too long to empty (gastroparesis), causing nausea, bloating, vomiting, diarrhoea, constipation, general discomfort or unintentional weight-loss.

Treatment: Your doctor will be able to prescribe tablets or treatments to help speed digestion and relieve the other symptoms.

Bladder

It can cause you to develop problems passing urine properly or you may feel that you have emptied your bladder completely, when you have not. If this goes untreated it could cause you to become incontinent or even lose the ability to pass urine altogether.

Treatment: You may need to visit the toilet every three hours even if you don’t feel you need to go.

Antibiotics may be needed if it causes a urine infection.

Penis

This area can lead to erectile dysfunction or impotence.

Treatment: Your doctor can prescribe various treatments to help including tablets, injection, vacuum pump or implant.

Blood vessels

You may get low blood pressure as you stand up, especially when you first get out of bed, which causes dizziness or weakness. Your ability to feel the pain of angina or a heart attack may also be impaired.

Treatment: Compression stockings may help treat dizziness from standing up too quickly.

Sweat glands

It can become difficult for your body to regulate temperature. An inability to sweat in the lower limbs can lead to the skin on the feet becoming dry and cracked. Gustatory (when eating) sweating may start quite soon after chewing and can be brought on by certain foods. It often starts on the forehead, and spreads to the face, scalp and neck, sometimes affecting the upper part of the body. This is very rare and there is no treatment other than good blood glucose control.

GENERIC NAME: pregabalin

AND NAME: Lyrica

DRUG DESCRIPTION

Pregabalin :

Is described chemically as (S)-3-(aminomethyl)-5-methylhexanoic acid. The molecular formula is C8H17NO2 and the molecular weight is 159.23. The chemical structure of pregabalin is:

Pregabalin :

It is a white to off-white, crystalline solid with a pKa1 of 4.2 and a pKa2 of 10.6. It is freely soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is – 1.35.

LYRICA (pregabalin) Capsules :

They are administered orally and are supplied as imprinted hard-shell capsules containing 25, 50, 75, 100, 150, 200, 225, and 300 mg of pregabalin, along with lactose monohydrate, cornstarch, and talc as inactive ingredients. The capsule shells contain gelatin and titanium dioxide. In addition, the orange capsule shells contain red iron oxide and the white capsule shells contain sodium lauryl sulfate and colloidal silicon dioxide. Colloidal silicon dioxide is a manufacturing aid that may or may not be present in the capsule shells. The

imprinting ink contains shellac, black iron oxide, propylene glycol, and potassium hydroxide.

LYRICA (pregabalin) oral solution, 20 mg/mL :

It is administered orally and is supplied as a clear, colorless solution contained in a 16 fluid ounce white HDPE bottle with a polyethylene-lined closure. The oral solution contains 20 mg/mL of pregabalin, along with methylparaben, propylparaben, monobasic sodium phosphate anhydrous, dibasic sodium phosphate anhydrous, sucralose, artificial strawberry #11545 and purified water as inactive ingredients.

DRUG CLASS AND MECHANISM:

Pregabalin is an oral medication that is chemically related to gabapentin (Neurontin, Gabarone). It is used for treating pain caused by neurologic diseases such as postherpetic neuralgia as well as seizures. It also is used for treating fibromyalgia. The mechanism of action of pregabalin is unknown. Pregabalin binds to calcium channels on nerves and may modify the release of neurotransmitters (chemicals that nerves use to communicate with each other). Reducing communication between nerves may contribute to pregabalin's effect on pain and seizures. The FDA approved pregabalin in December 2004.

The possible side effects of pregabalin (Lyrica) :

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Call your doctor at once if you have any of these serious side effects

SIDE EFFECTS:

The most common side effects of pregabalin are dizziness, drowsiness, dry mouth, edema (accumulation of fluid), blurred vision, weight gain, and difficulty concentrating. Other side effects include reduced blood platelet counts, and increased blood creatinine kinase levels. Increased creatinine kinase can be a sign of muscle injury, and in clinical trials three patients experienced rhabdomyolysis (severe muscle injury). Therefore, patients should report unexplained muscle pain, tenderness or weakness to their doctors, especially if associated with fever and malaise (reduced well-being). Pregabalin has rarely been associated with angioedema (swelling of the face, tongue, lips, and gums, throat and larynx).

Antiepileptic medications have been associated with increased risk of suicidal thinking and behavior. Anyone considering the use of antiepileptic drugs must balance this risk of suicide with the clinical need. Patients who are started on therapy should be closely observed for clinical worsening, suicidal thoughts, or unusual changes in behavior.

PREPARATIONS:

Capsules: 25, 50, 75, 100, 150, 200, 225, and 300 mg. Oral

DOSING:

Pregabalin may be taken with or without food. The initial dose for neuropathic pain is 50 mg three times a day (150 mg/day). The dose may be increased to a maximum dose of 100 mg 3 times daily (300 mg/day) after one week. The recommended dose for postherpetic neuralgia is 75-150 mg twice daily or 50-100 mg three times daily. Begin dosing at 75 mg two times a day or 50 mg three times a day (150 mg/day). The dose may be increased to 100 mg 3 times daily (300 mg/day) after one week. If pain relief is inadequate after 2-4 weeks of treatment at 300 mg/day, the dose may be increased to 300 mg twice daily or 200 mg three times daily. Doses greater than 300 mg cause more side effects.

The recommended dose for treating seizures is 150-600 mg/day divided into 2 or 3 doses, starting at at 150 mg daily and increasing based on response and tolerability. Fibromyalgia is treated with 300-450 mg/day in 2 or 3 divided doses.

DOSAGE AND ADMINISTRATION

LYRICA is given orally with or without food. When discontinuing LYRICA, taper gradually over a minimum of 1 week.

Solution: 20 mg/ml

STORAGE:

Pregabalin should be stored at room temperature, between 15-30 C (59-86 F).

PRESCRIBED FOR:

Pregabalin is used for neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia and in combination with other drugs to treat partial onset seizures in adults. It also is used for treating fibromyalgia.

INDICATIONS

LYRICA is indicated for:

Management of neuropathic pain associated with diabetic peripheral neuropathy

Management of postherpetic neuralgia

Adjunctive therapy for adult patients with partial onset seizures

Management of fibromyalgia

Management of neuropathic pain associated with spinal cord injury

DRUG INTERACTIONS:

Alcohol and drugs that cause sedation may increase the sedative effects of pregabalin. Pioglitazone (Actos) and rosiglitazone (Avandia) cause weight gain,

fluid retention and possibly heart failure. Therefore, combining pregabalin with these drugs may increase the occurrence of weight gain and fluid retention.

