Gabapentinoids Pharmacology (Gabapentin and Pregabalin)

Quick Answer

Gabapentinoids (gabapentin and pregabalin) are anticonvulsant medications that bind to the α2δ subunit of voltage-gated calcium channels (VGCCs), reducing presynaptic calcium influx and neurotransmitter release (glutamate, substance P, noradrenaline). Despite structural similarity to GABA, they do not bind GABA receptors or affect GABA metabolism. Gabapentin has saturable L-amino acid transporter-dependent absorption (bioavailability 60% at 300 mg, declining to 33% at 1600 mg), requiring TID dosing and slow titration. Pregabalin has linear pharmacokinetics with >90% bioavailability regardless of dose, allowing faster titration and BID dosing. Both are eliminated unchanged by the kidneys (t½ 5-7 hours), requiring dose adjustment in renal impairment. Approved indications include neuropathic pain and epilepsy (both), plus generalised anxiety disorder (pregabalin only in Australia). Perioperative use for anxiolysis and opioid-sparing remains controversial following the POGO trial (2019) showing no analgesic benefit, and the FDA Boxed Warning (2019) regarding respiratory depression with concurrent opioids. [1-8]

ANZCA Primary Exam Relevance: High-yield topic. Understand the α2δ-VGCC mechanism, pharmacokinetic differences between gabapentin and pregabalin (saturable vs linear absorption), renal dose adjustment, and the evidence debate regarding perioperative use.

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1. Physicochemical Properties

Chemical Structure

Gabapentinoids are structural analogues of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) but do not interact with GABA receptors.

Structure-Activity Relationships

Both gabapentin and pregabalin are cyclic or branched amino acid derivatives with a lipophilic cyclohexane ring (gabapentin) or isobutyl side chain (pregabalin) attached to the GABA backbone. These structural modifications:

1. Prevent GABA receptor binding - the cyclohexane/isobutyl groups create steric hindrance preventing binding to GABA-A or GABA-B receptors
2. Enable α2δ subunit binding - the lipophilic moiety fits into the binding pocket on the α2δ-1 subunit
3. Allow recognition by L-amino acid transporters - structural similarity to L-leucine enables active transport

Pregabalin is the S-enantiomer of 3-isobutyl GABA with approximately 6-fold higher binding affinity for the α2δ subunit compared to gabapentin (Kd 32 nM vs 190 nM). [1,9,10]

Clinical Pearl: Despite being designed as GABA analogues, gabapentinoids have no direct GABAergic activity. Their mechanism is entirely through α2δ subunit binding on voltage-gated calcium channels.

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2. Mechanism of Action

α2δ Subunit of Voltage-Gated Calcium Channels

Gabapentinoids exert their therapeutic effects through high-affinity binding to the α2δ-1 and α2δ-2 subunits of voltage-gated calcium channels (VGCCs). These auxiliary subunits modulate the trafficking, membrane expression, and gating properties of the channel-forming α1 subunit.

Voltage-Gated Calcium Channel Structure:

The α2δ subunit is a single glycoprotein cleaved post-translationally into α2 (extracellular) and δ (membrane-anchored) components linked by disulfide bonds. Four α2δ isoforms exist (α2δ-1 to α2δ-4), with gabapentinoids binding selectively to α2δ-1 (abundant in dorsal root ganglia, spinal cord, brain) and α2δ-2 (cerebellum, brainstem). [2,11,12]

Signal Transduction Mechanism

Intracellular Effects of Gabapentinoid Binding:

1. Reduced calcium channel trafficking to membrane

   • α2δ binding promotes endoplasmic reticulum retention of VGCCs
   • Decreased cell surface expression of functional channels
   • This effect develops over hours to days (explaining delayed therapeutic onset)

2. Reduced presynaptic calcium influx

   • Binding alters VGCC gating properties
   • Decreased Ca²⁺ entry during action potential
   • Reduced vesicle fusion and neurotransmitter release

3. Decreased excitatory neurotransmitter release

   • Reduced release of glutamate, substance P, calcitonin gene-related peptide (CGRP), noradrenaline
   • Diminished spinal cord dorsal horn sensitization
   • Reduced pain signal transmission

4. Modulation of synaptic plasticity

   • Interference with synaptogenesis pathways involving thrombospondin
   • May contribute to anxiolytic effects

Exam Focus: The α2δ subunit binding does NOT directly block the calcium channel pore. Instead, it reduces channel trafficking to the membrane and modulates channel function, explaining the delayed onset of therapeutic effect (days to weeks) compared to direct channel blockers.

