Pregabalin

What is pregabalin?

Pregabalin (Lyrica®) is a gabapentinoid drug that has anticonvulsant and analgesic properties. It is used off-label in dermatology to treat chronic pruritus and cutaneous dysaesthesia.


What is pregabalin used for?

Pregabalin is approved for the treatment of neuropathic pain, including that secondary to spinal cord injury, diabetic neuropathy, and post-herpetic neuralgia. It is also approved as an adjunctive treatment for partial onset seizures. 

In dermatology, pregabalin is increasingly being used off-label to manage certain skin conditions, including:

• Chronic kidney disease-associated pruritus (CKD-aP)
• Paraneoplastic pruritus
• Neuropathic pruritus (eg, brachioradial pruritus, notalgia paraesthetica, post-burn pruritus)
• Chronic idiopathic pruritus
• Nodular prurigo
• Cutaneous dysaesthesia, including red scrotum syndrome.

There are many other non-dermatological off-label uses for pregabalin, including but not limited to:

• Complex regional pain syndrome
• Chronic refractory cough
• Generalised anxiety disorder
• Insomnia
• Restless legs syndrome
• Social anxiety disorder.

What are the contraindications and precautions for pregabalin?

Contraindications

• Patients with demonstrated hypersensitivity (eg, angioedema) to pregabalin or any excipients
• Patients with rare hereditary disorders of lactose/galactose intolerance or glucose/galactose malabsorption

Warnings/precautions

• Risk of angioedema — use with caution in patients with a history of angioedema episodes or taking other medications known to cause angioedema (eg, ACE-inhibitors)
• Risk for misuse and dependence — caution should be exercised when prescribing to patients with a history of substance misuse 
• Suicidal ideation or behaviour — small risk associated with all anticonvulsants; patients should be monitored for changes in mood and behaviour
• Mental or physical impairment — patients should not drive, operate machinery, or undertake other hazardous activities until the effects are known
• Respiratory depression — use with caution when patient is taking concomitant central nervous system depressants eg, opioids
• Withdrawal symptoms may occur on cessation of pregabalin, even from low doses, and should be tapered gradually (over at least 1 week) as tolerated

Use in renal and hepatic impairment

Pregabalin is eliminated primarily by renal excretion. Dose adjustment is required in patients with renal impairment. Dose adjustments are not required for hepatic impairment.

Use in elderly and paediatric populations

Pregabalin should be used with caution in elderly and frail patients. It has been associated with dizziness and drowsiness, which may increase the risk of falls. However, no dose adjustment is strictly necessary unless renal function is impaired.

The safety and efficacy of pregabalin in patients younger than 18 years have not been established.

Use in pregnancy and lactation

• Pregabalin use in the first trimester of pregnancy may cause birth defects in the unborn child. Patients of childbearing potential must use effective contraception during treatment.
• Pregabalin is excreted in human breast milk and is not recommended for use during breastfeeding.

What is the mechanism of action and dosage of pregabalin

Mechanism of Action

Pregabalin is derived from gamma-aminobutyric acid (GABA), but does not act on GABA receptors. Instead, pregabalin binds presynaptically to the alpha2-delta (α₂δ) subunits of voltage-gated calcium channels in the central nervous system, reducing calcium influx into neurons and decreasing the release of excitatory neurotransmitters (eg, glutamate, substance P, noradrenaline). 

Gabapentin, another gabapentinoid, shares a similar mechanism of action.

Pregabalin exhibits a linear dose-response relationship across its recommended dose range and has ≥90% oral bioavailability. It is excreted renally in urine, with negligible hepatic metabolism.

Formulation and dosage

Pregabalin is available as capsules, extended-release tablets, and an oral solution. It can be taken with or without food.

The usual dosage ranges from 150 mg to 600 mg per day in two or three divided doses. Lower initial doses (eg, 25 mg to 75 mg OD) and/or slower titration should be considered in patients susceptible to CNS adverse effects, such as the elderly or frail.


Off-label suggested doses for dermatological conditions:

• Neuropathic pruritus (eg, brachioradial pruritus, notalgia paraesthetica) or paraneoplastic pruritus: 75 mg BD, increased up to 150–300 mg per day in two or three divided doses
• CKD-associated pruritus: 25 mg OD, titrated up to a maximum dose of 75 mg OD
  • For haemodialysis patients, pregabalin should be administered post-haemodialysis on dialysis days

What are the benefits of pregabalin?

• The dose-response relationship is linear and predictable.
• Dose adjustment is not required for hepatic impairment.
• Multiple randomised controlled trials of post-herpetic neuralgia have shown significant improvements in pain and sleep.
• Small trials report itch reduction in haemodialysis patients who were refractory to typical treatments such as oral antihistamines, moisturisers, and topical steroids.
• Low-certainty evidence also suggests benefit in other pruritic disorders such as post-burn pruritus, nodular prurigo, and chronic idiopathic pruritus.
• A case series of five patients with red scrotum syndrome reported complete remission within 1–3 months, without recurrence at mean follow-up of 9.4 months.

What are the disadvantages of pregabalin?

• Use in dermatological conditions (ie, pruritus and cutaneous dysaesthesia) is off-label.
• Large, high-quality controlled trials of pregabalin in pruritus and cutaneous dysaesthesia are lacking, and long-term efficacy and safety data are limited for these particular conditions.
• Important pharmacodynamic drug interactions must be considered when prescribed with other CNS depressants.
• Signs of dependence, misuse, withdrawal phenomena, and suicidal ideation must be monitored for. 

What are the side effects and risks of pregabalin?

Very common (>10%)

• Somnolence/drowsiness
• Dizziness
• Headache

Common (1–10%)

• Blurred vision
• Dry mouth
• Fatigue
• Gastrointestinal effects, including nausea, vomiting, constipation, and flatulence
• Neurological effects, including ataxia, tremor, memory impairment, confusion, and depersonalisation
• Peripheral oedema 
• Weight gain

Uncommon or rare but serious

• Angioedema
• Stevens–Johnson syndrome / toxic epidermal necrolysis
• Suicidal ideation or tendencies
• Respiratory depression
• Rhabdomyolysis 

Withdrawal symptoms

Reported withdrawal symptoms include headache, nausea, diarrhoea, fatigue, hyperhidrosis, anxiety/agitation, confusion, and insomnia. Rarely, delirium, psychoses, and seizures occur from discontinuation.

Approved datasheets are the official source of information for medicines, including approved uses, doses, and safety information. Check the individual datasheet in your country for information about medicines.
 
We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA), UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).