Gabapentinoids

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 polyneuropathyDerry 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
==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 itHägg, S et al. Current Evidence on Abuse and Misuse of Gabapentinoids. Drug Safety 2020.43, 1235–1254
==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
==References==
Category:Pharmacology