Pregabalin

Introduction to Pregabalin

Pregabalin is a medicine used to treat partial epilepsy [2], generalized anxiety disorder [3][4], neuralgia [5][2] and fybromyalgia [6], which has been on the U.S. market since 2005. It is a more potent succesor of Gabapentin. For epilepsy doses of 150mg-600mg/day are used (divided doses). In post-herpetic neuralgia the recommended dose is 150 to 300 mg/day (again, divided doses) although doses up to 600mg per day have been used. For neuropathic pain a dose of 300mg per day in divided doses is used. [7][4]

Despite being a GABA analogue, Pregabalin does not directly bind to GABAA, GABAB or benzodiazepine receptors (and there is no change in GABA concentrations for short term usage); Pregabalin has a high affinity for the α2-δ (alpha-2-delta) subunit of voltage gated calcium channels; calcium influx is reduced. This in turn reduces the calcium-dependant release of certain neurotransmitters (e.g. substance P, Glutamate and noradrenaline). [5][2][8][9]

Pregabalin increases the activity of the glutamic acid decarboxylase enzyme; which converts glutamate into GABA, so GABA concentrations increase [8]. Continued application of Pregabalin use increases the concentration of GABA transporter proteins, which increases the rate of GABA transport. [2]

Pregabalin is officially considered to have a low potential for abuse [10], but many users have reported pleasant recreational effects [7], often with doses much higher than those used in a medical setting. It can cause relaxation, euphoria and loss of coordination, and has been compared to both ethanol and benzodiazepines. [7]

Using Pregabalin

Ways of administration

Oral

Oral usage is the only method of administration used in a medical setting, and information about other administration methods is sparse. Administration of Pregabalin with food does decrease absorption slightly, though not enough to be considered clinically relevant. From a medical perspective, Pregabalin can be taken with or without food. [2]

Pregabalin oral dosages Dose in milligrams
Threshold 75-150 mg
Light 150-450 mg
Common 450-750 mg
Strong 750-1400 mg
Heavy 1400+ mg
[7]

Rectal

Pregabalin is active when administered anally. [11] Anecdotal reports suggest that Pregabalin is considered more effective with this method of administration, being around twice as potent. [7][12]

Insufflation

Pregabalin is active intranasally. [11] There have been several reports of Pregabalin being successfully insufflated. [13][7]

Transdermal

Transdermal administration is possible, though no form of Pregabalin transdermal patch currently exists. [11]

Injection

Pregabalin may be administered via injection, including intravenous, intramuscular and subcutaneous use. [11] Such administration is not recommended outside of a medical setting, due to the recognised risks involved.

Effects of Pregabalin

Peak plasma concentrations of Pregabalin occur at 1.5 hours, under fasting conditions. The oral bioavailability is ≥90% and is independent of dose. Following repeated administration, steady state is achieved within 24 to 48 hours. [2][7]

It has been claimed by some that the onset of Pregabalin is 30 minutes, though others report that onset may take up to 3 hours. The majority of effects are over in 5 hours. After-effects, including mild loss of coordination, mental fuzziness and thirst may last up to 9 hours after the drug was taken. [7] These times seem to vary greatly.

POSITIVE

  • Euphoria
  • Mood lift
  • Heightened sense of humour; laughter
  • Strong sense of relaxation
  • Urge to get work done; rise in motivation
  • Signifcant increase in confidence; fewer inhibitions
  • Surroundings appear to be more interesting

NEUTRAL

  • Light headedness
  • Mild visual distortions
  • Complex trains of thought that divert a lot of attention but are soon forgotten
  • Vivid imagination/day dreams

NEGATIVE

  • Tendancy to fall asleep frequently
  • Loss of coordination
  • Dizziness
  • Clouded thoughts; "mind fuzz"
  • Thirst
  • Grogginess

Combinations with Pregabalin

Alcohol

Pregabalin greatly potentiates alcohol, and causes a general increase in euphoria. Achieving a balance here is difficult, and excessive alcohol consumption can exacerbate problems with coordination and memory loss. This combination causes a hangover; the "fuzzy headed" feeling reaches a very strong plateau and is comparable to a tickling/buzzing throughout the skull. [7]

Benzodiazepines

Because Pregabalin increases the activity of the enzyme glutamic acid decarboxylase, the rate of glutamate into GABA is also increased, and for this reason Pregabalin potentiates benzodiazepines. [8] It is reported that Pregabalin combinations with both benzodiazepines and Z-drugs is enjoyable. [7]

Cannabis

As with alcohol, this combination makes each drug become more intense than when either one is used on it's own, enhancing the cannabis euphoria. The high is very relaxing, and while there may be problems with coordination, this is less obvious than when Pregabalin is combined with alcohol. [7]

Cocaine

There is a report claiming that cocaine complements Pregabalin, and that only a small dose of cocaine is needed to vibrantly improve the Pregabalin high. [7]

Gabapentin

It has been claimed that Pregabalin can lengthen the duration of MDMA experiences, though the combination can be a little messy. Pregabalin is good at stopping/preventing comedowns. [7]

