generation run 2026-04-28
75 min completedmodel pipeline-v5plan not recordedrun/3f31e748…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- taper_protocol_general
- cross_taper_single_case
Reproduce
- inputs
- 41 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
- pipeline-v5
- streams
- none — agent transcripts are persisted from 2026-09 onward
21 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubChem | pregabalin | 1 | 1 | — |
| 2 | PubMed | pregabalin pharmacology mechanism alpha-2-delta calcium channel | 10 | 4 | — |
| 3 | PubMed | pregabalin dependence withdrawal syndrome discontinuation | 10 | 4 | — |
| 4 | ClinicalTrials.gov | pregabalin neuropathic pain anxiety | 10 | 3 | — |
| 5 | OpenAlex | pregabalin misuse dependence abuse gabapentinoid | 8 | 1 | — |
| 6 | PubMed | pregabalin overdose toxicity death case report | 2 | 1 | — |
| 7 | OpenAlex | pregabalin alpha-2-delta calcium channel mechanism | 10 | 3 | — |
| 8 | PubMed | pregabalin pharmacokinetics bioavailability human | 10 | 3 | — |
| 9 | PubMed | pregabalin abuse misuse dependence recreational | 10 | 5 | — |
| 10 | OpenAlex | pregabalin drug related deaths Scotland gabapentinoid forensic | 8 | 4 | — |
| 11 | WebSearch | pregabalin SMILES structure CAS number bioavailability | 10 | 2 | — |
| 12 | PubMed | pregabalin renal elimination creatinine clearance dose adjustment | 1 | 1 | — |
| 13 | OpenAlex | pregabalin history synthesis Andruszkiewicz Silverman Northwestern | 4 | 1 | — |
| 14 | PubMed | pregabalin adverse effects dizziness somnolence weight gain clinical trial | 8 | 3 | — |
| 15 | UK GOV.UK | pregabalin UK Class C controlled substance rescheduling 2019 | 1 | 1 | — |
| 16 | WebSearch | pregabalin FDA approval dates Lyrica 2004 2005 indications | 10 | 1 | — |
| 17 | PubMed | pregabalin generalized anxiety disorder efficacy placebo controlled trial | 8 | 4 | — |
| 18 | PubMed | pregabalin adverse effects safety adverse event profile | 8 | 2 | — |
| 19 | OpenAlex | get_openalex_work W2076516150 (Ben-Menachem 2004) | 1 | 1 | — |
| 20 | PubMed | pregabalin pregnancy congenital malformations teratogenicity | 5 | 1 | — |
| 21 | WebSearch | pregabalin scheduling Australia Canada EU | 10 | 3 | — |
99 claims by section — every cited sentence, checked against its source
safety40 · 30 ok
Physical dependence develops within as few as two months of therapeutic use, with withdrawal including insomnia, anxiety, tremor, and in severe cases seizuressupported
Withdrawal can occur with short-term use (as short as 2 months). Psychopathological symptoms, vegetative symptoms, and neurological complications documented. npr2.12195
Claim in safety — inconclusiveinconclusiveworking →
Shintani-Ishida et al. (2024) reported a fatal case with femoral blood pregabalin concentration of 18.5 µg/mL, in a patient co-prescribed flunitrazepam and zolpidem; pregabalin was assessed as playing a primary but not independent role in the deathsupported
Femoral blood concentration 18.5 µg/mL. Patient co-prescribed flunitrazepam and zolpidem. Pregabalin played primary role in death but not independently. j.legalmed.2024.102522
French addictovigilance data (2010–2019) identified 31 gabapentinoid-related deaths (25 pregabalin-associated), with adverse outcomes including coma, dyspnea, convulsions, and cardiac conduction disorders; virtually all severe or fatal cases involved polydrug use.supported
31 gabapentinoid-related deaths (25 pregabalin, 6 gabapentin). Adverse outcomes: coma, dyspnea, convulsion, conduction disorders. fpsyt.2021.639780
Claim in safety — inconclusiveinconclusiveworking →
Common adverse effects are dose-dependent and predominantly mild to moderate in severity:supported
AEs generally mild-moderate. Dizziness and somnolence appear early but resolve before end of treatment in most patients. 11632660-000000000-00000
Common adverse effects are dose-dependent and predominantly mild to moderate in severity:supported
Most common AEs: dizziness, peripheral edema, weight gain, somnolence. j.pain.2005.02.032
Claim in safety — inconclusiveinconclusiveworking →
