Gabapentinoids

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Gabapentin and pregabalin are together referred to as gabapentinoids. They were originally designed as antiepileptics however they have been used in a very wide range of conditions including pain conditions despite limited evidence for use.

Gabapentin

• First discovered in 1970s in an attempt to create a GABA analogue
• Whilst it resembles GABA, it does not act on the GABA receptor.
• Later discovered to act on α2δ subunits of voltage-dependent calcium channels to reduce calcium influx
  • Precise mechanism of analgesia unclear
• Inhibits release of excitatory neurotransmitters: glutamate, NA, substance P
• Medsafe licenced for: neuropathic pain, adjunct anti-epileptic
• Pharmacokinetics
  • Absorption: Saturable transporter so delayed peak levels at higher doses. Drugs that reduce motility (e.g opiates) increase bioavailability. Peak serum conc 3 hours
  • Distribution: Less lipophilic so requires active transport across the BBB
  • Metabolism: minimal
  • Elimination: Renal excretion, half life 5-7 hours. Dose adjustment in renal impairment

Pregabalin

• Similar to gabapentin. Binds to α2δ subunits of voltage-dependent calcium channels to reduce calcium influx
  • Inhibits release of excitatory neurotransmitters: glutamate, NA, substance P
• Medsafe licenced for: neuropathic pain, adjunct anti-epileptic
• Pharmacokinetics
  • Absorption: Rapid absorption after oral administration. Peak serum conc 1h
  • Distribution: Less lipophilic so requires active transport across the BBB
  • Metabolism: minimal, no active metabolites
  • Elimination: Renal excretion, half life 6.3 hours. Dose adjustment in renal impairment

Recommended prescribing: NZF

Gabapentin

• Day 1 300mg nocte
• Day 2 300mg bd
• Day 3 300mg tds
• Then increase by 300mg every 2-3 days to max dose 3600mg daily

Pregabalin

• Initially 75mg bd
• 150mg bd after 3-7 days
• Max dose 300mg bd after further 7 days

Titrate upwards until pain relief, side effects, or max dose reached

Remember to dose adjust for renal impairment: gabapentin if <80mL/min, pregabalin if <60mL/min

Caution in pregnancy (category B1); no clear data available,  use if benefits outweigh risks

Evidence

Post-herpetic neuralgia, diabetic peripheral neuropathy and fibromyalgia

• Moderate quality evidence supports the use of gabapentinoids to improve pain in those with post-herpetic neuralgia or diabetic peripheral neuropathy compared with placebo
• High quality evidence supports the use of pregabalin to improve pain in those with fibromyalgia compared to placebo
• The evidence for gabapentin in fibromyalgia is unclear because of the small number of trials and very low quality of evidence available
• NNTs
  • Moderate to severe post-herpetic neuralgia: Pregabalin 4, Gabapentin 7
  • Moderate to severe diabetic peripheral neuropathy: Pregabalin 8, Gabapentin 6
  • Fibromyalgia: Pregabalin 10

Low back and radicular pain

• Systematic review and meta-analysis of 7 RCTs compared gabapentin and pregabalin to placebo. Judged moderate-high quality data
• Low back pain with or without lumbar radicular pain
  • No difference in pain or disability at short, intermediate or long term follow up
• Lumbar radicular pain only
  • No difference in pain or disability at short, intermediate or long term follow up

Other conditions

• Central neuropathic pain: Pregabalin 10 (95% CI 6-28), dose >1200mg daily
• Mixed: Pregabalin 7 (95% CI 5.4-11), dose 600mg daily
• Low quality studies showing no evidence of benefit in HIV neuropathy, neuropathic cancer pain, or polyneuropathy

Adverse Effects

• Pregabalin and gabapentin similar profiles
• Dose-dependent
• No serious adverse effects c.f placebo
• Some common effects:
  • Dizziness
  • Somnolence
  • Blurred vision
  • Fatigue
  • Weight gain and peripheral oedema
  • Dry mouth
  • Ataxia
• NNHs
  • Moderate to severe neuropathic pain: Pregabalin 8, Gabapentin 7

Misuse and Abuse

• Supratherapeutic doses cause relaxation and euphoria.
  • Taken in combination with other drugs e.g opiates, potentiates effect
  • May assist with opioid withdrawal symptoms
• Those with a history of substance abuse (in particular opioids) at increased risk abuse
• UK survey: Lifetime prevalence of misuse 1.1% for gabapentin, 0.5% pregabalin
• Increasing death rate as per Finland, Sweden, Germany, UK post-mortem toxicology registers (almost all cases due to multisubstance)
• Misused gabapentinoids obtained from healthcare providers in 63% cases (UK and US study)
• In 2019, UK re-classified as scheduled class C drug (1 month prescriptions and no repeats)
• Think twice when prescribing and check indication if patient presents already on it

Summary

• First line treatment for some patients with post-herpetic neuralgia and diabetic peripheral neuropathy
• Moderate to high quality evidence that not effective for low back pain or radicular pain
• Limited evidence for other conditions