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Pregabalin: Difference between revisions
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The pharmacological action of pregabalin is mediated by binding to the α2δ-1 site of voltage-gated calcium channels.<ref>{{cite journal | vauthors=((Field, M. J.)), ((Cox, P. J.)), ((Stott, E.)), ((Melrose, H.)), ((Offord, J.)), ((Su, T.-Z.)), ((Bramwell, S.)), ((Corradini, L.)), ((England, S.)), ((Winks, J.)), ((Kinloch, R. A.)), ((Hendrich, J.)), ((Dolphin, A. C.)), ((Webb, T.)), ((Williams, D.)) | journal=Proceedings of the National Academy of Sciences | title=Identification of the α 2 -δ-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin | volume=103 | issue=46 | pages=17537–17542 | date=14 November 2006 | url=https://pnas.org/doi/full/10.1073/pnas.0409066103 | issn=0027-8424 | doi=10.1073/pnas.0409066103}}</ref><ref name="thromb">{{cite journal | vauthors=((Eroglu, Ç.)), ((Allen, N. J.)), ((Susman, M. W.)), ((O’Rourke, N. A.)), ((Park, C. Y.)), ((Özkan, E.)), ((Chakraborty, C.)), ((Mulinyawe, S. B.)), ((Annis, D. S.)), ((Huberman, A. D.)), ((Green, E. M.)), ((Lawler, J.)), ((Dolmetsch, R.)), ((Garcia, K. C.)), ((Smith, S. J.)), ((Luo, Z. D.)), ((Rosenthal, A.)), ((Mosher, D. F.)), ((Barres, B. A.)) | journal=Cell | title=Gabapentin Receptor α2δ-1 Is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS Synaptogenesis | volume=139 | issue=2 | pages=380–392 | date= October 2009 | url=https://linkinghub.elsevier.com/retrieve/pii/S0092867409011854 | issn=00928674 | doi=10.1016/j.cell.2009.09.025}}</ref> This site has also been referred to as the gabapentin receptor, as it is the target of the related substance [[gabapentin]] (also developed by Pfizer). Advantages to pregabalin over gabapentin include higher bioavailability and potency. | The pharmacological action of pregabalin is mediated by binding to the α2δ-1 site of voltage-gated calcium channels.<ref>{{cite journal | vauthors=((Field, M. J.)), ((Cox, P. J.)), ((Stott, E.)), ((Melrose, H.)), ((Offord, J.)), ((Su, T.-Z.)), ((Bramwell, S.)), ((Corradini, L.)), ((England, S.)), ((Winks, J.)), ((Kinloch, R. A.)), ((Hendrich, J.)), ((Dolphin, A. C.)), ((Webb, T.)), ((Williams, D.)) | journal=Proceedings of the National Academy of Sciences | title=Identification of the α 2 -δ-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin | volume=103 | issue=46 | pages=17537–17542 | date=14 November 2006 | url=https://pnas.org/doi/full/10.1073/pnas.0409066103 | issn=0027-8424 | doi=10.1073/pnas.0409066103}}</ref><ref name="thromb">{{cite journal | vauthors=((Eroglu, Ç.)), ((Allen, N. J.)), ((Susman, M. W.)), ((O’Rourke, N. A.)), ((Park, C. Y.)), ((Özkan, E.)), ((Chakraborty, C.)), ((Mulinyawe, S. B.)), ((Annis, D. S.)), ((Huberman, A. D.)), ((Green, E. M.)), ((Lawler, J.)), ((Dolmetsch, R.)), ((Garcia, K. C.)), ((Smith, S. J.)), ((Luo, Z. D.)), ((Rosenthal, A.)), ((Mosher, D. F.)), ((Barres, B. A.)) | journal=Cell | title=Gabapentin Receptor α2δ-1 Is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS Synaptogenesis | volume=139 | issue=2 | pages=380–392 | date= October 2009 | url=https://linkinghub.elsevier.com/retrieve/pii/S0092867409011854 | issn=00928674 | doi=10.1016/j.cell.2009.09.025}}</ref> This site has also been referred to as the gabapentin receptor, as it is the target of the related substance [[gabapentin]] (also developed by Pfizer). Advantages to pregabalin over gabapentin include higher bioavailability and potency. | ||
Although pregabalin is a chemical derivative of [[GABA]], it displays no activity at any GABA receptors, including GABA<sub>A</sub>, GABA<sub>B</sub> and the [[benzodiazepine]] site. Pregabalin, despite its GABA backbone, does not appear to alter GABA levels in the brain, so its pharmacological activity is presumed to be unrelated to GABA.<ref>{{cite journal | vauthors=((Taylor, C. P.)), ((Angelotti, T.)), ((Fauman, E.)) | journal=Epilepsy Research | title=Pharmacology and mechanism of action of pregabalin: The calcium channel α2–δ (alpha2–delta) subunit as a target for antiepileptic drug discovery | volume=73 | issue=2 | pages=137–150 | date= February 2007 | url=https://linkinghub.elsevier.com/retrieve/pii/S0920121106003895 | issn=09201211 | doi=10.1016/j.eplepsyres.2006.09.008}}</ref> Instead, it is its binding to the α2δ-1 site of voltage-gated calcium channels which appears to be the source of its subjective effects. By binding to this site, pregabalin reduces the release of several excitatory neurotransmitters, including [[glutamate]], [[substance P]], [[acetylcholine]] and [[norepinephrine]]. | Although pregabalin is a chemical derivative of [[GABA]], it displays no activity at any GABA receptors, including GABA<sub>A</sub>, GABA<sub>B</sub> and the [[benzodiazepine]] site. Pregabalin, despite its GABA backbone, does not appear to alter GABA levels in the brain, so its pharmacological activity is presumed to be unrelated to GABA.