Analgesic Mechanisms

Spinal Cord Level:

• Reduced glutamate and substance P release from primary afferent terminals
• Decreased excitability of dorsal horn neurons
• Attenuation of central sensitization and wind-up phenomenon
• Reduced pain hypersensitivity (allodynia, hyperalgesia)

Supraspinal Level:

• Modulation of descending inhibitory pathways
• Effects on periaqueductal grey, rostral ventromedial medulla
• Anxiolysis (limbic system α2δ binding)

Peripheral Level:

• Reduced α2δ expression in injured dorsal root ganglia
• Decreased ectopic discharge from damaged neurons

The upregulation of α2δ-1 subunit in dorsal root ganglia following nerve injury is a key finding explaining why gabapentinoids are effective in neuropathic but not acute nociceptive pain. This upregulation increases the number of targets for gabapentinoid binding. [13-16]

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3. Pharmacokinetics

Gabapentin Pharmacokinetics

Absorption

Gabapentin absorption is the most clinically important pharmacokinetic difference from pregabalin.

Saturable Absorption Explained:

Gabapentin is absorbed in the small intestine via the L-amino acid transporter type 1 (LAT1), also known as system L. This transporter has limited capacity, becoming saturated at higher doses:

• At 300 mg: ~60% bioavailability (180 mg absorbed)
• At 600 mg: ~47% bioavailability (280 mg absorbed)
• At 1200 mg: ~35% bioavailability (420 mg absorbed)
• At 1600 mg: ~33% bioavailability (530 mg absorbed)

This saturable absorption means that doubling the dose does not double the plasma concentration, necessitating TID dosing to achieve adequate drug exposure. [3,17,18]

Clinical Pearl: Gabapentin enacarbil is an extended-release prodrug that uses high-capacity monocarboxylate transporters (MCT-1) instead of LAT1, achieving more predictable absorption. However, it is not available in Australia.

Distribution

Metabolism and Elimination

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Pregabalin Pharmacokinetics

Absorption

Linear Pharmacokinetics Explained:

Unlike gabapentin, pregabalin absorption involves both LAT1 transport and significant passive diffusion due to its higher membrane permeability. This results in:

• Consistent >90% bioavailability across the dose range (75-600 mg)
• Predictable plasma concentrations with dose increases
• Faster achievement of steady-state
• Suitability for BID dosing

This predictable pharmacokinetics allows for faster titration and more reliable dosing. [4,19,20]

Distribution

Metabolism and Elimination

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Pharmacokinetic Comparison Table

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4. Dosing and Titration

Gabapentin Dosing

Neuropathic Pain (standard titration):

Perioperative Use (if used - note evidence debate):

• Preoperative anxiolysis: 600-1200 mg, 1-2 hours preoperatively
• Postoperative analgesia: 300-600 mg TID (start preoperatively, continue postoperatively)

Pregabalin Dosing

Neuropathic Pain:

Generalised Anxiety Disorder (TGA-approved indication):

• Starting: 75 mg BD (150 mg/day)
• Titrate: Increase by 150 mg/day weekly
• Effective range: 150-600 mg/day
• Maximum: 600 mg/day

Perioperative Use (if used):

• Preoperative anxiolysis: 75-150 mg, 1-2 hours preoperatively
• Postoperative: 75-150 mg BD

Renal Dose Adjustment

Warning: Both gabapentinoids are renally excreted unchanged. Failure to adjust dose in renal impairment leads to accumulation and toxicity (sedation, myoclonus, encephalopathy).