MDMA

It has been claimed that Pregabalin can lengthen the duration of MDMA experiences, though the combination can be a little messy. Pregabalin is good at stopping/preventing comedowns. [7]

Tramadol

There is a report that combining low doses of tramadol and Pregabalin produces a pleasant but messy high, that is very similar to an opiate/benzodiazepine combination. [14]

Other opioids

Pregabalin is known to be synergistic with opioids in the medical sense [15] but information regarding recreational combination is lacking. Pregabalin may be useful in reducing the effects of opiate withdrawal or PAWS. [16]

Theoretically, it is possible that combining CNS depressants such as alcohol, opiates and benzodiazepines with Pregabalin could be dangerous, due to cumulative CNS depression. [2]

There is also a report that using small amounts of Pregabalin can return a stimulant high back to the baseline with no comedown. [7]

Here are some threads discussing various combinations with Pregabalin:
Is Pregabalin and selegiline dangerous?
Pregabalin, Alprazolam and Cyclobenzaprine (Lyrica, Xanax and Flexeril)
Combination: Tramadol + Pregabalin
Chill Juice" SWIM's prep for opiate w/d's...

Pharmacology of Pregabalin

Chemistry of Pregabalin

Column 1 Column 2
Systematic (IUPAC) name: (3S)-3-(aminoethyl)-5-methylhexanoic acid
Synonyms: (S)-(+)-4-amino-3-(2-methylpropyl)butanoic acid, (S)-(+)-(3)-isobutyl-[gamma]-aminobutyric acid, CI-1008, PD-144723, Lyrica
Molecular Formula: C8H17NO2
Molar mass: 159.23 g/mol
CAS Registry Number: 148553-50-8
Melting Point: 186-188°C
Boiling Point: no data
Flash Point: no data
Solubility: freely soluble in water and both basic and acidic solutions
Additionnal data: pKa1 4.2, pKa2 10.6, log(P) (octanol/0.0M pH buffer) -1.34 (pH 7.4)
Notes: aspect : white to off white crystalline solid

[17]

The dangers of Pregabalin

Overdose

Pregabalin seems to be relatively benign in overdose. There is a report of an overdose where 8 grams of Pregabalin were taken with no clinically unexpected effects arising, and a report of an 11.5 gram overdose with more serious consequences. General supportive care of the patient is indicated, and in overdose side effects such as agitation, coma, seizures, haemopoetic suppression, sinus tachycardia, and urinary retention are possible. [2][18]

Toxicity

Pregabalin is mostly excreted unchanged by the kidney, and is not metabolized by the liver (so there is no hepatoxicity associated with this drug). Excessive use may cause issues with the kidney however, and in a medical setting patients with renal problems need reduced dosages; such people should avoid recreational doses of Pregabalin altogether, because this would be dangerous. [19]

Addiction potential and tolerance

Pregabalin has some tolerance issues; in a medical setting dosage increases may be required to combat this. This means that over time a frequent Pregabalin user may require a higher dosage in order to achieve the same effect. [7]

With regular use, addiction is possible (medically, tapering usage over one week is preferred to ceasing treatment abruptly). [7] Withdrawal effects can be present, and may include insomnia, nausea, headache, diarrhoea, sweating, shaking, depression, cravings, panic and irritability. [20][21] In some reports, the withdrawals have been compared to those of GHB, and are considered almost as bad in severity. [7]

Problems with combining Pregabalin

Theoretically, it is possible that combining CNS depressants such as alcohol, opiates and benzodiazepines with Pregabalin could be dangerous, due to cumulative CNS depression. [2]

Adverse reactions

The following adverse reactions have been associated with Pregabalin [22][18][23][9]. Frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients:

Body as a Whole – Frequent: Abdominal pain, Allergic reaction, Fever, Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction, Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock

Cardiovascular System – Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation

Digestive System – Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess

Hemic and Lymphatic System – Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia
Metabolic and Nutritional Disorders – Rare: Glucose Tolerance Decreased, Urate Crystalluria

Musculoskeletal System – Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm

Nervous System – Frequent: Anxiety, Depersonalization, Hypertonia, Hypesthesia, Libido decreased, Nystagmus, Paresthesia, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, increased Libido, Myoclonus, Neuralgia, Rare: Addiction, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, Trismus

Respiratory System – Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, Yawn

Skin and Appendages – Frequent: Pruritus, Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule

Special senses – Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis

Urogenital System – Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention, Urine abnormality; Rare: Acute kidney failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis

Forms of Pregabalin

Pregabalin is marketed by Pfizer under the brand name Lyrica, and generic versions are available. Lyrica comes in capsule form with 25mg, 50mg, 75mg, 100mg, 150mg, 200mg, 225mg and 300mg versions available.
The following inactive ingredients are present inside the capsule: lactose monohydrate, cornstarch and talc.
The capsule shells may contain: gelatin and titanium dioxide, red iron oxide, sodium lauryl sulfate and colloidal silicon dioxide.
The imprinting ink used on the Lyrica capsules contains: black iron oxide, propylene glycol, and potassium hydroxide. [2]

Pregabalin is a white/off-white crystal solid freely soluble in water, as well as acidic and basic aqueous solutions. [2]

Ideally, Pregabalin should be stored at 25°C (77°F); though temperatures from 15°C to 30°C (59°F to 86°F) are acceptable. [2]

[​IMG]

Legal status of Pregabalin

Pregabalin is a controlled substance : 21 CFR 1308.15

Australia

Pregabalin is a schedule 4 drug in Australia.

