Continuing Education Activity

Pregabalin is approved by the United States Food and Drug Administration (FDA) to treat neuropathic pain associated with diabetic peripheral neuropathy, spinal cord injury, and postherpetic neuralgia. Pregabalin is FDA-approved for the treatment of fibromyalgia. Pregabalin also has FDA approval as adjunctive therapy for partial-onset seizures in adults with epilepsy. Off-label uses include generalized anxiety disorder, social anxiety disorder, bipolar disorder, insomnia, and chronic pain conditions not otherwise approved by the FDA. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for interprofessional team members.

Objectives:

• Identify the mechanism of action of pregabalin.
• Describe the adverse effects of pregabalin.
• Outline the important dosage considerations of pregabalin.
• Review the importance of improving care coordination amongst interprofessional team members to improve outcomes for patients prescribed pregabalin.

Indications

Pregabalin got approval from the United States Food and Drug Administration (FDA) in 2004. It is used to treat pain and seizures.

FDA-approved Indications[1][2][3][4]

• Treatment of neuropathic pain associated with diabetic peripheral neuropathy
• Treatment of neuropathic pain associated with spinal cord injury
• Neuropathic pain originating from postherpetic neuralgia
• Treatment of fibromyalgia 
• Adjunctive therapy for partial-onset seizures in adults with epilepsy

Off-label Uses[5][6][7]

• Generalized anxiety disorder
• Social anxiety disorder
• Bipolar disorder
• Insomnia
• Chronic pain conditions
• Chronic Pruritus
• Chronic cough
• Restless leg syndrome

There is significant disagreement regarding the effectiveness of pregabalin for the psychiatric disorders listed above. Therefore, prescribers should be careful and monitor patients for therapeutic success when treating patients with pregabalin.

Mechanism of Action

Pregabalin is structurally similar to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). It has been modified to be a lipophilic analog to enhance diffusion across the blood-brain barrier. However, pregabalin does not directly bind to GABA-A or GABA-B receptors. Additionally, it is not metabolized to a GABA receptor agonist. In animal models, pregabalin binds to presynaptic voltage-gated calcium channels at the alpha-2-delta subunit in central nervous system tissues. The binding of the alpha-2-delta subunit decreases the depolarization-induced influx of calcium into neurons and reduces the release of excitatory neurotransmitters. This action may account for the anticonvulsant and analgesic effects of pregabalin. Pregabalin has no known activity at sodium channels, dopamine receptors, serotonin receptors, opiate receptors and does not modify cyclooxygenase activity.[8]

Administration

Pregabalin is administered orally and is available in capsules or oral solutions. Following oral administration, pregabalin reaches peak plasma concentrations within 1.5 hours and achieves a steady-state within 24 to 48 hours. The absorption of pregabalin is independent of the dose. Pregabalin readily crosses the blood-brain barrier. Humans cannot significantly metabolize pregabalin. Its elimination is primarily as an unchanged drug (less than 2% metabolized) by renal excretion. In patients with normal renal function, the mean elimination half-life is 6.3 hours. Researchers have studied pregabalin at dosages up to 600 mg per day. However, they did not find 600 mg per day to provide significant additional benefit and was less well tolerated due to side effects.

When discontinuing pregabalin, the recommendation is to taper the drug gradually over one week. In patients with seizure disorders, withdraw pregabalin gradually to minimize the risk of increased seizure.