PREGNANCY:

There are no adequate studies of pregabalin in pregnant women.

NURSING MOTHERS:

It is not known whether pregabalin is excreted in human breast milk.

pregabalin, Lyrica Related Pictures & Quizzes

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Neuropathic Pain Associated with Diabetic Peripheral Neuropathy :

The maximum recommended dose of LYRICA is 100 mg three times a day (300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Begin dosing at 50 mg three times a day (150 mg/day). The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function.

Although LYRICA was also studied at 600 mg/day, there is no evidence that this dose confers additional significant benefit and this dose was less well tolerated. In view of the dose-dependent adverse reactions, treatment with doses above 300 mg/day is not recommended [see ADVERSE REACTIONS].

Adjunctive Therapy for Adult Patients with Partial Onset Seizures

LYRICA at doses of 150 to 600 mg/day has been shown to be effective as adjunctive therapy in the treatment of partial onset seizures in adults. Both the efficacy and adverse event profiles of LYRICA have been shown to be dose-related. Administer the total daily dose in two or three divided doses. In general, it is recommended that patients be started on a total daily dose no greater than 150 mg/day (75 mg two times a day, or 50 mg three times a day). Based on individual patient response and tolerability, the dose may be increased to a maximum dose of 600 mg/day.

Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function.

The effect of dose escalation rate on the tolerability of LYRICA has not been formally studied.

The efficacy of add-on LYRICA in patients taking gabapentin has not been evaluated in controlled trials. Consequently, dosing recommendations for the use of LYRICA with gabapentin cannot be offered.

Management of Fibromyalgia

The recommended dose of LYRICA for fibromyalgia is 300 to 450 mg/day. Begin dosing at 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient benefit with 300 mg/day may be further increased to 225 mg two times a day (450 mg/day). Although LYRICA was also studied at 600 mg/day, there is no evidence that this dose confers additional benefit and this dose was less well tolerated. In view of the dose-dependent adverse reactions, treatment with doses above 450 mg/day is not recommended [see ADVERSE REACTIONS]. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function.

Neuropathic Pain Associated with Spinal Cord Injury

The recommended dose range of LYRICA for the treatment of neuropathic pain associated with spinal cord injury is 150 to 600 mg/day. The recommended starting dose is 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient pain relief after 2 to 3 weeks of treatment with 150 mg two times a day and who tolerate LYRICA may be treated with up to 300 mg two times a day [see Clinical Studies]. Because

LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function.

Patients with Renal Impairment

In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 1. To use this dosing table, an estimate of the patient's CLcr in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation:

Males:(weight in kg) x (140 – age)

(72) x serum creatinine (mg/100 mL)

Females (0.85) x (above value)

Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for a patient with normal renal function (CLcr ≥ 60 mL/min). Then refer to Table 1 to determine the corresponding renal adjusted dose.

(For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr ≥ 60 mL/min), receives a total daily dose of 150 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily dose of 75 mg/day pregabalin administered in two or three divided doses.)

For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 1).

Table 1: Pregabalin Dosage Adjustment Based on Renal Function

Creatinine Clearance (CLcr) (mL/min)

Total Pregabalin Daily Dose (mg/day)*

Dose Regimen

≥ 60 150 300 450 600 BID or TID

30–60 75 150 225 300 BID or TID

15–30 25–50 75 100– 150 QD or BID

150

<15 25 25–50 50–75 75 QD

Supplementary dosage following hemodialysis (mg)† Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg Patients on the 25–50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg Patients on the 50–75 mg QD regimen: take one supplemental dose of 75 mg or 100 mg Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg TID= Three divided doses; BID = Two divided doses; QD = Single daily dose. * Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose. † Supplementary dose is a single additional dose.

Oral Solution Concentration and Dispensing

The oral solution is 20 mg pregabalin per milliliter (mL) and prescriptions should be written in milligrams (mg). The pharmacist will calculate the applicable dose in mL for dispensing (e.g., 150 mg equals 7.5 mL oral solution).

Dosage Forms And Strengths

Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg Oral Solution: 20 mg/mL [see DESCRIPTION and Storage and Handling].

25 mg capsules

White, hard-gelatin capsule printed with black ink &lduqo;Pfizer&rduqo; on the cap, &lduqo;PGN 25&rduqo; on the body; available in:

Bottles of 90: NDC 0071-1012-68

50 mg capsules

White, hard-gelatin capsule printed with black ink &lduqo;Pfizer&rduqo; on the cap, &lduqo;PGN 50&rduqo; and an ink band on the body, available in:

Bottles of 90: NDC 0071-1013-68Unit-Dose Blister Packages of 100: NDC 0071-1013-41

75 mg capsules

White/orange hard gelatin capsule printed with black ink &lduqo;Pfizer&rduqo; on the cap, &lduqo;PGN 75&rduqo; on the body; available in:

Bottles of 90: NDC 0071-1014-68Unit-Dose Blister Packages of 100: NDC 0071-1014-41

100 mg capsules

Orange, hard-gelatin capsule printed with black ink &lduqo;Pfizer&rduqo; on the cap, &lduqo;PGN 100&rduqo; on the body, available in:

Bottles of 90: NDC 0071-1015-68Unit-Dose Blister Packages of 100: NDC 0071-1015-41

150 mg capsules

White hard gelatin capsule printed with black ink &lduqo;Pfizer&rduqo; on the cap, &lduqo;PGN 150&rduqo; on the body, available in:

Bottles of 90: NDC 0071-1016-68Unit-Dose Blister Packages of 100: NDC 0071-1016-41

200 mg capsules

Light orange hard gelatin capsule printed with black ink &lduqo;Pfizer&rduqo; on the cap, &lduqo;PGN 200&rduqo; on the body, available in:

Bottles of 90: NDC 0071-1017-68

225 mg capsules:

White/light orange hard gelatin capsule printed with black ink &lduqo;Pfizer&rduqo; on the cap, &lduqo;PGN 225&rduqo; on the body; available in:

Bottles of 90: NDC 0071-1019-68

300 mg capsules

White/orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 300" on the body, available in:

Bottles of 90: NDC 0071-1018-68

20 mg/mL oral solution

16 fluid ounce white high density polyethylene (HDPE) bottle with a polyethylene-lined closure:

16 fluid ounce bottle NDC 0071-1020-01

Storage and Handling

`Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (see USP Controlled Room Tempera

Pharmacokinetics

Pregabalin is well absorbed after oral administration, is eliminated largely by renal excretion, and has an elimination half-life of about 6 hours.