Canada

Pregabalin is currently available by prescription in Canada. It is not considered an over the counter product; however, no legal restrictions on the possession or sale of it are in affect as of Sept. 2016.

UK

Pregabalin is classed as a Prescription Only Medicine (POM) in the UK.

USA

Pregabalin is a Schedule V drug in the united states. [10]

History of Pregabalin

Pregabalin was developed at Northwestern University in the USA, by medicinal chemist Richard Bruse Silverman. It was designed to replace Gabapentin - both drugs work in similar ways, but Pregabalin has a higher potency.

In July 2004, Pregabalin (Marketed by Pfizer under the trade name Lyrica) was approved in Europe for the treatment of peripheral neuropathic pain and as a therapy for partial seizures in patients with epilepsy.

Approval by the US FDA for the management of neuropathic pain associated with diabetic peripheral neuropathy and post-herpetic neuralgia (neuropathic pain following an outbreak of herpes zoster (shingles)) followed in December 2004. [5] In June 2007, the FDA approved Lyrica as a treatment for fibromyalgia.

In 2007, Pregabalin was approved by the EU to tread Generalized Anxiety Disorder.

Pregabalin

Relationship to Gabapentin

Pregabalin was designed as a more potent succesor to Gabapentin, which is also marketed by Pfizer (under the trade name Neurontin). Gabapentin first went on the US market in 1994, which is eleven years before Pregabalin. Pregabalin and Gabapentin are considered to have almost identical mechanisms of action, though it has been shown that the drugs have a synergy when combined; lower doses are needed to achieve pain relief, which in turn reduces the presence of side effects. Pregabalin and Gabapentin show no cross tolerance. [11] [24]

References

  1. ^https://www.nlm.nih.gov/medlineplus/druginfo/meds/a605045.html
  2. ^ a b c d e f g h i j k lPfizer. Data sheet for Pregabalin. march 2006.
  3. ^Rosario B. Hidalgo, Larry A. Tupler and Jonathan R. T. Davidson.An effect-size analysis of pharmacologic treatments for generalized anxiety disorder. 2007.
  4. ^ a bAm J Psychiatry. Pregabalin in Generalized Anxiety Disorder: A Placebo-Controlled Trial
  5. ^ a b cRobert H. Dworkin and Peter Kirkpatrick. Fresh From the Pipeline - Pregabalin. Nature Publishing Group, June 2005.
  6. ^Lauren Kim, MD. Sarah Lipton, MD. Atul Deodhar, MD. Pregabalin for fibromyalgia: Some relief but no cure. April 2009.
  7. ^ a b c d e f g h i j k l m n o p q rThe Pregabalin experiences thread.
  8. ^ a b cPregabalin (this is a major chemical house and does not supply private or commercial buyers; therefore its not a source). 2009
  9. ^ a bRandinitis EJ, Posvar EL, Alvey CW, Sedman AJ, Cook JA, Bockbrader HN. Pharmacokinetics of Pregabalin in subjects with various degrees of renal function. 2003.
  10. ^ a bPubmed. Schedules of controlled substances: placement of Pregabalin into schedule V. Final rule. July 2005.
  11. ^ a b c d eBrummel, Roger N., Singh, Lakhbir. A SYNERGISTIC COMBINATION: GABAPENTIN AND PREGABALIN, European Patent EP1196160. 2005.
  12. ^A thread discussing anal use of Pregabalin.
  13. ^A thread mentioning Pregabalin insufflation.
  14. ^A thread discussing the combination of tramadol and Pregabalin.
  15. ^Bruce M. Freedman, Elizabeth O'Hara. Pregabalin Has Opioid-Sparing Effects Following Augmentation Mammaplasty. 2008.
  16. ^A thread discussing the use of Pregabalin to treat opiate withdrawal/PAWS.
  17. ^Merck Index, fifteenth edition (2013)
  18. ^ a bA. J. Braga, K. Chidley. Self-poisoning with lamotrigine and Pregabalin. 2007.
  19. ^Daniel G. Healy, Gordon T. Ingle, Barry Moynihan, Peter Brown. Pregabalin- and Gabapentin-associated myoclonus in a patient with chronic renal failure.
  20. ^A thread reporting on Pregabalin withdrawals.
  21. ^A thread discussing Pregabalin addiction
  22. ^Pfizer. Lyrica (Pregabalin) capsules adverse reactions. 2009.
  23. ^Timothy L Smith, Aaron Baldwin, Larry L Cunningham Jr, and Aaron M Cook. Rash Associated with Pregabalin Use. 2008.
  24. ^Pfizer. Gabapentin (Neurontin) Data Sheet. 2005.

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