Gabapentin Renal Dosing:

Pregabalin Renal Dosing:

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5. Clinical Uses

Neuropathic Pain

Gabapentinoids are first-line agents for various neuropathic pain conditions:

Number Needed to Treat (NNT) for 50% Pain Reduction:

• Pregabalin (neuropathic pain): NNT 4-7
• Gabapentin (neuropathic pain): NNT 5-8

Number Needed to Harm (NNH) for Withdrawal Due to Adverse Events:

• Pregabalin: NNH 12-15
• Gabapentin: NNH 15-20

[5,21,22]

Perioperative Use

The perioperative use of gabapentinoids for anxiolysis and opioid-sparing has been controversial since publication of negative trials.

Historical Rationale:

1. Preoperative anxiolysis without respiratory depression
2. Opioid-sparing analgesia (reduced postoperative opioid consumption)
3. Prevention of chronic postsurgical pain development
4. Reduction of postoperative nausea and vomiting

Current Evidence:

The POGO trial (Pregabalin in Postoperative Pain, 2019) was a large multicentre RCT (n=556) that found pregabalin 150 mg BD provided no benefit for opioid consumption, pain scores, or quality of recovery after major surgery, but significantly increased sedation and visual disturbance. [6,7,23]

Exam Focus: The POGO trial and FDA Boxed Warning have significantly reduced routine perioperative gabapentinoid use. If asked about perioperative gabapentinoid use, discuss the evolving evidence and current caution.

Anxiety Disorders

Generalised Anxiety Disorder (GAD):

• Pregabalin is TGA-approved for GAD in Australia
• Efficacy comparable to benzodiazepines and SSRIs
• Faster onset than SSRIs (within 1 week vs 4-6 weeks)
• No hepatic metabolism (advantage in liver disease)
• Alternative for patients intolerant of SSRIs/SNRIs

Epilepsy

Both gabapentinoids are approved as adjunctive therapy for focal (partial) seizures:

• Gabapentin: Adults and children ≥6 years
• Pregabalin: Adults ≥18 years

Not effective for generalised seizures (absence, myoclonic) and may worsen them.

Other Uses

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6. Adverse Effects

Common Adverse Effects (>10%)

Serious Adverse Effects

Respiratory Depression (FDA Boxed Warning 2019):

Warning: The FDA issued a Boxed Warning in December 2019 regarding serious breathing difficulties in patients using gabapentinoids with opioids or other CNS depressants, or in patients with underlying respiratory conditions.

Risk factors for gabapentinoid-associated respiratory depression:

• Concurrent opioid use (primary risk factor)
• Concurrent benzodiazepine or other CNS depressant use
• Elderly patients (>65 years)
• Chronic obstructive pulmonary disease (COPD)
• Obstructive sleep apnoea (OSA)
• History of substance use disorder
• Renal impairment (drug accumulation)

Clinical manifestations:

• Decreased respiratory rate
• Hypoxia, hypercapnia
• Respiratory arrest (rare but reported)

The FDA warning was based on case reports of serious respiratory adverse events, with many cases occurring when gabapentinoids were used concomitantly with opioids. [8,24]

Suicidal Ideation:

• FDA warning (2008) for all anticonvulsants
• Monitor patients for emergence of suicidal thoughts
• Risk appears small (approximately 1 in 500 patients)

Other Serious Effects:

Drug Interactions

Clinical Pearl: Gabapentinoids have minimal pharmacokinetic drug interactions due to lack of CYP450 metabolism and low protein binding. Their main interactions are pharmacodynamic (additive CNS depression).

