Pregabalin

Pregabalin is a structural analog of GABA (gamma-aminobutyric acid), with an isobutyl group substituted on the beta carbon of the aminobutyric chain. Pregabalin is similar in structure to other gabapentinoids, such as gabapentin and phenibut. Pregabalin contains a carboxylated chain of hexane called hexanoic acid. This carbon chain is substituted with an amine group through a methyl bridge in (S) conformation at R₃ and a methyl group at R₅.

Pharmacodynamics

The pharmacological action of pregabalin is mediated by binding to the α2δ-1 site of voltage-gated calcium channels.^[8][9] 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_A, GABA_B 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.^[10] 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.

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.^[11] 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.^[9]

As pregabalin treats conditions and neurotransmitters associated with overexcitability of the brain (anxiety, epilepsy, neuropathic pain), its modulation results in the sedating (or calming) effects of pregabalin on the nervous system.^{[citation needed]}

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%.^[12] Administration with food, however, has no clinically significant effect on the extent of absorption.^[13]

Pregabalin undergoes negligible metabolism in humans. In experiments using nuclear medicine techniques, it was revealed that approximately 98% of the radioactivity recovered in the urine was unchanged pregabalin. The primary metabolite is N-methyl pregabalin.

Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged substance. Renal clearance of pregabalin is 73 mL/minute.^[14]

Each individual can have a very different reaction to pregabalin, thus it is essential to start at lower doses to ensure that it does not have any severe adverse effects such as peripheral edema or muscle pain. Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), a research literature based on anecdotal reports and the personal experiences of PsychonautWiki contributors. As a result, they should be regarded with a healthy degree of skepticism. It is worth noting that these effects will not necessarily occur in a predictable or reliable manner, although higher doses are more liable to induce the full spectrum of effects. Likewise, adverse effects become much more likely with higher doses and may include addiction, serious injury, or death.

Experience reports

Anecdotal reports which describe the effects of this compound within our experience index include:

• Experience:225mg Pregabalin +Cannabis -Bliss and Serenity; a hedonistic evening
• Experience:50mg Pregabalin - Surprisingly strong
• Experience:Pregabalin (2,625 mg, oral) - Pharmaceutical Sunshine

Additional experience reports can be found here:

• Erowid Experience Vaults: Pregabalin

Pregabalin is used in a medical setting, usually prescribed in capsules, to treat epilepsy, neuropathic pain, fibromyalgia, and generalized anxiety disorder. Its use for epilepsy is as an add-on therapy for partial seizures with or without secondary generalization in adults. Some off-label uses of pregabalin include restless leg syndrome, prevention of migraines, social anxiety disorder, and alcohol withdrawal.

Seizures

Pregabalin is useful when added to other treatments, when those other treatments are not controlling partial epilepsy. Its use alone is less effective than some other seizure medications. It is unclear how it compares to gabapentin for this use.

Neuropathic pain

The European Federation of Neurological Societies recommends pregabalin as a first line agent for the treatment of pain associated with diabetic neuropathy, post-herpetic neuralgia, and central neuropathic pain. A minority obtain substantial benefit, and a larger number obtain moderate benefit. Other first line agents, including gabapentin and tricyclic antidepressants, are given equal weight as first line agents, and unlike pregabalin, are available as less expensive generics.

Anxiety disorders

The World Federation of Biological Psychiatry recommends pregabalin as one of several first line agents for the treatment of generalized anxiety disorder, but recommends other agents such as SSRIs as first line treatment for obsessive-compulsive disorder and post-traumatic stress disorder. It appears to have anxiolytic effects similar to benzodiazepines with less risk of dependence.

The effects of pregabalin appear after 1 week of use and is similar in effectiveness to lorazepam, alprazolam, and venlafaxine, but pregabalin has demonstrated superiority by producing more consistent therapeutic effects for psychosomatic anxiety symptoms. Long-term trials have shown continued effectiveness without the development of tolerance, and, in addition, unlike benzodiazepines, it has a beneficial effect on sleep and sleep architecture, characterized by the enhancement of slow-wave sleep. It produces less severe cognitive and psychomotor impairment compared to those drugs and may be preferred over the benzodiazepines for these reasons.

Substance disorders

Opioids

Anecdotal reports^[22] exist of successful discontinuation of opioid use by supplementing with pregabalin.

