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Pregabalin

Also known as

Lyrica

Classification

Gabapentinoid

Overview

Pregabalin is a prescription only medicine used to treat epilepsy, neuropathic pain (which is the result of damage to nerve tissue which can produce a burning, shooting or scalding feeling) and anxiety.

A prescription only medicine can only be prescribed following a consultation with a doctor.

Pregabalin can produce feelings of relaxation, calmness and euphoria, like tranquillisers.

It can enhance the euphoric effects of other drugs, like opiates, and is likely to increase the risks when taken in this way [1].

What does it look like?

Pregabalin comes as white, yellow or orange tablets/capsules. They are normally swallowed, although powder from capsules may be snorted [2]. Pregabalin is manufactured as either white, white/orange or orange capsules [1].

Street price

50p to £1 on the street [3].

How long do its effects last?

Onset of effects

  • oral - 30 - 90 minutes [4].
  • all ROA's - 90 - 150 minutes [5].

Duration of effects

  • oral - 6 - 14 hours [4].
  • all ROA's - 6 - 14 hours [5].

After-effects

  • all ROA's - 1 - 12 hours [5].

Pharmacology

Pharmacodynamics

The pharmacological action of pregabalin is mediated by binding to the α2δ-1 site of voltage-gated calcium channels [6], [7]. 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 GABAA, GABAB 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 [8]. 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 [9]. 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 [7], [4].

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% [10]. Administration with food, however, has no clinically significant effect on the extent of absorption [11].

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 [12].

Absorption

Pregabalin is well absorbed after oral administration. When an oral administration of pregabalin under fasting conditions is given, the pharmacokinetic parameters are as follows - tmax = 1.5 hours; time to steady state = 24 - 48 hours [13].

Bioavailability

Oral bioavailability = >90% (independent of dose) [13].

Half-life

6.3 hours [13].

Elimination

90% of the dose was recovered in the urine as the parent compound. The N-methylated derivative of pregabalin, the major metabolite was found in the urine and accounted for 0.9% of the dose [13].

Lethal dosage

Both rat and mouse oral acute LD50 have been established to be greater than 5000mg/kg. Rat IV LD50 was also determined to be greater than 300mg/kg [14], [4].

Toxicity

Most common adverse reactions (≥5% and twice placebo) are dizziness, somnolence, dry mouth, oedema, blurred vision, weight gain and thinking abnormal (primarily difficulty with concentration/attention) [13].

Tolerance

Tolerance will develop to the depressant effects within several days of continuous use. After cessation, the tolerance returns to baseline in 7 - 14 days. Withdrawal symptoms or rebound symptoms may occur after ceasing usage abruptly following a few weeks or longer of steady dosing and may necessitate a gradual dose reduction [4].

Mechanism of action

Pregabalin binds with high affinity to the alpha2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues. Although the mechanism of action of pregabalin is unknown, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha2-delta subunit may be involved in pregabalin's antinociceptive and antiseizure effects in animal models. in-vitro, pregabalin reduces the calcium-dependent release of several neurotransmitters, possibly by modulation of calcium channel function. Studies also suggest that the descending noradrenergic and serotonergic pathways originating from the brainstem may be involved with the mechanism of pregabalin. Interestingly, although pregabalin is a structural derivative of inhibitory neurotransmitter GABA, it does not bind directly to GABA or benzodiazepine receptors. The sodium channels, opiate receptors, and cyclooxygenase enzymes are not involved with the mechanism of pregabalin. It is also inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake [13].

Mode of use

Pregabalin capsules are normally swallowed [1].

Effects

Common

Pregabalin can produce feelings of -

  • euphoria,
  • relaxation,
  • calmness [1].

It can also enhance/increase the euphoric effects of other drugs, like opiates [1].

Uncommon

Less commonly, pregabalin can cause -

  • hallucinations,
  • heart problems (including heart failure),
  • depression,
  • agitation,
  • panic attacks [1].

Physical effects

  • muscle relaxation,
  • physical euphoria,
  • motor control loss,
  • pain relief,
  • respiratory depression,
  • sedation,
  • seizure suppression,
  • dizziness,
  • muscle spasms [4].

Cognitive effects

  • cognitive euphoria,
  • dream potentiation,
  • empathy, love, and sociability enhancement,
  • increased libido,
  • increased music appreciation,
  • motivation enhancement,
  • amnesia,
  • anxiety suppression,
  • decreased libido,
  • disinhibition,
  • information processing suppression,
  • thought deceleration [4].

Visual effects

  • colour enhancement,
  • acuity suppression,
  • internal hallucinations [4].

Auditory effects

  • auditory distortion,
  • auditory enhancement [4].

Side-effects

  • constipation,
  • vomiting,
  • nausea,
  • flatulence,
  • poor muscle control,
  • trouble sleeping,
  • weight gain,
  • visual disturbances like blurred vision [1].