• Management of Neuropathic Pain Associated with Diabetic Peripheral Neuropathy: The recommended maximum therapeutic dose is 300 mg/day. The suggested starting dose is 50 mg three times per day. The dose can increase up to 300 mg/day within one week of starting treatment.[1]
• Management of Neuropathic Pain Associated with Spinal Cord Injury: The recommended therapeutic dose is 150 mg to 600 mg per day. The recommended starting dose is 75 mg twice per day. The dose may be increased to 150 mg twice per day within one week of initiating treatment. Patients with suboptimal pain relief following 2 to 3 weeks of treatment with 150 mg twice a day may be increased up to 300 mg twice per day. In spinal cord injury, pain improvement can be seen as early as one week after initiating treatment. However, to evaluate the efficacy of pregabalin, it is recommended to try the medication for 4 to 6 weeks if tolerated by the patient.[9]
• Management of Postherpetic Neuralgia: The recommended therapeutic dose is 150 mg to 300 mg per day, divided into dosing twice or three times per day. The recommended starting dose is 75 mg two times per day or 50 mg three times per day. The dose can increase up to 300 mg per day within one week of starting treatment. After 2 to 4 weeks of treatment with 300 mg per day, patients with suboptimal pain relief can be increased to 600 mg per day, divided into twice per day or three times per dosing.  
• Management of Fibromyalgia: The recommended therapeutic dose is 300 mg to 450 mg per day. The recommended starting dose is 150 mg/day divided into twice per day dosing. The dose can increase to 300 mg per day within one week of starting treatment. Patients with suboptimal pain relief on 300 mg per day may further increase to 450 mg per day, divided into twice per day dosing.
• Adjunctive Therapy for Adults with Partial Onset Seizures: Pregabalin is FDA-approved only as an adjunctive for treating partial-onset seizures. The effective dose is 150 mg to 600 mg per day, divided twice or three times per dosing. The suggested starting dose is no greater than 150 mg per day. The total dose can increase to a maximum of 600 mg per day. 
• Cough and Chronic Refractory: Pregabalin is off-label used in cough and chronic refractory conditions. The initial starting dose is 75 mg per day, which may increase by 75 mg per day during the first week of treatment. The maximum dose can be up to 300 mg per day, divided into three times per dosing.[10]
• Generalized Anxiety Disorder: Pregabalin is also off-label used in generalized anxiety disorder. The initial starting dose is 75 mg per day, which may increase by 75 mg per day during the first week of treatment. The maximum dose can be up to 300 mg per day, divided into three times per dosing.[11]
• Chronic Pruritus: Pregabalin is also off-label used as a preferred treatment in patients with pruritus resistance. The initial starting dose is 75 mg twice daily, which may increase by 150 mg to 300 mg in two to three divided doses daily. This dose may go up to 600 mg daily in oncology patient populations.[12]
• Restless Legs Syndrome: Another off-label use of pregabalin is in restless legs syndrome. The initial starting dose is 50 mg to 75 mg daily before bedtime, which may increase by 75 mg to 150 mg every week. The usual therapeutic dose is up to 150 mg to 450 mg daily based on the effectiveness and tolerability of therapy.[13]
• Social Anxiety Disorder: Pregabalin is off-label used as mono or adjuvant therapy in social anxiety disorder, cough, and chronic refractory conditions. The initial starting dose is 100 mg three times a day, which may increase by 150 mg per day over one week. This dose may go up to 600 mg daily based on response and tolerability.[14]

Specific Population

• Renal Impairment: Pregabalin is eliminated primarily by renal excretion. Adjust the dose in patients with impaired renal function. According to prescription drug manufacturers following are recommendations on dose reductions for patients with reduced creatinine clearance and those undergoing hemodialysis.
  • CrCl greater than or equal to 60 mL/min- no dose modification recommended
  • CrCl  30 - 60 mL/min - 50% dose of recommended daily dose 
  • CrCl  15- 30 mL/min - 25% dose of recommended daily dose
  • CrCl  less than or equal to 15 mL/min - 16% to 8% dose of recommended daily dose
  • Supplementary dosage of approximately an additional 25 mg of recommended daily dose following hemodialysis is recommended
• Hepatic Impairment: Although not explicitly studied, because pregabalin is not protein-bound, it is unlikely that patients with hepatic impairment require dosing modifications.
• Pregnancy: To monitor pregnancy outcomes in women exposed to pregabalin during pregnancy and provide information on the effects of in utero exposure to pregabalin, clinicians should help enroll pregnant patients in the North American Antiepileptic Drug (NAAED) Pregnancy Registry.
• Breastfeeding Women: Because the potential risk outweighs the benefits, breastfeeding or pregabalin should be stopped, especially while nursing newborns or infants.[15]