Withdrawal Syndrome

Abrupt discontinuation after prolonged use (>2 weeks) may cause withdrawal symptoms:

Tapering Recommendation: Reduce dose by no more than 25-50% per week over minimum 1-2 weeks. [25]

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7. Perioperative Evidence

Key Clinical Trials

POGO Trial (Pregabalin in Postoperative Pain) - 2019:

PMID: 30916014 [6]

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ENIGMA-II Gabapentin Substudy - 2014:

PMID: 24824387 [26]

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Meta-analyses Summary:

Earlier meta-analyses (pre-2019) suggested modest opioid-sparing effects, but more rigorous recent analyses incorporating trial sequential analysis suggest the evidence was overstated. The Cochrane review (2016) noted moderate quality evidence for small reductions in opioid consumption but highlighted publication bias concerns. [7,23]

FDA Respiratory Depression Warning (2019)

The FDA reviewed the FAERS database and medical literature, identifying serious cases of respiratory depression, some fatal, associated with gabapentinoid use, particularly in combination with opioids.

Key Findings:

• 49 cases of serious breathing difficulties reported (2012-2017)
• 12 deaths reported
• Most cases involved concurrent opioid use
• Risk factors included COPD, elderly, renal impairment

FDA Requirements:

1. Boxed Warning added to prescribing information
2. New Warnings and Precautions section
3. Required updates to patient Medication Guide
4. Healthcare professional communication issued

Clinical Implications:

• Assess respiratory risk before prescribing gabapentinoids with opioids
• Use lowest effective doses when combination unavoidable
• Monitor for respiratory depression, especially during initiation
• Educate patients about respiratory depression symptoms

[8,24]

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8. Special Populations

Renal Impairment

Both gabapentinoids require dose reduction proportional to creatinine clearance reduction (see dosing section). In dialysis patients, supplemental doses are required post-dialysis as gabapentinoids are readily dialysed.

Hepatic Impairment

No dose adjustment required for either gabapentinoid as there is negligible hepatic metabolism. This is an advantage in patients with liver disease.

Elderly Patients

• Increased sensitivity to CNS effects (sedation, ataxia, confusion)
• Higher risk of falls
• Often have reduced renal function requiring dose adjustment
• Start at lower doses and titrate slowly
• Consider morning dosing to reduce nocturnal sedation/falls

Pregnancy and Lactation

Obesity

Limited pharmacokinetic data in obesity. Given hydrophilic properties and distribution in total body water, dosing based on actual body weight is generally appropriate, but clinical response and adverse effects should guide titration.

Paediatric Patients

Gabapentin:

• Approved for epilepsy in children ≥6 years
• Dose: Start 10 mg/kg/day TID, increase over 3 days to 25-35 mg/kg/day
• Higher clearance in children; may require higher mg/kg doses

Pregabalin:

• Not approved for paediatric use in Australia
• Limited paediatric data

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9. Indigenous Health Considerations

Aboriginal, Torres Strait Islander, and Māori Patient Considerations

When prescribing gabapentinoids to Aboriginal, Torres Strait Islander, or Māori patients, several important factors warrant consideration:

Higher Prevalence of Chronic Pain and Neuropathic Conditions: Indigenous Australians experience chronic pain at higher rates than non-Indigenous Australians, with prevalence estimates suggesting 1.5-2 times higher rates of severe chronic pain. Diabetes-related neuropathy is particularly common given the 2-4 times higher prevalence of type 2 diabetes, often with earlier onset and more complications. This creates greater potential need for neuropathic pain management with gabapentinoids.

Renal Impairment Considerations: Chronic kidney disease is 3-5 times more common in Aboriginal and Torres Strait Islander populations, often underdiagnosed in remote communities. Given that gabapentinoids are exclusively renally eliminated, assessment of renal function is essential before prescribing and during treatment. Dose adjustment may be required more frequently than in non-Indigenous populations. Where laboratory testing is not immediately available in remote settings, conservative initial dosing is advisable.

Access and Adherence Considerations: Remote Indigenous communities may have limited access to regular medication supplies and medical review. The requirement for TID dosing with gabapentin may present adherence challenges; pregabalin with its BID dosing may be preferable where adherence is a concern. Cost considerations may also be relevant, as pregabalin is generally more expensive. Culturally appropriate education about the purpose of the medication, expected timeline to benefit, and importance of not stopping suddenly is essential.