<ref>{{cite journal | vauthors=((Taylor, C. P.)), ((Angelotti, T.)), ((Fauman, E.)) | journal=Epilepsy Research | title=Pharmacology and mechanism of action of pregabalin: The calcium channel α2–δ (alpha2–delta) subunit as a target for antiepileptic drug discovery | volume=73 | issue=2 | pages=137–150 | date= February 2007 | url=https://linkinghub.elsevier.com/retrieve/pii/S0920121106003895 | issn=09201211 | doi=10.1016/j.eplepsyres.2006.09.008}}</ref> Instead, it is its binding to the α2δ-1 site of voltage-gated calcium channels which appears to be the source of its subjective effects. By binding to this site, pregabalin reduces the release of several excitatory neurotransmitters, including [[glutamate]], [[substance P]], [[acetylcholine]] and [[norepinephrine]]. | ||
Reduction in the release of glutamate and acetylcholine might be the cause of dissociative / deliriant like effects in high doses. | Reduction in the release of glutamate and acetylcholine might be the cause of dissociative / deliriant like effects in high doses. | ||
One study has also shown that pregabalin promotes deep sleep, thus enhancing sleep quality. This may be substantial because reductions in slow-wave sleep have been associated with anxiety and fibromyalgia.<ref>{{cite journal | vauthors=((Hindmarch, I.)), ((Dawson, J.)), ((Stanley, N.)) | journal=Sleep | title=A double-blind study in healthy volunteers to assess the effects on sleep of pregabalin compared with alprazolam and placebo | volume=28 | issue=2 | pages=187–193 | date= February 2005 | issn=0161-8105 | doi=10.1093/sleep/28.2.187}}</ref> | One study has also shown that pregabalin promotes deep sleep, thus enhancing sleep quality. This may be substantial because reductions in slow-wave sleep have been associated with anxiety and fibromyalgia.<ref>{{cite journal | vauthors=((Hindmarch, I.)), ((Dawson, J.)), ((Stanley, N.)) | journal=Sleep | title=A double-blind study in healthy volunteers to assess the effects on sleep of pregabalin compared with alprazolam and placebo | volume=28 | issue=2 | pages=187–193 | date= February 2005 | issn=0161-8105 | doi=10.1093/sleep/28.2.187}}</ref> | ||
Also, an independent action of the gabapentin site on the neurogenesis of excitatory synapses has been discovered. The endogenous neurochemical thrombospondin also binds to this site and is important for the generation of new excitatory synapses. Gabapentin and pregabalin, having a high affinity for this site, block this action and result in lower levels of excitatory synapses in animal models.<ref name="thromb" /> | Also, an independent action of the gabapentin site on the neurogenesis of excitatory synapses has been discovered. The endogenous neurochemical thrombospondin also binds to this site and is important for the generation of new excitatory synapses. Gabapentin and pregabalin, having a high affinity for this site, block this action and result in lower levels of excitatory synapses in animal models.<ref name="thromb" /> | ||
As pregabalin treats conditions and [[neurotransmitter]]s associated with overexcitability of the brain (anxiety, epilepsy, neuropathic pain), its modulation results in the [[sedating]] (or [[anxiety suppression|calming]]) effects of pregabalin on the nervous system.{{citation needed}} | |||
===Pharmacokinetics=== | ===Pharmacokinetics=== | ||
Pregabalin is rapidly absorbed when administered on an empty stomach, with peak plasma concentrations occurring within 1 to 1.5 hours. Pregabalin oral bioavailability is estimated to be greater than or equal to 90%. The rate of pregabalin absorption is decreased when given with food, resulting in delay of approximately 3 hours to reach peak plasma concentrations, with peak levels themselves, decreased by about 25 to 30%.<ref>https://www.drugs.com/ppa/pregabalin.html</ref> Administration with food, however, has no clinically significant effect on the extent of absorption.<ref>http://web.archive.org/web/20160305012454/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000546/WC500046602.pdf</ref> | Pregabalin is rapidly absorbed when administered on an empty stomach, with peak plasma concentrations occurring within 1 to 1.5 hours. Pregabalin oral bioavailability is estimated to be greater than or equal to 90%. The rate of pregabalin absorption is decreased when given with food, resulting in delay of approximately 3 hours to reach peak plasma concentrations, with peak levels themselves, decreased by about 25 to 30%.<ref>https://www.drugs.com/ppa/pregabalin.html</ref> Administration with food, however, has no clinically significant effect on the extent of absorption.<ref>http://web.archive.org/web/20160305012454/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000546/WC500046602.pdf</ref> | ||