Tobacco

One placebo-controlled four-day trial (n=24 completed) investigated the effects of pregabalin on smoking cessation in non-treatment-seeking smokers.^[23] This study did not find any statistically significant effect on smoking behavior, although pregabalin reduced some withdrawal symptoms: anxiety, irritability, and frustration. Pregabalin also reduced the measure of subjective "liking" after smoking a cigarette.

Alcohol

A meta-review of five studies concerning the use of pregabalin in treating alcoholism or alcohol withdrawal found positive results for relapse prevention in sober patients at dosages of 150-450 mg/day, but conflicting results for the treatment of acute alcohol withdrawal.^[24] Two of the studies concerned the only maintenance of abstinence. Both showed positive results. In one of them (n=59), pregabalin compared favorably to naltrexone on the measure of days abstinent from any amount of alcohol.

Benzodiazepines

One open-label pilot study^[25] of 15 individuals with high-dose benzodiazepine dependence reported that all subjects have successfully discontinued benzodiazepines within 14 weeks, while taking supplemental doses of 225-900mg pregabalin/day. The patients also showed reduced anxiety levels and better cognitive functioning. Pregabalin was well tolerated.

Pregabalin likely has a low toxicity relative to dose. However, it is potentially lethal when mixed with depressants like alcohol or opioids.

It is strongly recommended that one use harm reduction practices when using this substance.

Lethal dosage

The LD₅₀ for rodents has been established to be greater than 5000mg/kg. Rat IV LD50 was also determined to be greater than 300mg/kg.^[26]

In terms of humans, there exists a case report of a man who ingested 8,400mg pregabalin and eventually fell into a coma but was managed with supportive care alone until he regained consciousness.^[27] For comparison, the maximum recommended a therapeutic dose of pregabalin is 600mg/day.^[28] Pfizer's official package insert for Lyrica states that the highest accidental ingestion of pregabalin during clinical trials was 8 g, with no significant consequences.^[29]

Tolerance and addiction potential

Pregabalin was initially thought to be non-addictive with a low abuse potential and little tolerance development. However, recreational use of the substance has caused a re-evaluation of this assessment. The euphoric effects of the substance and the development of tolerance can lead to the use of dosages far above the therapeutic range, which suggests both the potential for recreational use and addiction.^[30][31]

Tolerance will develop to the depressant effects within several months of continuous use. After cessation, the tolerance returns to baseline in 7 - 14 days. Withdrawal symptoms or rebound symptoms are likely to occur after ceasing usage abruptly following a few months or longer of steady dosing and may necessitate a gradual dose reduction.

The withdrawal effects of abrupt cessation of chronic use include anxiety, insomnia, sweating, muscle spasms, gastrointestinal problems, hot and cold flashes, nausea, and a flu-like feeling.

Interactions

One report of a patient entering serotonin syndrome following perioperative Oxycodone and pregabalin exists.^[32] However, several studies have failed to find any serotonergic effect whatsoever from pregabalin. One paper states, "Although pregabalin is a structural analog of GABA, it has no clinically significant effects at GABA-A or GABA-B receptors, and it is not converted metabolically into GABA or a GABA agonist. Pregabalin is not a serotonin reuptake inhibitor and does not act as a glutamate receptor antagonist."^[33] A more recent study writes that "Pregabalin has no involvement with serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake."^[34] Pregabalin's main mechanism of action is binding and blocking sub receptor on Voltage-Gated Calcium Channels, leading to a downstream reduction of overactive neurons.

If pregabalin has serotonergic effects, it could interact negatively with other serotonergic substances, including SSRIs, MDMA, various analgesics, and possibly other recreational and medical substances. Given the total lack of evidence for any serotonergic activity in multiple studies, it seems possible that the one reported adverse event was a freak accident, caused by unknown factors.

Pregabalin is regulated as a prescription drug in most countries.

