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pregabalin (Lyrica,'son of gabapentin')

Tradename: Lyrica (FDA-approved in 2004) DEA-controlled substance: class 5 Indications: 1) diabetic neuropathy [6] 2) post-herpetic neuralgia [7] 3) fibromyalgia [3,9,11] FDA-approved 06/2007 4) spinal cord injury 5) partial seizures [4] 6) anxiety [9] {investigational} 7) restless legs syndrome [15] 8) chronic pain (not FDA-approved) - marked increase in use for pain 2002-2015 [22] Contraindications: - combined use gabapentin & pregabalin not indicated [10]; combination not studied in controlled trials; gabapentin & pregabalin synergistic in an animal model [10] - ineffective for neurogenic claudication (sciatica) [21] - ineffective for acute shingles, traumatic nerve injury, burn injury, sickle cell pain, complex regional pain syndrome [25] Benefit/risk: - number needed to treat to benefit one patient with diabetic neuropathy is 5 [16] Dosage: (adults, not recommended for children) 1) start 50 mg PO TID; 50 mg QHS in elderly [29] 2) increase to PO 100 mg TID, after 1 week if tolerated 3) increase to PO 200 mg TID, after 2 weeks if tolerated 4) avoid abrupt discontinuation, taper over 1 week [5] 5) maximum dose = 600 mg/day * no dosage adjustment in liver failure [13] Dosage adjustment in renal failure: 1) reduce dose for creatinine clearance < 60 mL/min 2) give supplemental dose after hemodialysis Pharmacokinetics: 1) bioavailabiility is 90%, not affecte by food 2) time to peak concentration after oral dose is 1 hour 3) 98% unchanged by the kidneys 4) not protein bound 5) t1/2 is about 6 hours Adverse effects: 1) most adverse effects are mild to moderate [3,6] & dose-dependent 2) dizziness (24-34%) 3) somnolence, sedation (22-41%) 4) dry mouth (5%) 5) peripheral edema, weight gain (11%) 6) blurred vision, amblyopia 7) difficulty with concentration or attention, amnesia, confusion (7%) 8) adverse effects on cognition - 600 mg daily adversely affects cognition [12] - pregabalin, given for postoperative pain, associated with adverse effects on cognition (spatial working memory & executive function) [24] 9) euphoria, some patients feel 'high' (4%) [4,6] 10) accidental injury (4%) 11) pregabalin but not gabapentin associated with increased suicidality in young adults [26] 12) constipation (7%) 13) may be withdrawal is stopped abruptly - headache, nausea [4] 14) birth defects ? [18,19] 15) respiratory depression in patients with COPD [28] Drug interactions: - few drug interactions - no cyt P450 interactions - much of the increase in use 2002-2015 in patients also using benzodiazepines &/or opioids [22] - coprescription of pregabalin & opioids is associated with increased risk of respiratory depression & increased mortality relative to opioids alone [23,28] Mechanism of action: 1) GABA analog 2) more potent than gabapentin 3) binds to alpha-2 delta subunit of voltage-gated Ca+2 channel 4) does NOT bind GABA receptors 5) may improve both pain & sleep in fibromyalgia [11] Notes: 1) Manufacturer: Pfizer 2) 1st generic FDA approved July 2019 [27]

Interactions

drug interactions drug adverse effects of anticonvulsants monitor with anticonvulsants

Related

gabapentin (Neurontin, Gralise) voltage-dependent Ca+2 channel alpha-2/delta

General

gabapentinoid; GABA analog analgesic (antalgic)