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*'''[[Effect::Physical euphoria]]''' - This component, while prominent in the experience, is generally not as strong as the cognitive euphoria that can be induced. The sensation itself can be described as feelings of physical comfort, warmth and bliss. | *'''[[Effect::Physical euphoria]]''' - This component, while prominent in the experience, is generally not as strong as the cognitive euphoria that can be induced. The sensation itself can be described as feelings of physical comfort, warmth and bliss. | ||
*'''[[Effect::Tactile enhancement]]''' | *'''[[Effect::Tactile enhancement]]''' | ||
*'''[[Effect::Dry mouth]]''' | |||
*'''[[Effect::Muscle twitching]]''' - Somewhat paradoxically, since pregabalin is used as an adjunct treatment for epilepsy, pregabalin, especially in higher doses, can produce muscle spasms.{{citation needed}} Anecdotally, seizures have been reported in overdose.{{citation needed}} | *'''[[Effect::Muscle twitching]]''' - Somewhat paradoxically, since pregabalin is used as an adjunct treatment for epilepsy, pregabalin, especially in higher doses, can produce muscle spasms.{{citation needed}} Anecdotally, seizures have been reported in overdose.{{citation needed}} | ||
*'''[[Effect::Respiratory depression]]''' - While pregabalin may cause respiratory depression, this effect is not as strong as those with [[opioids]] and [[benzodiazepines]].<ref>{{cite journal | vauthors=((Eipe, N.)), ((Penning, J.)) | journal=Pain Research & Management : The Journal of the Canadian Pain Society | title=Postoperative respiratory depression associated with pregabalin: A case series and a preoperative decision algorithm | volume=16 | issue=5 | pages=353–356 | date= 2011 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206785/ | issn=1203-6765}}</ref> | *'''[[Effect::Respiratory depression]]''' - While pregabalin may cause respiratory depression, this effect is not as strong as those with [[opioids]] and [[benzodiazepines]].<ref>{{cite journal | vauthors=((Eipe, N.)), ((Penning, J.)) | journal=Pain Research & Management : The Journal of the Canadian Pain Society | title=Postoperative respiratory depression associated with pregabalin: A case series and a preoperative decision algorithm | volume=16 | issue=5 | pages=353–356 | date= 2011 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206785/ | issn=1203-6765}}</ref> | ||
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*'''[[Effect::Frequent urination]]''' | *'''[[Effect::Frequent urination]]''' | ||
*'''[[Effect::Motor control loss]]''' | *'''[[Effect::Motor control loss]]''' | ||
*'''[[Effect::Seizure suppression]]'''<ref> | *'''[[Effect::Seizure suppression]]'''<ref>{{Citation | title=Pregabalin | url=https://www.epilepsy.com/tools-resources/seizure-medication-list/pregabalin}}</ref><ref>{{cite journal | vauthors=((Ryvlin, P.)), ((Perucca, E.)), ((Rheims, S.)) | journal=Neuropsychiatric Disease and Treatment | title=Pregabalin for the management of partial epilepsy | volume=4 | issue=6 | pages=1211–1224 | date= December 2008 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646650/ | issn=1176-6328}}</ref> | ||
{{Citation | title=Pregabalin | url=https://www.epilepsy.com/tools-resources/seizure-medication-list/pregabalin}}</ref><ref>{{cite journal | vauthors=((Ryvlin, P.)), ((Perucca, E.)), ((Rheims, S.)) | journal=Neuropsychiatric Disease and Treatment | title=Pregabalin for the management of partial epilepsy | volume=4 | issue=6 | pages=1211–1224 | date= December 2008 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646650/ | issn=1176-6328}}</ref> | |||
}} | }} | ||
{{effects/visual| | {{effects/visual| | ||
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*'''[[Effect::Double vision]]'''- This effect is quite mild and inconsistently appears at high doses. Sleep deprivation might magnify this effect. | *'''[[Effect::Double vision]]'''- This effect is quite mild and inconsistently appears at high doses. Sleep deprivation might magnify this effect. | ||
====Hallucinatory states==== | ====Hallucinatory states==== | ||
While pregabalin isn't commonly thought off as a ''trip'' drug, it still can cause dissociative and even psychotic like effects at higher doses. Sleep deprivation and genetics might play a | While pregabalin isn't commonly thought off as a ''trip'' drug, it still can cause dissociative and even psychotic like effects at higher doses. Sleep deprivation and genetics might play a roll into the hallucinatory states of Pregabalin. Pregabalin's hallucinatory states are (but not limited to) : | ||
*'''[[Effect::Internal hallucination]]''' - At high dosages, one may experience dream-like states and [[hypnagogia]]. | *'''[[Effect::Internal hallucination]]''' - At high dosages, one may experience dream-like states and [[hypnagogia]]. | ||