Absorption and Distribution

Following oral administration of LYRICA capsules under fasting conditions, peak plasma concentrations occur within 1.5 hours. Pregabalin oral bioavailability is ≥ 90% and is independent of dose. Following single- (25 to 300 mg) and multiple- dose (75 to 900 mg/day) administration, maximum plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) values increase linearly. Following repeated administration, steady state is achieved within 24 to 48 hours. Multiple-dose pharmacokinetics can be predicted from single-dose data.

The rate of pregabalin absorption is decreased when given with food, resulting in a decrease in Cmax of approximately 25% to 30% and an increase in Tmax to approximately 3 hours. However, administration of pregabalin with food has no clinically relevant effect on the total absorption of pregabalin. Therefore, pregabalin can be taken with or without food.

Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0.5 L/kg. Pregabalin is a substrate for system L transporter which is responsible for the transport of large amino acids across the blood brain barrier. Although there are no data in humans, pregabalin has been shown to cross the blood brain barrier in mice, rats, and monkeys. In addition, pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats.

Metabolism and Elimination

Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabeled pregabalin, approximately 90% of the administered dose was recovered in the urine as unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose. In preclinical studies, pregabalin (Senantiomer) did not undergo racemization to the R-enantiomer in mice, rats, rabbits, or monkeys.

Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug with a mean elimination half-life of 6.3 hours in subjects with normal renal function. Mean renal clearance was estimated to be 67.0 to 80.9 mL/min in young healthy subjects. Because pregabalin is not bound to plasma proteins this clearance rate indicates that renal tubular reabsorption is involved. Pregabalin elimination is nearly proportional to creatinine clearance (CLcr) [see DOSAGE AND ADMINISTRATION].

Pharmacokinetics in Special Populations

Race

In population pharmacokinetic analyses of the clinical studies in various populations, the pharmacokinetics of LYRICA were not significantly affected by race (Caucasians, Blacks, and Hispanics).

Gender

Population pharmacokinetic analyses of the clinical studies showed that the relationship between daily dose and LYRICA drug exposure is similar between genders.

Renal Impairment and Hemodialysis

Pregabalin clearance is nearly proportional to creatinine clearance (CLcr). Dosage reduction in patients with renal dysfunction is necessary. Pregabalin is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%. For patients on hemodialysis, dosing must be modified [see DOSAGE AND ADMINISTRATION].

Elderly

Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in CLcr. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function [see DOSAGE AND ADMINISTRATION].

Pediatric Pharmacokinetics

Pharmacokinetics of pregabalin have not been adequately studied in pediatric patients.

Drug Interactions

In Vitro Studies

Pregabalin, at concentrations that were, in general, 10-times those attained in clinical trials, does not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 enzyme systems. In vitro drug interaction studies demonstrate that pregabalin does not induce CYP1A2 or CYP3A4 activity. Therefore, an increase in the metabolism of coadministered CYP1A2 substrates (e.g. theophylline, caffeine) or CYP 3A4 substrates (e.g., midazolam, testosterone) is not anticipated.

In Vivo Studies

The drug interaction studies described in this section were conducted in healthy adults, and across various patient populations.

Gabapentin

The pharmacokinetic interactions of pregabalin and gabapentin were investigated in 12 healthy subjects following concomitant single-dose administration of 100-mg pregabalin and 300-mg gabapentin and in 18 healthy subjects following concomitant multiple-dose administration of 200-mg pregabalin every 8 hours and 400-mg gabapentin every 8 hours. Gabapentin pharmacokinetics following single- and multiple-dose administration were unaltered by pregabalin coadministration. The extent of pregabalin absorption was unaffected by gabapentin coadministration, although there was a small reduction in rate of absorption.

Oral Contraceptive

Pregabalin coadministration (200 mg three times a day) had no effect on the steady-state pharmacokinetics of norethindrone and ethinyl estradiol (1 mg/35 μg, respectively) in healthy subjects.

Lorazepam

Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of lorazepam single-dose pharmacokinetics and single-dose administration of lorazepam (1 mg) had no effect on the steady-state pharmacokinetics of pregabalin.

Oxycodone

Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of oxycodone single-dose pharmacokinetics. Single-dose administration of oxycodone (10 mg) had no effect on the steady-state pharmacokinetics of pregabalin.

Ethanol

Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of ethanol single-dose pharmacokinetics and single-dose administration of ethanol (0.7 g/kg) had no effect on the steady-state pharmacokinetics of pregabalin.

Phenytoin, carbamazepine, valproic acid, and lamotrigine

Steady-state trough plasma concentrations of phenytoin, carbamazepine and carbamazepine 10,11 epoxide, valproic acid, and lamotrigine were not affected by concomitant pregabalin (200 mg three times a day) administration.

Population pharmacokinetic analyses in patients treated with pregabalin and various concomitant medications suggest the following:

Therapeutic class Specific concomitant drug studied

Concomitant drug has no effect on the pharmacokinetics of pregabalin

Hypoglycemics Glyburide, insulin, metformin

Diuretics Furosemide

Antiepileptic Drugs Tiagabine

Concomitant drug has no effect on the pharmacokinetics of pregabalin and pregabalin has no effect on the pharmacokinetics of concomitant drug

Antiepileptic DrugsCarbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproic acid

Dry mouth 11

Constipation 8.2

Nausea 4.9

Vomiting 2.7

A novel method for spectrophotometric determination of pregabalin in pure form and in capsules

Pregabalin (PRG), (S)-3-(aminomethyl)-5-methylhexanoic acid (Figure 1),

is an antiepileptic and structurally related to the inhibitory neurotransmitter

aminobutyric acid (GABA) It was recently approved for adjunctive treatment of

partial seizures in adults [1,2] in United States and Europe and for the treatment of

neuropathic pain from post therapeutic neuralgia and diabetic neuropathy.