Cultural Safety: Pain expression and reporting may differ culturally, and some Indigenous patients may underreport pain or medication side effects. Family and community involvement in healthcare decisions should be facilitated where appropriate. Aboriginal Health Workers or Indigenous Liaison Officers can provide valuable support in medication education. For Māori patients in New Zealand, whānau-centred care principles should be applied, with consideration of tikanga and cultural preferences in treatment planning.

Potential for Misuse: Gabapentinoids have recognised abuse potential, with gabapentin now classified as a controlled substance in some Australian jurisdictions. Careful prescribing practices and monitoring are important, while avoiding stereotyping or discriminatory assumptions about individual patients.

[27,28]

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10. ANZCA Primary Examination Focus

High-Yield Points for Written Examination

1. Mechanism of action: Binding to α2δ-1 and α2δ-2 subunits of voltage-gated calcium channels → reduced calcium channel trafficking and presynaptic calcium influx → decreased glutamate, substance P, and noradrenaline release

2. NOT a GABA agonist: Despite structural similarity to GABA, does not bind GABA-A or GABA-B receptors

3. Pharmacokinetic differences:

   • Gabapentin: Saturable L-amino acid transporter absorption (bioavailability decreases with dose: 60% at 300 mg → 33% at 1600 mg), TID dosing required
   • Pregabalin: Linear pharmacokinetics (>90% bioavailability constant), BID dosing

4. Renal elimination: Both eliminated unchanged by kidneys (t½ 5-7 hours), dose adjustment mandatory in renal impairment

5. Clinical uses: Neuropathic pain (first-line), epilepsy (adjunctive for focal seizures), GAD (pregabalin only)

6. Perioperative evidence: POGO trial showed no benefit for opioid-sparing, increased sedation

7. FDA Boxed Warning: Respiratory depression risk with concurrent opioids or CNS depressants

8. Adverse effects: Sedation, dizziness, peripheral oedema, weight gain, withdrawal syndrome

Viva Examination Topics

Commonly examined areas include:

• Describe the mechanism of action of gabapentinoids
• Compare the pharmacokinetics of gabapentin and pregabalin
• Discuss the evidence for perioperative gabapentinoid use
• Explain the FDA warning regarding respiratory depression
• Outline dose adjustment in renal impairment
• Discuss the place of gabapentinoids in multimodal analgesia

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11. Assessment Content

SAQ Practice Question (20 marks)

Question: A 58-year-old man with poorly controlled type 2 diabetes (HbA1c 9.2%) presents with a 6-month history of bilateral burning pain, numbness, and tingling in his feet, worse at night. Examination reveals reduced sensation to light touch and pinprick in a stocking distribution, absent ankle reflexes bilaterally, but preserved motor power. His eGFR is 45 mL/min/1.73m². You plan to start gabapentin for diabetic peripheral neuropathy.

(a) Describe the mechanism of action of gabapentin relevant to neuropathic pain. (6 marks)

(b) Explain why gabapentin requires three times daily dosing while pregabalin can be given twice daily. (4 marks)

(c) Outline an appropriate dosing regimen for this patient, taking into account his renal function. (5 marks)

(d) What adverse effects would you counsel him about, and what precautions are relevant to his comorbidities? (5 marks)

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Model Answer

(a) Mechanism of Action (6 marks)

Gabapentin exerts its analgesic effect through binding to the α2δ subunit of voltage-gated calcium channels (VGCCs) (1 mark).

Primary mechanism:

• Gabapentin binds with high affinity to the α2δ-1 subunit (Kd ~190 nM) on presynaptic VGCCs in the spinal cord dorsal horn and brain (1 mark)
• This binding reduces trafficking of calcium channels to the presynaptic membrane, decreasing functional channel density (1 mark)
• Reduced presynaptic calcium influx during depolarisation decreases vesicle fusion and neurotransmitter release (1 mark)
• Specifically reduces release of excitatory neurotransmitters: glutamate, substance P, and calcitonin gene-related peptide (CGRP) (1 mark)

Relevance to neuropathic pain:

• Following nerve injury, α2δ-1 subunit expression is upregulated in dorsal root ganglia neurons
• This increases the number of targets for gabapentin binding, explaining why it is effective in neuropathic but not acute nociceptive pain (1 mark)

