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.

Mechanism

Gabapentin and pregabalin exert their primary effect by binding with high affinity to the α2δ-1 and α2δ-2 auxiliary subunits of voltage-gated calcium channels (VGCCs). This interaction inhibits calcium influx, particularly at presynaptic terminals, thereby reducing the release of excitatory neurotransmitters such as glutamate, substance P, and norepinephrine. This action is thought to dampen neuronal hyperexcitability. Gabapentinoids do not act directly on GABA receptors despite their structural similarity to GABA. Emerging evidence suggests additional potential mechanisms, including interference with α2δ subunit trafficking and interaction with NMDA receptors, potentially contributing to their effects in neuropathic pain. Pregabalin generally exhibits higher binding affinity for the α2δ subunit than gabapentin. These agents are established first-line treatments for various neuropathic pain conditions.

The mechanism of reducing excitatory neurotransmitter release directly addresses a key component of CS maintenance driven by excessive afferent input. Experimental studies in humans have shown that gabapentin can reduce temporal summation evoked by electrical stimulation of the skin. In a clinical trial involving patients with painful chronic pancreatitis, pregabalin efficacy was significantly predicted by a lower pretreatment electrical pain detection threshold (ePDT) ratio (pancreatic area vs. control area), suggesting that patients with greater localized hypersensitivity (interpreted as a sign of central sensitization of spinal neurons related to visceral input) were more likely to respond. Another study found an association between gabapentin use and elevated Pain-60 thresholds (temperature required to elicit a pain rating of 60/100), potentially indicating improved pain sensitivity. These findings link gabapentinoid action to modulation of specific CS-related phenomena.

The established efficacy of gabapentinoids in conditions like post herpetic neuralgia and diabetic neuropathy supports their role in modulating CS driven by peripheral nerve pathology. Their primary mechanism (reducing presynaptic neurotransmitter release via α2δ modulation) may be most effective when central sensitisation is substantially maintained by ongoing abnormal peripheral afferent input. When CS is driven more by dysfunctional descending modulation or autonomous central changes, gabapentinoids alone may be less effective.

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

Numerous randomized controlled trials (RCTs) and meta-analyses support the efficacy of gabapentinoids for postherpetic neuralgia (PHN) and painful diabetic neuropathy (PDN). Meta-analyses report Numbers Needed to Treat (NNTs) for substantial pain relief (e.g., ≥50% reduction) typically in the range of 6 to 8, indicating that while effective, only a minority of patients achieve this level of benefit with monotherapy. Pregabalin may offer slightly greater efficacy than gabapentin in some comparisons but often comes with a higher incidence of adverse effects. Evidence for efficacy in fibromyalgia is present but perhaps less consistent or robust compared to neuropathic pain.

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

The adverse effects are dose dependent. The most common adverse effects are related to the central nervous system and include dizziness, somnolence, fatigue, ataxia, and cognitive difficulties (e.g., concentration problems). Peripheral edema and weight gain can also occur. While generally considered distinct from addiction, euphoria has been reported (more with pregabalin), contributing to concerns about misuse potential. There is also a recognized risk of respiratory depression, particularly when combined with opioids or in patients with underlying respiratory compromise. Dose adjustments are necessary in renal impairment. Numbers needed to harm for moderate to severe neuropathic pain are 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