Currently, there is no official analytical procedure for pregabalin in any

pharmacopeia. Several reports are there in literature for PRG determination based

on chromatographic methods, i.e., gas chromatography-mass spectrophotometry

(GC-MS), LC-MS-MS [3,4], HPLC [5-7] coupled with varying detection

techniques like tandem mass spectrometry [8], fluorometry [9] and enantiospecific

analysis [10]. These methods may involve procedural variations including pre-

and post- column derivatization [10]. Recently, capillary electrophoresis and

nuclear magnetic resonance technique was reported for PRG involving

complexation with cyclodextrins [11]. All these are complex trace analysis

techniques most of which have been employed for PRG determination in

biological fluid samples. However, routine analysis of the drug in bulk powder

and pharmaceutical preparations in research laboratories and pharmaceutical

industry requires a relatively uncomplicated and a more cost effective method like

UV/visible spectrophotometry or spectrofluorometry. Pregabalin, as such, has a

poor UV/visible absorbance profile (Figure 2) and very few reported methods

have relied on generation of a chromophoric product by reaction of the drug with

some suitable reagent. Considering the limited literature reports available in this

area [12-14], we found it very pertinent to investigate and develop a novel

spectrophotometric method for determination of pregabalin in bulk powder and

pharmaceutical preparations. Ninhydrin has been used as a chromogenic agent in

spectrophotometric analysis of several amino acids, peptides and amines [15]. The

present study describes the evaluation of ninhydrin as a chromogenic reagent in

the development of simple and a rapid spectrophotometric method for the

determination PGB in its pharmaceutical dosage forms. The procedure does not

involve any extraction step with any organic solvent and can be directly carried

out in phosphate buffer pH 7.4 which makes it ideal for routine analysis of the

drug in bulk or in pharmaceutical formulations.

Figure 1. Chemical structure of pregabalin.

Results and discussion Method

In our efforts to design a novel spectrophotometric method for

quantification of pregabalin, we investigated its derivatization with ninhydrin

((triketohydrindene hydrate) for generation of a chromophoric product. Figure 3

shows the UV/visible spectrum of the chromophoric derivative. The procedure

involves formation of purple colored product by reaction of pregabalin with

ninhydrin by heating at a temperature of 70-75°C for 20 minutes. Reaction of

ninhydrin 1 with amines, alpha amino acids, peptides, and proteins yields an

aldehyde with one carbon atom less than the alpha-amino acid; and carbon

dioxide in stoichlometric amounts and varying amounts of ammonia, hydrindantin

and a chromophoric compound known as Ruhemann's Purple (2-(3-hydroxy-1-

oxo-1H-inden-2-ylimino)-2H-indene-1,3-dione). This pigment serves as the basis

of detection and quantitative estimation of alpha-amino acids.13 Mechanism

proposed (Figure 4) for the reaction involves removal of a water molecule from

ninhydrin hydrate 1 to generate 1,2,3-indantrione 2 in the first step, which then,

forms a Schiff's base with the amino group of pregabalin resulting in the ketimine

3. Removal of the aldehyde RCHO generates an intermediate amine 4 (2-amino-

l,3-indandione). Condensation of this intermediate amine with another molecule

of ninhydrin follows to form the expected chromophore 5 (Ruhemann's Purple).

The rate-determining step in the entire sequence of the ninhydrin reaction is the

nucleophilic-type displacement of a hydroxy group of ninhydrin hydrate by a non-

protonated amino group.

Effect of pH

Of the buffers investigated (acetate buffer, phosphate buffer), colour

development was noted in case of phosphate buffer. The optimum buffer pH was

found to be 7.4 and lower pH ranges resulted in an insufficient colour

development.

Effect of reagent concentration

The addition of 1.0 mL of ninhydrin solution (0.2% w/v) was sufficient to

obtain the maximum and reproducible absorbance values for the various

concentration ranges of PGB. Smaller amounts resulted in incomplete reaction.

Further increase in the concentration had no significant effect on complex

formation, although absorbance increased slightly owing to the reagent

background used.

Effects of temperature and heating time

The effects of temperature and heating time on the formation of the

coloured complex were also optimized. At room temperature, the addition of

ninhydrin did not lead to the formation of any coloured product and higher

temperatures were required to accelerate the reaction. The colour intensity

increased with increasing temperature and maximum absorbance was obtained

following heating on a water bath at a temperature of 70-75°C for 20 minutes.

Further heating caused no appreciable change in the colour. The complex obtained

was highly stable for more than 6 h.

Validation

The method was validated with respect to linearity and range, accuracy and

precision, limit of detection (LOD) and limit of quantification (LOQ), selectivity

and robustness. The developed method was validated for the pure drug as well as

marketed formulation of pregabalin (Pregabalin 75; Torrent pharmaceuticals) and

the various validation parameters are shown in Table 1.

Table 1. Validation data for determination of pregabalin by proposed method

Linearity and range

The regression plots showed compliance with Beer Lambert's law

(linearity) in the concentration range of 50 μg/mL-1000 μg/mL with a correlation

coefficient (r2) of 0.992. The standard plot is given in Figure 5. Table 1

summarizes the performance data and statistical parameters for the proposed

method including concentration ranges, linear regression equation, correlation

coefficient, molar absorptivity, Sandell sensitivity limit and these indicate a good

linearity over the working concentration ranges.

Precision

Precision were investigated by analyzing different concentrations of

pregabalin (0.2-1.4 mg/mL) in three independent replicates on the same day

(intra-day precision) and on three consecutive days (inter-day precision). The data

is represented as relative standard deviation (RSD) and results have been shown in

Table 2. Low relative standard deviation (RSD) values for intra- day and inter-

day analysis indicate good precision of the method.

Table 2. Precision of the proposed methods for the analysis of pregabalin

Accuracy

The accuracy of the method signifies the closeness of the measured value to the

true value for the sample. To determine the accuracy of the proposed method,

different levels of drug concentrations were prepared from independent stock

solutions and analyzed. To provide an additional support to the accuracy of the

developed assay method, a standard addition method was employed, which

involved the addition of different concentrations of pure drug to a known pre

analyzed dilution of the pure drug as well as formulation sample and the total

concentration was determined using the proposed method. Accuracy was assessed

as the percentage relative error Er and mean % recovery. The percentage recovery

of the added pure drug was calculated as:

% recovery = C t - C i ∕ C a × 1 0 0 ,

Where

Ct is the total drug concentration measured after standard addition;

Ci drug concentration in the formulation sample;

Ca, drug concentration added.