Sexual dysfunction — including erectile dysfunction, decreased libido, and ejaculatory disorders — occurs in a dose-related manner, predominantly at doses ≥900 mg/day equivalents.supported
Documents sexual dysfunctions as adverse effects of pregabalin. Majority dose-related (>=900 mg/day for gabapentin equivalents). wnf.0000000000000286
Long-term pregabalin use may affect calcium homeostasis and musculoskeletal tissue, a concern raised by the shared α₂δ biology between neuronal and non-neuronal calcium channelssupported
Reviews mechanism of action of gabapentinoids and potential consequences of long-term treatment on musculoskeletal system; calcium homeostasis effects. s11914-022-00750-x
In animal models (rats, 150–300 mg/kg/day for 90 days), pregabalin decreased testosterone, increased FSH/LH/prolactin, induced testicular genotoxicity via BAX/BCL2 reversal, and increased oxidative stress markerssupported
High-dose pregabalin (150 and 300 mg/kg/day for 90 days in rats): decreased testosterone, increased FSH/LH/prolactin, reversal of BAX/BCL2 ratio, increased p38 MAPK, oxidative stress. s11033-020-05894-6
Patorno et al. (2017) assessed first-trimester pregabalin exposure and major congenital malformation risk in a human cohortsupported
Assessment of whether first-trimester pregabalin exposure is associated with increased risk of major congenital malformations. wnl.0000000000003959
Cognitive impairment: Dose-related sedation, dizziness, and reduced psychomotor performance impair cognitive function and driving ability. These effects are most pronounced during dose titration and at higher doses.supported
Common AEs: dizziness (PHN 24.9%, DPN 23.0%), somnolence (PHN 15.1%, DPN 13.4%). AEs generally mild-moderate. Dizziness and somnolence appear early. 11632660-000000000-00000
Mood destabilization on withdrawal: Abrupt discontinuation produces rebound anxiety and insomnia that can exceed the severity of the original symptom being treated.partially supported
Psychopathological symptoms, vegetative symptoms, and neurological complications documented. npr2.12195
Mood destabilization on withdrawal: Abrupt discontinuation produces rebound anxiety and insomnia that can exceed the severity of the original symptom being treated.partially supported
Discontinuation accompanied by rebound insomnia. 1984-0063.20200129
Claim in safety — inconclusiveinconclusiveworking →
Physical dependence on pregabalin develops within as few as two months of continuous use at therapeutic doses, even in patients without psychiatric disorders or substance use historysupported
Three cases of pregabalin withdrawal without psychiatric comorbidity at regular doses (150–600 mg/d). Withdrawal can occur with short-term use (as short as 2 months). npr2.12195
Withdrawal symptoms include insomnia (rebound), anxiety, agitation, nausea, diaphoresis, headache, tremor, and in severe cases, seizures.supported
Psychopathological symptoms, vegetative symptoms, and neurological complications documented. npr2.12195
Withdrawal symptoms include insomnia (rebound), anxiety, agitation, nausea, diaphoresis, headache, tremor, and in severe cases, seizures.partially supported
Discontinuation accompanied by rebound insomnia. 1984-0063.20200129
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Abrupt discontinuation should be avoided; gradual tapering over at least one week is recommendedsupported
Risk of withdrawal generally low when discontinued gradually over 1 week. s40263-014-0192-0
In severe dependence with rebound insomnia, diazepam cross-tapering has been used successfully in inpatient settings.supported
Cross-tapering with diazepam showed promising results for withdrawal. 1984-0063.20200129
Claim in safety — inconclusiveinconclusiveworking →
In the UK, prescribing trends showed rapid growth preceding the 2019 rescheduling, and Scottish national mortality data linked gabapentinoid prescribing to drug-related deathspartially supported
UK primary care prescribing trends for gabapentinoids; context for UK rescheduling impact. j.lanepe.2022.100579