• Germany: Pregabalin is a prescription medicine, according to Anlage 1 AMVV.^[35]
• Norway: Pregabalin is in prescription schedule B alongside most benzodiazepines and painkillers. It was rescheduled to schedule B from the less restrictive schedule C because of reported recreational use, tolerance development and addiction.^[36]
• Sweden: Pregabalin is a prescription drug. classified as a controlled substance, as a schedule V drug, since 24 july 2018 ^[37]
• Switzerland: Pregabalin is listed as a "Abgabekategorie B" pharmaceutical, which requires a prescription.^{[citation needed]}
• Turkey: Pregabalin is a 'green prescription' only substance^[38] and illegal when sold or possessed without a prescription.^{[citation needed]}
• United Kingdom: The Misuse of Drugs Act 1971 makes it illegal to possess the drug without a prescription and, for such purposes, it is classified as a Class C drug.^[39]
• United States: Pregabalin is in Schedule V, indicating "low potential for abuse." For comparison, benzodiazepines are in Schedule IV.^[40]

• Responsible use
• Gabapentin
• Benzodiazepines

• Pregabalin (Wikipedia)
• Pregabalin (Erowid Vault)
• Pregabalin (TiHKAL / Isomer Design)
• Pregabalin (Drugs.com)

• Field, M. J., Cox, P. J., Stott, E., Melrose, H., Offord, J., Su, T., … Williams, D. (2006). Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proceedings of the National Academy of Sciences of the United States of America, 103(46), 17537–42. https://doi.org/10.1073/pnas.0409066103
• Eroglu, Ç., Allen, N. J., Susman, M. W., O’Rourke, N. A., Park, C. Y., Özkan, E., … Barres, B. A. (2009). Gabapentin Receptor α2δ-1 Is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS Synaptogenesis. Cell, 139(2), 380–392. https://doi.org/10.1016/j.cell.2009.09.025
• Taylor, C. P., Angelotti, T., & Fauman, E. (2007). Pharmacology and mechanism of action of pregabalin: The calcium channel ??2-?? (alpha2-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Research, 73(2), 137–150. https://doi.org/10.1016/j.eplepsyres.2006.09.008
• Hindmarch, I., Dawson, J., & Stanley, N. (2005). A double-blind study in healthy volunteers to assess the effects on sleep of pregabalin compared with alprazolam and placebo. Sleep, 28(2), 187–93. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16171242
• Wood, D. M., Berry, D. J., Glover, G., Eastwood, J., & Dargan, P. I. (2010). Significant Pregabalin Toxicity Managed with Supportive Care Alone. Journal of Medical Toxicology, 6(4), 435–437. https://doi.org/10.1007/s13181-010-0052-3
• Braga, A. J., & Chidley, K. (2007). Self-poisoning with lamotrigine and pregabalin. Anaesthesia, 62(5), 524–527. https://doi.org/10.1111/j.1365-2044.2006.04913.x
• Kavoussi, R. (2006). Pregabalin: From molecule to medicine. European Neuropsychopharmacology, 16, S128–S133. https://doi.org/10.1016/j.euroneuro.2006.04.005
• Song, H.-K. (2013). Serotonin syndrome with perioperative oxycodone and pregabalin. Pain Physician, 16(October), E632-3. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/24077214
• Herman, A. I., Waters, A. J., McKee, S. A., & Sofuoglu, M. (2012). Effects of pregabalin on smoking behavior, withdrawal symptoms, and cognitive performance in smokers. Psychopharmacology, 220(3), 611–617. https://doi.org/10.1007/s00213-011-2507-x
• Guglielmo, R., Martinotti, G., Clerici, M., & Janiri, L. (2012). Pregabalin for alcohol dependence: A critical review of the literature. Advances in Therapy, 29(11), 947–957. https://doi.org/10.1007/s12325-012-0061-5
• Kämmerer, N., Lemenager, T., Grosshans, M., Kiefer, F., & Hermann, D. (2012). [Pregabalin for the reduction of opiate withdrawal symptoms]. Psychiatrische Praxis, 39(7), 351–2. https://doi.org/10.1055/s-0032-1305042
• Bobes, J., Rubio, G., Terán, A., Cervera, G., López-Gómez, V., Vilardaga, I., & Pérez, M. (2012). Pregabalin for the discontinuation of long-term benzodiazepines use: An assessment of its effectiveness in daily clinical practice. European Psychiatry, 27(4), 301–307. https://doi.org/10.1016/j.eurpsy.2010.12.004
• Oulis, P., Konstantakopoulos, G., Kouzoupis, A. V., Masdrakis, V. G., Karakatsanis, N. A., Karapoulios, E., … Papadimitriou, G. N. (2008). Pregabalin in the discontinuation of long-term benzodiazepines’ use. Human Psychopharmacology: Clinical and Experimental, 23(4), 337–340. https://doi.org/10.1002/hup.937