The percentage relative error was calculated as: Er % = [(found - added)/added] ×

100

Recovery values from standard addition method followed for the bulk drug

analysis ranged from 96.5 to 100.3% (Table 3). Recovery studies with marketed

formulation returned values ranging from 97.09 to 99.74% (Table 4).

Table 3. Results of recovery studies with pure drug pregabalin by standard addition method

Table 4. Recovery studies with pregabalin capsules by standard addition method

Interference

Satisfactory values of the mean recovery values ± SD, RSD % and Er % in

recovery studies in drug formulation (Table 4) revealed that there is no potential

interference of the excipients listed by the manufacturer, i.e., talc, lactose

monohydrate and maize starch. This may be attributed to the dependence of the

reaction in the proposed method on the presence of a primary aliphatic amino

group in the drug molecule which is not present in any of these excepients.

Limit of detection (LOD) and limit of quantitation (LOQ)

LOD and LOQ of the method were established using calibration standards

(Table 1). LOD and LOQ were calculated as 3.3 σ/s and 10 σ/s, respectively, as

per ICH definitions, where, σ is the mean standard deviation of replicate

determination values under the same conditions as the sample analysis in the

absence of the analyte (blank determination), and s is the sensitivity, namely the

slope of the calibration graphs.

Robustness

Repeatability is based on the results of the method operating over short

interval of time under same conditions. Robustness was examined by evaluating

the small variations in different experimental conditions such as heating

temperatures (± 2° C), working wavelengths, volume and concentration of

reagents. Three replicate determinations at six different concentration levels of the

drugs were carried out. The within-day RSD values were found to be less than

0.6% indicating that the proposed method has reasonable robustness.

Stability

The stability of the final sample solutions was examined by their

absorbance values and responses were found to be stable for at least 6 hours at

room temperature.

Analysis of marketed formulation (Pregabalin capsules)

Table 5 gives the results of the assay for pregabalin carried out on marketed

formulation by the proposed method and revealed that there is close agreement

between the results obtained by the proposed methods and the label claim. The

recovered drug content was found to be 99.48%.

Analytical applications

The results with the proposed method for the determination of pregabalin in its

pharmaceutical formulation (Pregabalin75 capsules) suggest satisfactory recovery.

Further, standard addition technique followed to check the validity of the method

have given good recoveries of the drug in presence of formulation suggesting a

noninterference from formulation excepients. Hence, this method can be

recommended for adoption in routine analysis of pregabalin in in quality control

laboratories.

Conclusion

The method proposed is simple, rapid, inexpensive and sensitive for the

determination of pregabalin in bulk as well as in marketed form (capsules). There

is no requirement of any sophisticated apparatus as in chromatographic methods.

Omission of an extraction step with organic solvents is an added advantage. The

method has been validated in terms of its sensitivity, simplicity, reproducibility,

precision, accuracy and stability of the coloured species for ≥ 6 h suggesting its

suitablility for the routine analysis of PGB in pure form (in bulk analysis) as well

as pharmaceutical formulations without interference from excipients.

Experimental

Apparatus

All absorption spectra were recorded using a Perkin Elmer lambda 15 UV-

Visible spectrophotometer (German) with a scanning speed of 60 nm/min and a

band width of 2.0 nm, equipped with 10 mm matched quartz cells. A CyberScan

pH 510 (Eutech instruments) pH meter was used for checking the pH of buffer

solutions.

Materials and reagents

All chemicals and materials were of analytical grade and were purchased

from Qualigens fine chemicals, Mumbai, India. All solutions were freshly

prepared in double distilled water.

Pure samples

Pregabalin (PGB) pure grade was graciously provided as a gift samples by

Vardhman Chemtech limited, Derabassi, Punjab, India.

Market samples

Pregabalin75 capsules (label amount 75 mg PGB/Capsule) Torrent

Pharmaceuticals were purchased from the market.

Preparation of phosphate buffer pH 7.4

Phosphate buffer pH 7.4 was prepared by mixing 250 mL of 0.2 M

potassium dihydrogen phosphate with 195.5 ml of 0.2 M NaOH and making up

the volume to 1000 ml with distilled water. The pH of the buffer was adjusted to

7.4 using a precalibrated pH meter.

Standard Stock solutions

Stock solution of pregabalin (2 mg/ml) was prepared by dissolving 200 mg of

pregabalin in 100 mL of phosphate buffer (pH 7.4).

Preparation of ninhydrin solution

The 0.2% solution of ninhydrin was prepared by dissolving 200 mg of ninhydrin

in 100 ml of ethanol and was kept in an amber colored bottle.

Method Standard plot

Different aliquots were taken from the stock solution (2 mg/ml) and diluted

with phosphate buffer pH 7.4 to prepare a series of concentrations ranging from

50 to 1000 μg/mL of pregabalin. To 5.0 mL of these aliquots taken in stoppered

tubes, 1.0 mL of ninhydrin solution (0.2% w/v) was added and heated on a water

bath at a temperature of 70-75°C for 20 minutes. The tubes were kept covered to

avoid the loss of solvent due to evaporation. After cooling the solution to room

temperature, the absorbance values were measured in triplicate at 402.6 nm

against mixture of 5.0 mL phosphate buffer (pH 7.4) and 1.0 mL 0.2% ninhydrin

as reagent blank. The calibration graph was obtained by plotting the absorbance

values at the λmax of the drug (402.6 nm) against corresponding concentration

values and compliance with Beer Lambert's law was assessed.

Analysis of pharmaceutical formulation

Preparation of capsule sample solution

The contents of twenty capsules were mixed and weighed accurately.

Separate quantities of the powder equivalent to 30 mg, 60 mg and 90 mg of PRG

were transferred into a 100 mL volumetric flasks, dissolved in water, and

sonicated for 5 min., the volume was then completed with water, shaken well for

5 min. and filtered into a dry flask. To 5.0 mL aliquots of the filtrate taken in

stoppered tubes, 1.0 mL of ninhydrin solution (2.0% w/v) was added and solution

heated on a water bath at a temperature of 70-75°C for 20 minutes. Solutions were

cooled to room temperature and the absorbance values noted in triplicate at 402.6

nm against reagent blank.

Treatment: Use an emollient (moisturiser) on your skin but do tell your doctor if the skin cracks open as infection can get in.