In the UK, prescribing trends showed rapid growth preceding the 2019 rescheduling, and Scottish national mortality data linked gabapentinoid prescribing to drug-related deathssupported
Studied national and regional gabapentinoid prescribing rates (2006-2016) in Scotland; identified associated co-prescriptions and mortality including drug-related deaths. j.bja.2020.05.017
A decade of European Medicines Agency adverse drug reaction data documents rising gabapentinoid misuse-related fatalities across the continent.supported
Analysis of EMA adverse drug reaction database: rising cases of gabapentinoid misuse and related fatalities despite low addictive liability at therapeutic doses. s40263-016-0359-y
All clinically significant pregabalin interactions are pharmacodynamic — the drug's pharmacokinetic profile (no protein binding, no hepatic metabolism, no CYP induction or inhibition) renders pharmacokinetic interactions negligible.supported
Does not bind plasma proteins, excreted virtually unchanged (<2% metabolism) by kidneys. Not subject to hepatic metabolism, does not induce/inhibit CYP450. pmid:15315511
Gabapentinoids significantly increase opioid-related morbidity and mortality through additive and potentially synergistic CNS and respiratory depressionsupported
Gabapentinoids significantly increase opioid-related morbidity/mortality when used concomitantly. jcph.1833
Gabapentinoids significantly increase opioid-related morbidity and mortality through additive and potentially synergistic CNS and respiratory depressionsupported
Examines risk to heroin users of concomitant gabapentinoid use. Key interaction study. add.13843
Gabapentinoids significantly increase opioid-related morbidity and mortality through additive and potentially synergistic CNS and respiratory depressionsupported
Toxicology increasingly implicates gabapentinoids in DRDs. j.bja.2020.05.017
Animal data suggest pregabalin enhances the potency of mu-opioid receptor agonists through a mechanism involving α₁-subunit voltage-gated calcium channels.supported
Gabapentinoids increase the potency of MOR agonists fentanyl and heroin via blockade of alpha1-VGCC dihydropyridine-binding sites. j.jpet.2025.103523
Recreational users frequently combine pregabalin with opioids to enhance euphoric effects, a practice that dramatically increases overdose risksupported
Gabapentinoids significantly increase opioid-related morbidity/mortality when used concomitantly. jcph.1833
Scottish national data confirm that gabapentinoid-opioid co-prescribing is a significant independent risk factor for drug-related death.supported
Identified associated sociodemographic factors, co-prescriptions and mortality including drug-related deaths. Toxicology increasingly implicates gabapentinoids in DRDs. j.bja.2020.05.017
A fatal case in Japan involved pregabalin co-administered with flunitrazepam and zolpidem, in which the combined respiratory depressant effects proved lethal.supported
Fatal case of pregabalin overdose. Patient co-prescribed flunitrazepam and zolpidem. Pregabalin played primary role in death but not independently. j.legalmed.2024.102522
Severe renal impairment without dose adjustment: Standard doses produce drug accumulation; dose reduction is mandatory for CLcr <60 mL/min.supported
50% dose reduction for CLcr 30-60 mL/min. Further 50% reduction per each additional 50% CLcr decrease. pmid:12638396
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Concurrent benzodiazepine or Z-drug use: Additive CNS depression; particularly dangerous with respiratory depressants.supported
Patient co-prescribed flunitrazepam and zolpidem. Pregabalin played primary role in death but not independently. j.legalmed.2024.102522
pharmacology15 · 13 ok
Pregabalin is a potent, selective ligand for the α₂δ-1 (and α₂δ-2) auxiliary subunit of voltage-gated calcium channels (VGCCs)supported
Pregabalin is a potent ligand for the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system. pmid:15315511
Pregabalin is a potent, selective ligand for the α₂δ-1 (and α₂δ-2) auxiliary subunit of voltage-gated calcium channels (VGCCs)supported