Note: Despite being a GABA analogue, gabapentin does NOT bind to GABA receptors or affect GABA metabolism

(b) Dosing Frequency Explanation (4 marks)

Gabapentin (TID):

• Absorption occurs via the L-amino acid transporter (LAT1) in the small intestine (1 mark)
• This transporter has limited capacity and becomes saturated at higher doses (1 mark)
• Bioavailability is dose-dependent: 60% at 300 mg, declining to ~33% at 1600 mg
• Splitting the total daily dose into three doses maximises absorption by avoiding transporter saturation

Pregabalin (BID):

• Absorption involves both LAT1 transport and passive diffusion due to higher membrane permeability (1 mark)
• This results in linear pharmacokinetics with >90% bioavailability regardless of dose (1 mark)
• Predictable absorption allows twice-daily dosing while achieving reliable plasma concentrations

(c) Dosing Regimen for Renal Impairment (5 marks)

Assessment of renal function:

• eGFR 45 mL/min/1.73m² corresponds to CKD Stage 3b (1 mark)
• Gabapentin is eliminated 100% unchanged by kidneys; dose reduction is mandatory (1 mark)

Recommended regimen:

• For CrCl 30-49 mL/min: Total daily dose should be 300-900 mg (1 mark)
• Starting dose: 100 mg TID or 300 mg once daily (more conservative for this patient) (1 mark)
• Titration: Increase by 100 mg TID every 3-7 days as tolerated
• Target range: 300-900 mg/day in divided doses (TID or can simplify to once daily if tolerated)
• Maximum: 900 mg/day for this level of renal function (1 mark)

If pregabalin were used: 75-300 mg/day maximum; start at 25-50 mg BD

(d) Adverse Effects and Precautions (5 marks)

Common adverse effects to counsel:

• Sedation/somnolence (20-25%): May affect driving and concentration; often improves with continued use (1 mark)
• Dizziness (15-25%): Risk of falls, especially initially
• Peripheral oedema (5-10%): Relevant as diabetes increases oedema risk (1 mark)

Specific precautions for this patient:

• Diabetic neuropathy affecting balance: Dizziness and ataxia from gabapentin may increase fall risk; start low and titrate slowly (1 mark)
• Renal impairment (CKD Stage 3b): Drug accumulation risk; monitor for signs of toxicity (myoclonus, excessive sedation); regular renal function monitoring (1 mark)
• If concurrent opioid use: FDA Boxed Warning regarding respiratory depression; assess carefully and use lowest effective doses of both agents (1 mark)

Additional counselling:

• Do not stop suddenly (withdrawal syndrome)
• Avoid alcohol (additive sedation)
• Report any mood changes or suicidal thoughts

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Viva Scenario (25 marks)

Clinical Scenario: A 45-year-old woman is scheduled for posterior spinal fusion surgery (L4-S1). She has a history of chronic lower back pain with radiculopathy and has been taking pregabalin 150 mg BD for 6 months with partial relief. Her BMI is 38 kg/m², she has well-controlled obstructive sleep apnoea on CPAP, and no other comorbidities. The surgeon asks about optimising her perioperative pain management and specifically whether you would continue or increase her pregabalin.

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Examiner Questions and Model Answers:

Q1: What is the mechanism of action of pregabalin? (4 marks)

Pregabalin binds with high affinity (Kd 32 nM) to the α2δ-1 subunit of voltage-gated calcium channels (1 mark).

This binding produces several effects:

• Reduced trafficking of calcium channels to the presynaptic membrane (0.5 marks)
• Decreased presynaptic calcium influx during neuronal depolarisation (0.5 marks)
• Reduced release of excitatory neurotransmitters: glutamate, substance P, noradrenaline, and CGRP (1 mark)

In the spinal cord dorsal horn, this reduces central sensitisation and wind-up phenomenon, providing analgesia for neuropathic pain (0.5 marks).