Novel Ion Selective Electrode for Determination ofPregabalin in Pharmaceutical Dosage Form and Plasma

Abstract-Ion selective electrode technique was developed for determination of pregabalin. The key to construct such an electrode is to produce a sensitive and selective membrane that responds to a particular ionic species. Such membrane is usually prepared by in corporating an appropriate ion exchanger and solvent mediator into a poly (vinyl chloride) or (PVC) membrane matrix. The present work originates from the fact that pregabalin behaves as a cation in 0.1 N HCl solution and forms a precipitate with anionic potassium tetrakis p-chlorophenyl borate which used in fabrication of the membrane sensor. The potentiometric response

was linear with constant slope over a drug concentration range of10-6–10-3 M with slope of 53±1 mV/decade .The developed method was applied successfullyfor the determination of pregabalin in the pure powder form, pharmaceutical formulation and in spiked human plasma without any interference.

Keywords- Pregabalin, Ion Selective Electrode, PVC, Potassium Tetrakis P-ChlorophenylBorate, Pharmaceutical Formulation, Spiked Plasma

INTRODUCTION

Pregabalin is a new anti-epileptic drug which is a structurally related to the

inhibitory neurotransmitter GABA. It has the following scheme

Anal. Bioanal. Electrochem., Vol. 4, No. 5, 2012, 507 – 517

COOHNH2

Scheme 1. Structural formula of (S)-3-(aminomethyl)-5-methylhexanoic acid

Pregabalin reduces the calcium dependent neurotransmitters, possibly by

modulation of calcium channel function [1,2].

Pregablin was analyzed by HPLC [3-6] and by colorimetry [7,8]. This work

suggests simple and accurate method of analysis of pregabalin using ion

selective electrode. Application of the suggested method to the routine analysis of

pregabalin in pharmaceutical formulations as well as spiked plasma is also important.

2. EXPERIMENTAL

2. 1. Apparatus

1) Potentiometric measurements were carried out using Jenway, U.K (model

3505) pH/mV meter. A single junction Ag/AgCl reference electrode was used

in conjugation with the drug sensor.

2) Bandelin sonorex, RK 510 S, magnetic stirrer.

3) Silver wire (3 mm diameter) immersed in the internal reference solution.

2. 2. Materials and reagents

1) Standard pure pregabalin: was kindly supplied by Pfizer Company, Cairo,

Egypt. The purity was found to be 99.93±1.45 according to the reference

method [7].

2) Lyrica ® capsule: manufactured by Pfizer Company, Cairo, Egypt (batch number

0458037 and 0366128). Each capsule is claimed to contain 150 mg pregabalin.

3) Potassium tetrakis p-chlorophenyl borate (Sigma, Germany): was

prepared as saturated alcoholic solution.

4) Tetrahyrdofuran (THF) 99% (Sigma, Germany).

5) Nitrophenyloctyl ether (NPOE) (Sigma, Germany).

6) Poly (vinyl chloride) (PVC) powder (Sigma, Germany).

7) Britton–Robinson (BR) buffer: prepared by mixing the acid mixture

containing phosphoric acid (0.04 M), acetic acid (0.04 M) and boric acid

(0.04 M). Buffer solutions of different pH values were adjusted by the

necessary amount of 0.2 M NaOH [9].

8) NaCl solution (10-2 M) for the internal reference solution.

Table 1. Elemental analysis of pregabalin–potassium tetrakis p-chlorophenyl borate complex

ParametersAnalysis

%

Carbon Hydrogen Nitrogen

Calculated % 62.43 5.52 2.27

Found% 61.76 5.83 2.68

The electrochemical cell of the suggested membrane for the determination of pregabalin

can be illustrated as follow:

Ag/AgCl reference electrode

Test solution

Association complex incorporated in PVC mb

Internal reference solution

Ag/AgCl internal reference wire

The reaction is represented as follow [22]:

ClCl

COOH

+ Cl

+ Cl B+

Cl KCOOH+

NH3Pregabalin HCl

NH3

Cl B Cl

Cl

Potassium tetrakis

(p-chlorophenyl) borate

ClIon association complex

Electrochemical performance characteristics of the proposed sensor were

evaluated according to the IUPAC recommendation data [24] in

Table 2. It was found that the calibration slope did not change by

more than 2 mV per decade over a period of 3 weeks. The response time

of the electrode was tested for concentrations of the drug from 10-7–10-

2 M.

The measurement was characterized by a fast stable response within 30 –35 s.

Table 2. Electrochemical response characteristics of the proposed electrode used for the determination of pregabalin

Parameter Suggested sensor

Slope (mV/decade) 53±1

Intercept (mV) 356

Response time (seconds) 30–35

Working pH range 6-9

Concentration range (M) 10-6–10-3

Stability (weeks) 3

Average recovery (%) 99.63

SD 0.96

Correlation coefficient 0.9997

The effect of pH on the electrode potential was investigated and

it was found that electrode gave useful pH from 6-9 as shown in Fig. 1.

The potentiometric response at the optimum pH was linear with

constant slope over a drug concentration range of 10-6–10-3 M as shown in Fig. 2.

The performance of the electrode in presence of commonly used

pharmaceutical additives used in drug formulations (e.g.: sodium

chloride, potassium chloride, lactose ……) was assessed.

E (

m V

)

E (

m v

)

160140120

100

8060

10^-4

10^-5

4020

00 2 4 6 8 10

12

pH

Fig. 1. Effect of pH on the response of proposed electrode

250

200

150

100

50

07 6 5 4 3 2 1

-log conc. (M)

Fig. 2. Profile of the potential in mV to -log concentration of pregabalin using the

proposed ion selective electrode method

Selectivity coefficient values (K pot A,B ) was calculated by the separate

solutions method where the potentials were measured for 10-3 M of the drug and

then for 10-3 M of the interferent solution, separately. The selectivity coefficients were calculated as shown in

Table 3 using the following equation [22]:

Where K pot A,B is the selectivity coefficient , EA and EB are the

potentials of the drug and the interferent solutions respectively, S is the

slope of the calibration plot , aA is the activity of the drug , ZA and ZB

are the charges on the drug and the interfering ions respectively

Table 3. Potentiometric selectivity coefficients for the proposed electrode used for the determination of pregabalin

Interferent Selectivity

NaCl 1.22×10-4

KCl 6.35×10-4

CaCl2 1.27×10-4

Mg stearate 7.86×10-3

NH4Cl 4.85×10-2

glucose 6.65×10-3

lactose 1.2×10-3

The accuracy of the proposed membrane sensor for the determination

of blind samples of pregabalin was assessed. The results showed mean

percent recovery of 99.63±0.96 as shown in the validation parameters in

Table 4.