Regulatory subunits of VGCCs. Targets of gabapentin and pregabalin. s00424-020-02420-2
Pregabalin is a potent, selective ligand for the α₂δ-1 (and α₂δ-2) auxiliary subunit of voltage-gated calcium channels (VGCCs)supported
Gabapentin and pregabalin bind alpha2delta and are among top-sold drugs for neuropathic pain. 164_2022_630
The binding affinity at the α₂δ subunit is Ki = 180 nM, comparable to that of gabapentin (Ki = 120 nM in the same binding assay).supported
Pregabalin Ki = 180 nM at alpha2delta subunit. Gabapentin Ki = 120 nM. pmid:16781071
The binding affinity at the α₂δ subunit is Ki = 180 nM, comparable to that of gabapentin (Ki = 120 nM in the same binding assay).supported
Pregabalin Ki = 180 nM at alpha2delta subunit. Gabapentin Ki = 120 nM. pmid:16781071
First, pregabalin binds presynaptic α₂δ-1 subunits and impairs their anterograde trafficking to presynaptic nerve terminalssupported
Pregabalin inhibits anterograde trafficking of alpha2delta-1 to presynaptic terminals, reducing neurotransmitter release and spinal sensitization. jneurosci.0356-09.2009
Claim in pharmacology — inconclusiveinconclusiveworking →
Second, this trafficking disruption reduces the membrane density of functional VGCCs, thereby decreasing depolarization-induced calcium influx and consequent release of excitatory neurotransmitters — including glutamate, noradrenaline, and substance P — at synaptic terminalssupported
Pregabalin inhibits anterograde trafficking of alpha2delta-1 to presynaptic terminals, reducing neurotransmitter release and spinal sensitization. jneurosci.0356-09.2009
Claim in pharmacology — inconclusiveinconclusiveworking →
Beyond canonical calcium channel modulation, the α₂δ-1 subunit interacts with additional protein partners that may contribute to pregabalin's therapeutic profile:supported
Discusses additional mechanisms beyond calcium channel modulation: interaction with NMDA receptors, neurexin-1α, and thrombospondin proteins via alpha2delta-1 binding. jpet.120.266056
Gabapentinoids may also exert indirect effects on the dopaminergic reward systemsupported
Dopaminergic reward system involvement possible. s40263-014-0164-4
Pregabalin exhibits favorable and highly predictable pharmacokinetics: high oral bioavailability, negligible protein binding, minimal hepatic metabolism, and exclusively renal elimination.supported
High bioavailability... Does not bind plasma proteins, excreted virtually unchanged (<2% metabolism) by kidneys. Not subject to hepatic metabolism, does not induce/inhibit CYP450. pmid:15315511
The mean elimination half-life is 6.3 hours, and steady-state plasma concentrations are achieved within 24–48 hours of regular dosingsupported
Mean elimination half life 6.3 h, dose-proportional PK. pmid:15315511
Pregabalin is excreted virtually unchanged in the urine, with total and renal clearance directly proportional to creatinine clearance (CLcr).supported
Total and renal pregabalin clearance proportional to creatinine clearance (CLcr). pmid:12638396
Pregabalin is efficiently cleared by hemodialysis, and supplemental doses may be necessary after each dialysis session.supported
Highly cleared by hemodialysis. pmid:12638396
clinical-evidence10 · 10 ok
Pregabalin has been investigated as a treatment for alcohol and other substance withdrawal syndromessupported
Reviews evidence for pregabalin in treatment of physical dependence and withdrawal symptoms from opioids, benzodiazepines, nicotine, cannabinoids, and alcohol. pmid:27848217
The landmark fixed- and flexible-dose trial by Freynhagen et al. (2005) established efficacy of pregabalin at 150–600 mg/day in a 12-week randomized, double-blind, placebo-controlled design, demonstrating clinically meaningful pain reduction and improved sleep quality at both fixed (600 mg) and flexible (150–600 mg) dosing regimens.supported
Both flexible (150-600 mg/day) and fixed (600 mg/day) pregabalin regimens significantly reduced pain in PHN and DPN versus placebo. j.pain.2005.02.032
