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Gabapentinoids: Difference between revisions

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m (I think gabapentin might have been a typo and the intention was to write gabapentin. That seems to be the conclusion of Deery et al in the paper below.)
 
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<u>Gabapentin</u>
{{partial}}
'''Gabapentin'''{{NZF|code=2629}} and '''pregabalin'''{{NZF|code=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
* First discovered in 1970s in an attempt to create a GABA analogue
* Whilst it resembles GABA, it does not act on the GABA receptor.
* 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
* Later discovered to act on α2δ subunits of voltage-dependent calcium channels to reduce calcium influx
** Precise mechanism of analgesia unclear
** Precise mechanism of analgesia unclear
* Inhibits release of excitatory neurotransmitters: glutamate, NA, substance P
* Inhibits release of excitatory neurotransmitters: glutamate, NA, substance P
* Medsafe licenced for: neuropathic pain, adjunct anti-epileptic
* Medsafe licenced for: neuropathic pain, adjunct anti-epileptic
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** Elimination: Renal excretion, half life 5-7 hours. Dose adjustment in renal impairment
** Elimination: Renal excretion, half life 5-7 hours. Dose adjustment in renal impairment


 
==Pregabalin==
<u>Pregabalin</u>
 
* Similar to gabapentin. Binds to α2δ subunits of voltage-dependent calcium channels to reduce calcium influx
* 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
** Inhibits release of excitatory neurotransmitters: glutamate, NA, substance P
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** Elimination: Renal excretion, half life 6.3 hours. Dose adjustment in renal impairment
** Elimination: Renal excretion, half life 6.3 hours. Dose adjustment in renal impairment


 
==Recommended prescribing: NZF==
<u>Recommended prescribing: NZF</u>
'''Gabapentin'''
 
Gabapentin


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


Pregabalin
'''Pregabalin'''


* Initially 75mg bd
* Initially 75mg bd
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Caution in pregnancy (category B1); no clear data available,  use if benefits outweigh risks
Caution in pregnancy (category B1); no clear data available,  use if benefits outweigh risks


==Evidence==
'''Post-herpetic neuralgia, diabetic peripheral neuropathy and fibromyalgia'''


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 <ref>{{#pmid:30673120}}</ref> <ref>{{#pmid:28597471}}</ref>
* Moderate quality evidence supports the use of gabapentinoids to improve pain in those with post-herpetic neuralgia or diabetic peripheral neuropathy compared with placebo <ref>{{#pmid:30673120}}</ref> <ref>{{#pmid:28597471}}</ref>
* High quality evidence supports the use of pregabalin to improve pain in those with fibromyalgia compared to placebo <ref>{{#pmid:27684492}}</ref>
* High quality evidence supports the use of pregabalin to improve pain in those with fibromyalgia compared to placebo <ref>{{#pmid:27684492}}</ref>
* The evidence for gabapentin in fibromyalgia is unclear because of the small number of trials and very low quality of evidence available <ref>{{#pmid:28045473}}</ref>
* The evidence for gabapentin in fibromyalgia is unclear because of the small number of trials and very low quality of evidence available <ref>{{#pmid:28045473}}</ref>
* NNTs
** Moderate to severe post-herpetic neuralgia: Pregabalin 4, Gabapentin 7
** Moderate to severe diabetic peripheral neuropathy: Pregabalin 8, Gabapentin 6
** Fibromyalgia: Pregabalin 10
[[File:Gabapentinoids vs placebo pain infographic Mathieson.png|600px]]
'''Low back and radicular pain'''
* Systematic review and meta-analysis of 7 RCTs compared gabapentin and pregabalin to placebo. Judged moderate-high quality data <ref>{{#pmid:29970367}}</ref>
* 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<ref>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</ref>
==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
[[File:Gabapentinoids vs placebo adverse effects infographic Mathieson.png|600px]]
==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<ref>Hägg, S et al. Current Evidence on Abuse and Misuse of Gabapentinoids. Drug Safety 2020.43, 1235–1254</ref>
==Summary==
*First line treatment for some patients with post-herpetic neuralgia and diabetic [[Peripheral Neuropathy and Polyneuropathy|peripheral neuropathy]]
*Moderate to high quality evidence that not effective for [[Chronic Low Back Pain|low back pain]] or [[Lumbar Radicular Pain and Radiculopathy|radicular pain]]
*Limited evidence for other conditions
==References==
[[Category:Pharmacology]]

Latest revision as of 11:41, 30 June 2023

This article is still missing information.

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: Pregabalin 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
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