Table 4. Validation parameters for the proposed electrochemical

method for the determination of pregabalin

Parameter Suggested

Range 10-6–10-3 M

Detection limit 2.23×10-7 MSlope 53±1 mV

Intercept 356 mV

Mean 99.63

SD 0.93

Variance 0.86

RSD 0.933 %

Correlation coefficient 0.9997

The proposed method was successfully applied for the determination

of pregabalin in capsules without any interference from the additives as

shown in Table 5.

Table 5. Determination of pregablin in its pharmaceutical dosage form

Pharmaceutical aformulation Taken Mean ±

SD

Lyrica®

capsuleBN

100.65±0.83

Reference

methodba Average of 3 determinations

b Reference method [7], colorimetric determination of pregabalin using NBD reagent

Table 6. Determination of pregablin in spiked human plasma

by the proposed electrochemical method

Concentration (M) Recovery % ± SDa

10-5 98.86±0.61

10-4 98.32±0.72

a Average of 3 determinations

On application to biological fluids, it has been found that the electrode

gave stable results without any interference from the plasma electrolytes

as revealed by the high accuracy and precision of the recovery results of

the spiked plasma samples as shown in Table 6. The sensitivity of the

method is more than satisfactory since Cmax of pregabalin (7.15 mg/L)

[25] after oral administration of one capsule (150 mg) was covered by

the linearity range of the proposed method.

Statistical analysis of the results of analysis of pregabalin by the

proposed electrode and the reference method showed no significant

difference as shown in Table 7.

Table 7. Statistical comparison between the results of the proposed electrochemical method for the determination of pregabalin and the reference method

Values Proposed method Reference

methodaMean 99.63 99.93

SD 0.93 1.45

RSD 0.933 % 1.451 %

Variance 0.86 2.10

n 5 6

Student’s t-test (2.22)b 0.72

F-value (5.05)b 2.44

4. CONCLUSION

The use of the developed sensor offers the advantages of fast

response, elimination of drug pretreatment or separation steps, selective,

low detection limit and direct determination of the drug in turbid and

colored solutions. The technique therefore can be used for routine

analysis of pregabalin in quality control laboratories

New Medicines Profile

January 2005 Issue No. 05/02

Pregabalin for Neuropathic PainConcise evaluated information to support the managed entry of new medicines in the NHS

Summary• Pregabalin is a new oral adjunctive therapy for the treatment of

neuropathic pain in adults. It has a similar pharmacological profile to gabapentin.

• Twelve trials using pregabalin to treat neuropathic pain have beencompleted, currently only three have been fully published (all of 8 weeks duration). The trials have only compared pregabalin with placebo. In the published trials pregabalin has often been addedto existing treatment in patients who have not achieved pain control.

• Compared to placebo, pregabalin reduced mean pain scoressignificantly and reduced sleep interference.

• Pregabalin has not been compared to established treatments for neuropathic pain, such as amitriptyline (unlicensed indication) and carbamazepine (licensed for trigeminal neuralgia). There is no published evidence that it is effective in patients who have not responded to gabapentin.

• The most common side effects of pregabalin seen in all trials were somnolence (~23%) and dizziness (~30%) (which may increase the potential for accidental falls in the elderly). Additionally, peripheral oedema and weight gain were notable findings.

• Pregabalin can be taken in either two or three divided doses. Both are efficacious in controlling pain, though it is more cost effective to use the twice daily dosing. It is priced to compare to the middle of gabapentin’s therapeutic dose range. However, it costs significantly more than older established therapies such as amitriptyline and carbamazepine.

Brand Name, (Manufacturer): Lyrica® (Pfizer)

BNF Therapeutic Class: 4.7.3 Neuropathic and functional pain

Licensed Indications: Pregabalin (Lyrica®) is indicated for the treatment of peripheral neuropathic pain in adults.

Dosage and Administration: Pregabalin treatment can be started at a dose of 150 mg per day. Based on individual patient response and tolerability, the dosage may be increased to 300 mg per day after an interval of 3 to 7 days, and if needed, to a maximum dose of 600 mg per day after an additional 7-day interval.

Marketed: July 2004 (secondary care), September 2004 (primary care).Cost Comparisons: Cost for 28 days treatment [MIMS October 2004- NB: pregabalin costs are the same regardless of capsule strength; 25mg,

Introduction

Pregabalin was launched in July 2004 as a treatment for peripheral neuropathic pain in adults. It is also licensed as an adjunctive therapy in adults with epilepsy who have partial seizures with or without secondary generalisation. 1

Pregabalin acts as an alpha2-delta (α2-δ) ligand that has analgesic, anxiolytic and anticonvulsant activity. 2 Pregabalin has a similar pharmacological profile to gabapentin, but with increased potency (6 fold).3

Evidence

Three of the 12 trials investigating the use of pregabalin for postherpetic neuropathy (PHN) and diabetic peripheral neuropathy (DPN), the two most common types of neuropathic pain, have been fully published and arereviewed below. An exclusion criteria for all three trials was failure to respond togabapentin therapy of ≥1200mg/day.The primary efficacy measure was the mean pain score over the last seven days’ diary entries. These trials used a30% or more decrease in pain scores to equate to much improved, which is considered clinically important. A 50%decrease equates to ratings of very much improved.

• Post-herpetic neuralgia

Two trials compared pregabalin to placebo in the treatment of PHN.2,3 With the exceptions of benzodiazepines and anticonvulsants both trials allowed patients to continue with concurrent pain medication and used an intentionto treat analysis.

The first trial, an 8 week, double-blind study, randomised 173 patients with PHN (mean age 71 years, mean duration of PHN 34 months) to

250mg, 75mg, 100mg, 200mg and 300mg strengths available] pregabalin or placebo. Pregabalin was

Amitriptiline 50mg ON

Carbamazepine 400mg CR BD

Gabapentin 400mg TDS (Neurontin®)

Gabapentin 600mg TDS (Neurontin®)

Pregabalin any dose BD

£1

£10

£53

£64

£89

titrated to 200mg three times a dayover two weeks, or dosed according to renal function.