Crofford et al. (2005) conducted the landmark randomized, double-blind, placebo-controlled trial establishing pregabalin 450 mg/day as effective for fibromyalgia symptom managementsupported
Pregabalin at 450 mg/day was efficacious for the treatment of FMS, reducing symptoms of pain, disturbed sleep, and fatigue compared with placebo. art.20983
Pande et al. (2004) demonstrated pregabalin efficacy in social anxiety disorder at 600 mg/day in a placebo-controlled, multicenter studysupported
Pregabalin 600 mg/d significantly decreased LSAS scores vs placebo in social anxiety disorder. pmid:15206660
The Cochrane Collaboration systematic review by Derry et al. (2019) provides the highest-quality synthesis of pregabalin efficacy in neuropathic painsupported
Cochrane systematic review of pregabalin for neuropathic pain in adults (update of prior review). 14651858.cd007076.pub3
A meta-epidemiological analysis by Cheng et al. (2023) raises an important methodological caveat: early pregabalin trials for PHN and DPN showed strong treatment effects that have not been replicated in more recent studiessupported
Early pregabalin neuropathic pain trials found strong treatment effects for PHN and DPN; more recent studies have failed to replicate these results. journal.pone.0280593
A rapid review and meta-analysis by Onakpoya et al. (2019) similarly found moderate benefits with a notable adverse effect burden.supported
Rapid review and meta-analysis assessing benefits and harms of pregabalin for neuropathic pain from RCTs. bmjopen-2018-023600
Onset of anxiolytic effect is rapid, typically occurring within the first week of treatment.supported
Rapid onset <=1 week. s40263-014-0192-0
The Lancet network meta-analysis by Slee et al. (2019), comparing pharmacological treatments for GAD, positioned pregabalin among effective first-line options alongside SSRIs, SNRIs, and benzodiazepinessupported
Network meta-analysis comparing pharmacological treatments for GAD. Pregabalin included as one of the established treatments. s0140-6736(18)31793-8
Kong et al. (2020) confirmed pregabalin's favorable tolerability profile relative to other GAD treatments in a systematic review with network meta-analysis of comparative remission rates.supported
Pregabalin comparable to placebo in tolerability. fphar.2020.580858
summary8 · 7 ok
Clinically dosed at 75–600 mg orally, it produces effects lasting 5–8 hours with a plasma half-life of 6.3 hours and distinguishes itself from gabapentin through non-saturable oral absorption (≥90% bioavailability) yielding linear, dose-proportional plasma concentrations.partially supported
High bioavailability, mean elimination half life 6.3 h, dose-proportional PK. pmid:15315511
Developed by Ryszard Andruszkiewicz and Richard Silverman at Northwestern University, pregabalin received FDA approval in December 2004 for neuropathic pain and partial-onset seizures, with subsequent indications for fibromyalgia (2007) and spinal cord injury neuropathic painpartially supported
Documents that Andruszkiewicz collaborated with Silverman at Northwestern University to develop pregabalin (Lyrica) through synthesis of GABA derivatives. biomedicines12092021
European regulatory agencies additionally approved it for generalized anxiety disorder (GAD), where network meta-analyses position it as a first-line agent alongside SSRIs and SNRIssupported
Pregabalin approved in EU for GAD. First-line agent per World Federation of Societies of Biological Psychiatry alongside SSRIs/SNRIs. s40263-014-0192-0
Pregabalin binds the α₂δ-1 auxiliary subunit of voltage-gated calcium channels (Ki = 180 nM), impairing anterograde trafficking of α₂δ-1 to presynaptic terminals and reducing depolarization-evoked release of glutamate, noradrenaline, and substance Ppartially supported
Pregabalin Ki = 180 nM at alpha2delta subunit. pmid:16781071
Pregabalin binds the α₂δ-1 auxiliary subunit of voltage-gated calcium channels (Ki = 180 nM), impairing anterograde trafficking of α₂δ-1 to presynaptic terminals and reducing depolarization-evoked release of glutamate, noradrenaline, and substance Ppartially supported