Risks

Pregabalin can cause these risks, all of which can put you at risk of hurting yourself [1].

  • dizziness,
  • drowsiness,
  • confusion [1].

Purity

It's likely that most of the pregabalin that is available on the black market has been either stolen from a hospital or pharmacy or stolen (possibly bought) from people who have been prescribed pregabalin.

They might have also been imported from abroad. You cannot normally be sure of the purity unless you are certain that the drug you have is a genuine pharmacy medicine [1].

Addiction

Pregabalin is moderately physically and psychologically addictive [4].

Can you get addicted

It is recommended that prescribed pregabalin use is not stopped abruptly as it may cause anxiety, insomnia, nausea, pain and sweating.

Substantial misuse of pregabalin has been reported. In view of this and in view of pregabalin known effects, it seems possible that dependence may develop in some regular users [1].

Withdrawal

The withdrawal effects of abrupt cessation of chronic usage include -

  • anxiety,
  • insomnia,
  • sweating,
  • muscle spasms,
  • gastrointestinal problems,
  • hot and cold flushes,
  • nausea,
  • flu-like feeling [4].

There exist reports of patients with history of both opioid and benzodiazepine abuse who considered pregabalin withdrawal to be worse than benzodiazepine or heroin withdrawal [15], [4].

Legality

Pregabalin is a prescription only medicine and can only be prescribed following a consultation with a doctor [1].

Did you know?

Like drinking and driving, driving while under the influence of drugs is illegal – with some drugs you can still be unfit to drive the day after using. You can get a heavy fine, be disqualified from driving or even go to prison [1].


References

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 Pregabalin, 2017, http://www.talktofrank.com/drug/pregabalin
  2. Pregabalin, 2016, http://www.drugwise.org.uk/pregabalin/
  3. Pregabalin, 2017, http://www.kfx.org.uk/drug_facts/drug_facts_pregabalin.php
  4. 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 Pregabalin, 2017, http://psychonautwiki.org/wiki/Pregabalin
  5. 5.0 5.1 5.2 Pregabalin, 2016, http://drugs.tripsit.me/pregabalin
  6. Field, M. J. and Cox, P. J. and Stott, E. and Melrose, H. and Offord, J. and Su, T. Z. and Bramwell, S. and Corradini, L. and England, S. and Winks, J. and Kinloch, R. A. and Hendrich, J. and Dolphin, A. C. and Webb, T. and Williams, D., Identification of the α2-δ-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, 2006, 103, 46, 17537-17542, https://doi.org/10.1073/pnas.0409066103, http://www.pnas.org/content/103/46/17537.abstract
  7. 7.0 7.1 Eroglu, Ç. and Allen, N. J. and Susman, M. W. and O'Rourke, N. A. and Park, C. Y. and Özkan, E. and Barres, B. A., Gabapentin Receptor α2δ-1 Is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS Synaptogenesis, Cell, 2009, 139, 2, 380-392, https://doi.org/10.1016/j.cell.2009.09.025, https://www.ncbi.nlm.nih.gov/pubmed/19818485
  8. Taylor, C. P. and Angelotti, T. and Fauman, E., Pharmacology and mechanism of action of pregabalin: The calcium channel  α2–δ (alpha2-delta) subunit as a target for antiepileptic drug discovery, Epilepsy Research, 2007, 73, 2, 137-150, https://doi.org/10.1016/j.eplepsyres.2006.09.008, http://www.sciencedirect.com/science/article/pii/S0920121106003895
  9. Hindmarch, I. and Dawson, J. and Stanley, N., A double-blind study in healthy volunteers to assess the effects on sleep of pregabalin compared with alprazolam and placebo, Sleep, 2005, 28, 2, 187-193, https://www.ncbi.nlm.nih.gov/pubmed/16171242
  10. Pregabalin, 2017, https://www.drugs.com/ppa/pregabalin.html
  11. Summary Of Product Characteristics, 2016, http://web.archive.org/web/20160305012454/http//www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000546/WC500046602.pdf
  12. Lyrica, 2016, http://web.archive.org/web/20160305071130/http//dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=41099
  13. 13.0 13.1 13.2 13.3 13.4 13.5 Pregabalin, 2017, https://www.drugbank.ca/drugs/DB00230
  14. Material Safety Data Sheet, 2012, http://www.pfizer.com/files/products/material_safety_data/722.pdf
  15. Nordmo, E. and Vorren, S., Lyrica - norske bivirkningsmeldinger om misbruk, 2014, http://web.archive.org/web/20150910231010/http//www.relis.no/Bivirkninger/Nytt_om_bivirkninger/2014/Misbruk_avhengighet_og_seponeringsreaksjoner_ved_bruk_av_Lyrica_norske_bivirkningsmeldinger