Compared to placebo, pregabalin produced superior pain relief from day two and this difference was significant throughout the 8-week period. Pregabalin was also associated with significant improvements in daily pain scores and sleep disturbances compared

£0 £20 £40 £60 £80 £100

N.B. Doses shown for general comparison and do not imply therapeutic equivalence

to placebo, but not with improvements in the domains of mood and quality oflife.

Placebo(n=84)

Pregabalin600mg(n=89)

Primary efficacy measures

End point mean pain score

5.29 ± 0.243.6 ± 0.24 p=0.0001

Pain reduction of≥30%

25%63% (p=0.001)NNT = 2.7

Pain reduction of≥50%

20%50% (p<0.05)NNT = 3.4

(Pregabalin (Lyrica®) – Neuropathic Pain)

Table 12

In the second 8-week double-blind trial,238 patients with PHN were randomised to pregabalin 150mg/day (50mg tds) or300mg/day (100mg tds), or to placebo.3

The mean age was approximately 71 years and the mean duration of PHN was 42 months.

Table 23

Primary efficacy measures

Placebo(n=81)

Pregabalin150mg(n=81)

Pregabalin300mg(n=76)

Mean endpoint pain score

6.33 ±0.22

5.14 ± 0.22 p=0.0002

4.76 ± 0.23 p=0.0001

Pain reduction of ≥30%

19% 37% NNT = 6

50% NNT = 3

Pain reduction of ≥50%

10%26%p=0.006NNT = 6

28%p=0.003NNT = 6

Clinically meaningful pain relief was evident after the first week of treatment with both doses. Some improvementsin quality of life were seen despite the trial’s short duration. Treatment effect was the same regardless of whether any concomitant medications were taken or whether any adverse effects wereexperienced.

• Diabetic Peripheral Neuropathy

A randomised, double-blind, multicentre, parallel-group study comparing pregabalin 100mg tds (fixed dose, no titration) with placebo enrolled146 patients with type 1 or type 2 diabetes. 4 All subjects had symmetrical painful symptoms in distal extremitiesfor at least one to five years attributable to DPN. Patients were not allowed touse other medications that could be used to treat the painful symptoms of DPN with the exception of paracetamoland SSRIs. Compared to placebo, a significant reduction in mean pain score was seen with pregabalin after week

one, and continued until the end of the study.

Table 34

Placebo(n=70)

Pregabalin300mg/day(n=76)

Primary efficacy measures

End point mean pain score

5.46 ±0.28

3.99 ± 0.26 (p=0.0001)

Pain reductionof ≥50%

14.5%40% (p=0.001) NNT = 4

Improvements in mean sleep score were seen in the pregabalin group after one week of treatment, and were maintained throughout the study. Patients also reported less tension and anxiety, and improvements in total mood disturbance scores.

Unpublished studies have been carried out over 12 weeks, although longer- term efficacy is more difficult toassess as only open-label studies are available.

Safety

During the 12 trials that have investigated pregabalin use in neuropathic pain, 65% of patients taking placebo and 79.6% taking pregabalin experienced adverse events. The most frequently reported side effects were dizziness (29.1% pregabalin vs. 8.7% placebo) and somnolence (22.6% pregabalin vs.7.8% placebo). These particular side effects may increase the occurrence of accidental injury or falls in the elderly population. Side effects that occurred more frequently inpregabalin treated patients included dry mouth, asthenia, amblyopia, nausea.

The incidence of peripheral oedema was greater in pregabalin-treated patients but is not considered to be due to secondary alterations in cardiovascular function.5

Place in Therapy

Tricyclic antidepressants, particularly amitriptyline (unlicensed indication) and carbamazepine (licensed for trigeminal neuralgia) are widely used for neuropathic pain. Pregabalin has not been directly compared with these therapies in clinical trials. In addition, there are no comparative trials of pregabalin and gabapentin, to which pregabalin is

pharmacologically related. Indeed, in the trials described above, patients who had not responded totherapeutic doses of gabapentin were excluded with two consequences; firstly this strategy is likely to favour pregabalin, and secondly, the trials fail to provide evidence as to whether gabapentin non-responders willrespond to pregabalin.

Pregabalin is more expensive than established first-line agents for the treatment of neuropathic pain. Its comparative cost in relation to branded gabapentin depends on whether it is used two or three times daily; however the cost of gabapentin is likely to fall following recent marketing of a generic product.

On the basis of current evidence, pregabalin cannot be recommended in place of established treatments forthe treatment of neuropathic pain. Itmay be useful as add-on therapy in patients who are not receiving adequate pain relief from their current first-line treatment.

References:

1. Summary of Product Characteristics. Lyrica capsules. Pfizer Limited 2004 w w w . em c . m e d icines . or g . uk Accessed: 20-7-2004

2. Dworkin RH, Corbin AE, Young JP et al. Pregabalin for the treatment of postherpetic neuralgia. Neurology2003; 60:1274-1283.

3. Sabatowski R, Galvez R, Cherry DA et al. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post- herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain 2004; 109:26-35.

4. Rosenstock J, Tuchman M, LaMoreaux L et al. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double- blind, placebo controlled trial. Pain2004; 110:628-638.

5. Scientific Discussion: Lyrica EMEA2004 Accessed: 9-8-2004

Risk ManagementIssues:Pregabalin is also licensed for the treatment of epilepsy. The dose titration for this indication is different to that for neuropathic pain treatment (it is slower). Prescribers should be made aware of this.

References

1. ̂  "Peripheral Neuropathy Fact Sheet: National Institute of Neurological Disorders and

Stroke (NINDS)". Retrieved 2008-11-30.

2. ̂  "What is neuropathy: What causes neuropathy?". MedicalBug. 8 January 2012.

Retrieved 2 March 2012.

3. ̂  Aggarwat, Sandeep K. (31 December 1999). "Neuropathy Signs & Symptoms".

HealthCommunities. Retrieved 2 March 2012.

4. ̂  "Dorlands Medical Dictionary:mononeuropathy".

5. ̂  "What is neuropathy and how will it affect my body?". What is neuropathy. Retrieved 10

March 2012.

6. ̂  "neuritis" at Dorland's Medical Dictionary

7. ̂  http://emedicine.medscape.com/article/819426-overview

8. ̂  Gabriel JM, Erne B, Pareyson D, Sghirlanzoni A, Taroni F, Steck AJ (1997). "Gene

dosage effects in hereditary peripheral neuropathy. Expression of peripheral myelin protein 22 in

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