Pregabalin inhibits anterograde trafficking of alpha2delta-1 to presynaptic terminals, reducing neurotransmitter release and spinal sensitization. jneurosci.0356-09.2009
Claim in summary — inconclusiveinconclusiveworking →
At recreational doses (3–20× therapeutic), users report euphoria, disinhibition, and bodily lightness — effects potentially mediated by indirect dopaminergic reward pathway activationsupported
Misusers self-administer 3-20 times clinical doses. Dopaminergic reward system involvement possible. s40263-014-0164-4
Pregabalin carries low acute toxicity at therapeutic doses but a significant polydrug mortality signal — virtually all fatal cases involve co-administration with opioids, benzodiazepines, or Z-drugspartially supported
31 gabapentinoid-related deaths (25 pregabalin, 6 gabapentin). Adverse outcomes: coma, dyspnea, convulsion, conduction disorders. fpsyt.2021.639780
history6 · 5 ok
Across Europe, a decade of European Medicines Agency adverse drug reaction data documented rising gabapentinoid misuse and associated fatalitiessupported
Analysis of EMA adverse drug reaction database: rising cases of gabapentinoid misuse and related fatalities despite low addictive liability at therapeutic doses. s40263-016-0359-y
Pregabalin emerged from a research program at Northwestern University led by Richard Silverman, in collaboration with Polish chemist Ryszard Andruszkiewiczsupported
Documents that Andruszkiewicz collaborated with Silverman at Northwestern University to develop pregabalin (Lyrica) through synthesis of GABA derivatives. biomedicines12092021
Claim in history — inconclusiveinconclusiveworking →
The European Medicines Agency approved pregabalin for epilepsy, neuropathic pain, and — notably — generalized anxiety disorder (GAD), an indication not granted by the FDAsupported
Pregabalin approved in EU for GAD. s40263-014-0192-0
Scottish national data linked gabapentinoid prescribing — particularly in combination with opioids — to rising drug-related mortality, and UK-wide prescribing trends showed rapid growth in pregabalin dispensing in the years preceding rescheduling.supported
Studied national and regional gabapentinoid prescribing rates (2006-2016) in Scotland; identified associated co-prescriptions and mortality including drug-related deaths. j.bja.2020.05.017
Scottish national data linked gabapentinoid prescribing — particularly in combination with opioids — to rising drug-related mortality, and UK-wide prescribing trends showed rapid growth in pregabalin dispensing in the years preceding rescheduling.partially supported
UK primary care prescribing trends for gabapentinoids; context for UK rescheduling impact. j.lanepe.2022.100579
neuroscience5 · 5 ok
By impairing α₂δ-1 trafficking to presynaptic terminals, pregabalin reduces the release of glutamate, noradrenaline, and substance P from hyperexcitable neurons — a state-dependent effect that preferentially suppresses pathological neurotransmission.supported
Pregabalin inhibits anterograde trafficking of alpha2delta-1 to presynaptic terminals, reducing neurotransmitter release and spinal sensitization. jneurosci.0356-09.2009
Pregabalin reverses this process by reducing the elevated α₂δ-1 membrane expression, restoring a degree of normal inhibitory tone in spinal pain circuits.supported
Pregabalin inhibits anterograde trafficking of alpha2delta-1 to presynaptic terminals, reducing neurotransmitter release and spinal sensitization. jneurosci.0356-09.2009
The rapid onset of anxiolytic effect (within one week) relative to SSRIs suggests a mechanism not dependent on synaptic remodeling but rather on acute reduction of excitatory neurotransmission.supported
Rapid onset <=1 week. s40263-014-0192-0
Gabapentinoids have been proposed to present 'direct/indirect effects on the dopaminergic reward system', but the precise mechanism — whether through disinhibition of VTA dopamine neurons via reduced GABAergic or glutamatergic input, or through an uncharacterized pathway — remains unresolved.supported