Importantly, despite being a GABA analogue, pregabalin does NOT bind to GABA receptors or affect GABA metabolism (0.5 marks).

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Q2: How does the pharmacokinetics of pregabalin differ from gabapentin? (4 marks)

(1 mark each for key differences: absorption kinetics, bioavailability pattern, dosing frequency, binding affinity)

Clinical significance: Pregabalin's linear pharmacokinetics allows faster titration and more predictable dosing, making it easier to achieve therapeutic levels.

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Q3: What is the current evidence for perioperative pregabalin use, and does this affect your recommendation? (5 marks)

Historical perspective: Earlier meta-analyses suggested pregabalin provided modest opioid-sparing effects (20-30% reduction) and reduced postoperative pain (1 mark).

POGO Trial (2019) – key evidence:

• Large multicentre RCT (n=556) of pregabalin 150 mg BD for major surgery (1 mark)
• No reduction in opioid consumption (63 mg vs 60 mg morphine equivalents)
• No improvement in pain scores or quality of recovery
• Significantly increased sedation (27% vs 14%) and visual disturbance (1 mark)

FDA Boxed Warning (2019):

• Serious respiratory depression risk with concurrent opioid use
• Particularly relevant in patients with OSA (as in this patient) (1 mark)

My recommendation: Given the lack of evidence for perioperative benefit, increased adverse events, and this patient's OSA (respiratory depression risk), I would:

• Continue her current pregabalin dose (150 mg BD) to avoid withdrawal
• Not increase the dose perioperatively
• Optimise multimodal analgesia with other agents (paracetamol, NSAIDs if appropriate, local anaesthesia) (1 mark)

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Q4: The patient has obstructive sleep apnoea. How does this affect your perioperative planning regarding gabapentinoids? (4 marks)

Increased respiratory depression risk:

• OSA patients have baseline vulnerability to respiratory depression (1 mark)
• Combining pregabalin with postoperative opioids creates significant risk per FDA warning (1 mark)

Risk factors this patient has:

• OSA (underlying respiratory vulnerability)
• Obesity (BMI 38) – associated with reduced FRC, upper airway compromise
• Will require postoperative opioids for spinal fusion

Perioperative precautions:

• Continue CPAP perioperatively; ensure CPAP available in PACU and ward (1 mark)
• Minimise opioid requirements through multimodal analgesia
• Extended PACU monitoring; consider HDU for first postoperative night
• Continuous pulse oximetry postoperatively
• Avoid benzodiazepines as adjuncts (1 mark)

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Q5: She asks about stopping pregabalin after surgery if she achieves good pain relief. What would you advise? (4 marks)

Withdrawal syndrome:

• Abrupt discontinuation after >2 weeks use can cause withdrawal symptoms (1 mark)
• Symptoms include: anxiety, insomnia, nausea, sweating, pain rebound, and rarely seizures
• Onset typically 12-48 hours after cessation

Tapering recommendation:

• Reduce dose by 25-50% per week over minimum 1-2 weeks (1 mark)
• Example: 150 mg BD → 75 mg BD (week 1) → 75 mg once daily (week 2) → stop
• Slower taper if any withdrawal symptoms emerge

Additional advice:

• Decision to cease should be made in conjunction with pain specialist or GP
• Assess whether radicular pain has resolved; may still need pregabalin for chronic neuropathic component (1 mark)
• If stopping pregabalin unmasks neuropathic pain, alternatives include gabapentin, SNRIs (duloxetine), or tricyclics (1 mark)

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Q6: What are the key dose adjustment considerations in renal impairment? (4 marks)

Renal elimination:

• Pregabalin is 98% eliminated unchanged by kidneys (1 mark)
• Half-life normally 5-6.5 hours; prolonged in renal impairment

Dose adjustment table:

(2 marks for showing understanding of dose reduction principles)

Dialysis: Pregabalin is dialysable; supplemental dose 25-75 mg after each haemodialysis session (1 mark)

Clinical implications: Failure to adjust dose leads to accumulation → toxicity (sedation, myoclonus, confusion, respiratory depression)

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12. Key Points Summary

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