Gabapentinoids

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GabapentinLink to NZF: 2629 and pregabalinLink to NZF: 2631 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 [1] [2]
  • High quality evidence supports the use of pregabalin to improve pain in those with fibromyalgia compared to placebo [3]
  • The evidence for gabapentin in fibromyalgia is unclear because of the small number of trials and very low quality of evidence available [4]
  • NNTs
    • Moderate to severe post-herpetic neuralgia: Pregabalin 4, Gabapentin 7
    • Moderate to severe diabetic peripheral neuropathy: Pregabalin 8, Gabapentin 6
    • Fibromyalgia: Gabapentin 10

Gabapentinoids vs placebo pain infographic Mathieson.png

Low back and radicular pain

  • Systematic review and meta-analysis of 7 RCTs compared gabapentin and pregabalin to placebo. Judged moderate-high quality data [5]
  • 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[6]

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

Gabapentinoids vs placebo adverse effects infographic Mathieson.png

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[7]

Summary

References

  1. Derry et al.. Pregabalin for neuropathic pain in adults. The Cochrane database of systematic reviews 2019. 1:CD007076. PMID: 30673120. DOI. Full Text.
  2. Wiffen et al.. Gabapentin for chronic neuropathic pain in adults. The Cochrane database of systematic reviews 2017. 6:CD007938. PMID: 28597471. DOI. Full Text.
  3. Derry et al.. Pregabalin for pain in fibromyalgia in adults. The Cochrane database of systematic reviews 2016. 9:CD011790. PMID: 27684492. DOI. Full Text.
  4. Cooper et al.. Gabapentin for fibromyalgia pain in adults. The Cochrane database of systematic reviews 2017. 1:CD012188. PMID: 28045473. DOI. Full Text.
  5. Enke et al.. Anticonvulsants in the treatment of low back pain and lumbar radicular pain: a systematic review and meta-analysis. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 2018. 190:E786-E793. PMID: 29970367. DOI. Full Text.
  6. Derry S et al. Pregabalin for neuropathic pain in adults. Cochrane Database Syst Rev 2019;1:CD007076. Wiffen PJ et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2017;6:CD007938
  7. Hägg, S et al. Current Evidence on Abuse and Misuse of Gabapentinoids. Drug Safety 2020.43, 1235–1254