Dopaminergic reward system involvement possible. s40263-014-0164-4
The interaction of α₂δ-1 with thrombospondins — extracellular matrix proteins that promote excitatory synapse formation — provides a framework for understanding pregabalin's long-term therapeutic effectssupported
Discusses additional mechanisms beyond calcium channel modulation: interaction with NMDA receptors, neurexin-1α, and thrombospondin proteins via alpha2delta-1 binding. jpet.120.266056
pharmacokinetic-detail5 · 4 ok
Pregabalin absorption, by contrast, is linear and dose-proportional across the entire clinical range, yielding predictable plasma concentrations at all doses.supported
Pregabalin has faster onset, increased bioavailability and potency, nonsaturable absorption vs gabapentin. jcph.1833
Pregabalin absorption, by contrast, is linear and dose-proportional across the entire clinical range, yielding predictable plasma concentrations at all doses.supported
Dose-proportional PK. pmid:15315511
This pharmacokinetic distinction has two consequences: first, pregabalin achieves therapeutic plasma concentrations more reliably; second, the dose-proportional absorption also means that dose escalation in misuse contexts produces proportionally higher plasma levels, contributing to the compound's greater misuse liability relative to gabapentin.supported
Pregabalin has faster onset, increased bioavailability and potency, nonsaturable absorption vs gabapentin. jcph.1833
Pregabalin clearance is directly proportional to creatinine clearance, with total and renal clearance declining by 56% and 58%, respectively, per proportional decrease in CLcr.partially supported
Total and renal pregabalin clearance proportional to creatinine clearance (CLcr). 50% dose reduction for CLcr 30-60 mL/min. pmid:12638396
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
receptor-pharmacology5 · 3 ok
The binding affinity has been characterized as Ki = 180 nM at the α₂δ subunit in radioligand displacement assays.supported
Pregabalin Ki = 180 nM at alpha2delta subunit. pmid:16781071
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
The α₂δ subunit family comprises four isoforms (α₂δ-1 through α₂δ-4), of which α₂δ-1 and α₂δ-2 are the gabapentinoid-sensitive subtypespartially supported
Four isoforms (alpha2delta-1 to -4)... Gabapentin and pregabalin bind alpha2delta. 164_2022_630
In neuropathic pain states, α₂δ-1 expression is upregulated, increasing the membrane density of VGCCs at presynaptic terminals and amplifying excitatory neurotransmitter release.supported
Pregabalin inhibits anterograde trafficking of alpha2delta-1 to presynaptic terminals, reducing neurotransmitter release and spinal sensitization. Key mechanism study in rat SNL neuropathy model. jneurosci.0356-09.2009
comparative-pharmacology4 · 4 ok
Its advantage over benzodiazepines is a potentially lower (though not negligible) dependence liability; its advantage over SSRIs/SNRIs is a more rapid onset of anxiolytic effect (within one week vs. 2–4 weeks)partially supported
Rapid onset <=1 week. Risk of withdrawal generally low when discontinued gradually over 1 week. s40263-014-0192-0
Despite gabapentin's marginally higher binding affinity at the α₂δ subunit (Ki = 120 nM vs. 180 nM), pregabalin achieves greater clinical potency due to its non-saturable absorption, delivering dose-proportional plasma concentrations that gabapentin cannot match at higher dosessupported
Pregabalin has faster onset, increased bioavailability and potency, nonsaturable absorption vs gabapentin. jcph.1833
Pregabalin does not activate these channels; at concentrations ≥10 µM, it is in fact inhibitorysupported
Pregabalin does NOT activate KCNQ2/3 and at >=10 uM is inhibitory. mol.118.112953
In network meta-analyses of GAD pharmacotherapies, pregabalin demonstrates comparable efficacy to SSRIs, SNRIs, and benzodiazepinessupported
Network meta-analysis comparing pharmacological treatments for GAD. Pregabalin included as one of the established treatments. s0140-6736(18)31793-8
chemistry1 · 0 ok
Claim in chemistry — inconclusiveinconclusiveworking →