Adverse Effects

• Most reported adverse effects caused by pregabalin were mild to moderate intensity, dose-dependent, and occurred within the first two weeks of initiating treatment.
• The most common adverse events were those affecting the central nervous system (CNS). Somnolence and dizziness occurred most frequently and were the most common adverse reactions that led to the discontinuation of pregabalin.[2]
• The most common adverse reactions reported across all patient populations in premarketing controlled trials, which occurred in greater than or equal to 5% of patients taking pregabalin and twice the rate reported by patients receiving placebo, were: somnolence, dizziness, blurred vision, difficulty with concentration/attention, dry mouth, edema, and weight gain.[16][17]
• Weight gain associated with pregabalin is dose-dependent and occurred in up to 14% of patients receiving 600 mg per day.
• Following rapid or abrupt discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache, anxiety, nervousness, irritability, hyperhidrosis, and diarrhea.[2]
• Chronic use of pregabalin can result in physical dependence, and there is a risk of abuse associated with its use, especially in patients on opioid medicines or who have a history of substance abuse.[18]

Contraindications

• Pregabalin is contraindicated in patients who have a known hypersensitivity to pregabalin. Hypersensitivity reactions have occurred in patients receiving pregabalin, including angioedema.[19]
• There are no adequate studies with pregabalin in pregnant women. Pregabalin may cause fetal harm. Advise patients there is a potential risk to the fetus.[20]
• Pregabalin has been detected in the milk of lactating women; thus, breastfeeding is not advisable, and an alternative agent is preferred.[15]

Monitoring

• Antiepileptic drugs such as pregabalin may increase the risk of suicidal thoughts or behavior. [21] Monitor patients under treatment with pregabalin for symptoms of new or worsening depression, suicidal ideation or behavior, and other changes in behavior or mood.
• Monitor patient weight gain, edema, respiratory rate, other adverse events, which could result in adherence issues of treatment with pregabalin.
• Monitor therapeutic success by periodic evaluation of disease and potential adverse effects that patient reports.

Toxicity

There is limited information regarding overdose with pregabalin. The highest known accidental overdose of pregabalin during clinical development was 8000 mg; this event was without significant clinical consequences. There is no specific antidote for overdose with pregabalin.

The most commonly reported adverse events with overdose were reduced consciousness, confusional state, agitation, depression/anxiety,  and restlessness in the postmarketing studies. In addition, heart block, seizures, and death have also been reported in some patients taking combination with other CNS depressants.[22]

Treatment

• If required, elimination of unabsorbed drugs can be performed by gastric lavage or emesis.  General supportive care should be provided to the patient. Maintain airway and monitor vital signs and clinical status of the patient. Contact a Certified Poison Control Center for up-to-date information on the management of overdose with pregabalin.
• Pregabalin can be removed by standard hemodialysis procedures, resulting in approximately 50% clearance of pregabalin in 4 hours.

Enhancing Healthcare Team Outcomes

Pregabalin is a widely used medication for the management of seizures and pain disorders. While the drug is relatively safe, the primary care provider, pharmacist, nurse practitioner, and internist must regularly monitor the patient. The drug is known to cause depression and suicidal thoughts, so a mental assessment is advisable at each visit. Patients should be educated about the other side effects and told not to drive when taking the drug or combine it with other anti-seizure medications or alcohol. Pharmacists should perform medication reconciliation and watch for potential drug interactions. Nurses should verify the dose before administering and report any concerns to clinicians. The patient should have a neurologist, psychiatrist, or specialist consult before changing the treatment plan.[3] [Level 2] Collaborative approach of all interprofessional health care team members can result in higher treatment success and improve patient outcomes with pregabalin therapy.