Database Correlations

PUBCHEM cid=125889

References

  1. Prescriber's Letter 11(10): 2004
  2. Prescriber's Letter 12(2): 2005 New Drugs Approved by the FDA in 2004 Detail-Document#: 210216 (subscription needed) http://www.prescribersletter.com
  3. Internal Medicine News, June 2005, pg 12
  4. Prescriber's Letter 12(8): 2005 New Drug: Lyrica (Pregabalin) Detail-Document#: 210809 (subscription needed) http://www.prescribersletter.com
  5. Monthly Prescribing Reference http://www.PrescribingReference.com
  6. Lesser H et al, Pregabalin relieves symptoms of painful diabetic neuropathy. A randomized controlled trial. Neurology 2004, 63:2104 PMID: 15596757
  7. Dworkin RH et al, Pregabalin for the treatment of postherpetic neuralgia. A randomized, placebo-controlled trial. Neurology 2003, 60:1274 PMID: 12707429
  8. Beydoun A et al, Safety and efficacy of two pregabalin regimens for add-on treatment of partial epilepsy. Neurology 2005, 64:475 PMID: 15699378
  9. Prescriber's Letter 14(5): 2007 Lyrica (Pregabalin) Update Detail-Document#: 230513 (subscription needed) http://www.prescribersletter.com
  10. Prescriber's Letter 14(10): 2007 Combined use of Gabapentin (Neurontin) and Pregablin (Lyrica) Detail-Document#: 231007 (subscription needed) http://www.prescribersletter.com
  11. Mease PJ et al, A randomized, double-blind, placebo-controlled, phase III trial of pregabalin in the treatment of patients with fibromyalgia. J Rheumatol 2008, 35:502 PMID: 18278830
  12. Salinsky M et al Cognitive effects of pregabalin in healthy volunteers: A double-blind, placebo-controlled trial. Neurology 2010 Mar 2; 74:755 PMID: 20194915
  13. Medical Knowledge Self Assessment Program (MKSAP) 16, 17, 18. American College of Physicians, Philadelphia 2012, 2015, 2018.
  14. Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD007076 PMID: 19588419
  15. Allen RP et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med 2014 Feb 13; 370:621 PMID: 24521108 http://www.nejm.org/doi/full/10.1056/NEJMoa1303646 - Chokroverty S Therapeutic Dilemma for Restless Legs Syndrome. N Engl J Med 2014; 370:667-668February 13, 2014 PMID: 24521115 http://www.nejm.org/doi/full/10.1056/NEJMe1313155
  16. Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004 - Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
  17. Markman JD et al. Double-blind, randomized, controlled, crossover trial of pregabalin for neurogenic claudication. Neurology 2015 Jan 20; 84:265 PMID: 25503625 http://www.neurology.org/content/84/3/265
  18. Winterfeld U et al Pregnancy outcome following maternal exposure to pregabalin may call for concern. Neurology. May 18, 2016 PMID: 27194385 http://www.neurology.org/content/early/2016/05/18/WNL.0000000000002767 - Pennell PB, Meador KJ A common medication for neuropsychiatric illnesses may cause common problems in pregnancy. Neurology. May 18, 2016 PMID: 27194382 http://www.neurology.org/content/early/2016/05/18/WNL.0000000000002780
  19. Winterfeld U, Merlob P, Baud D et al. Pregnancy outcome following maternal exposure to pregabalin may call for concern. Neurology 2016 Jun 14; 86:2251. PMID: 27194385 - Pennell PB, Meador KJ. A common medication for neuropsychiatric illness may cause common problems in pregnancy. Neurology 2016 Jun 14; 86:2224 PMID: 27194382
  20. Goodman CW, Brett AS. Gabapentin and pregabalin for pain - Is increased prescribing a cause for concern? N Engl J Med 2017 Aug 3; 377:411 PMID: 28767350 Free full text
  21. Mathieson S, Maher CG, McLachlan AJ et al Trial of Pregabalin for Acute and Chronic Sciatica. N Engl J Med 2017; 376:1111-1120. March 23, 2017 PMID: 28328324 http://www.nejm.org/doi/full/10.1056/NEJMoa1614292 - Attal N, Barrot M Is Pregabalin Ineffective in Acute or Chronic Sciatica? N Engl J Med 2017; 376:1169-1170. March 23, 2017 PMID: 28328344 http://www.nejm.org/doi/full/10.1056/NEJMe1701147
  22. Johansen ME. Gabapentinoid use in the United States 2002 through 2015. JAMA Intern Med 2018 Jan 2; PMID: 29297045 https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2666788
  23. Gomes T, Greaves S, van den Brink W et al Pregabalin and the Risk for Opioid-Related Death: A Nested Case-Control Study. Ann Intern Med. Aug 21, 2018 PMID: 30140853 http://annals.org/aim/article-abstract/2697572/pregabalin-risk-opioid-related-death-nested-case-control-study - Throckmorton DC, Woodcock J Combined Gabapentinoid and Opioid Use: The Consequences of Shifting Prescribing Trends. Ann Intern Med. Aug 21, 2018 PMID: 30140901 http://annals.org/aim/article-abstract/2698046/combined-gabapentinoid-opioid-use-consequences-shifting-prescribing-trends
  24. Myhre M, Jacobsen HB, Andersson S, Stubhaug A. Cognitive effects of perioperative pregabalin: Secondary exploratory analysis of a randomized placebo-controlled study. Anesthesiology 2019 Jan; 130:63 PMID: 30335626
  25. Goodman CW, Brett AS. A clinical overview of off-label use of gabapentinoid drugs. JAMA Intern Med 2019 Mar 25; PMID: 30907944 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2728959
  26. Molero Y et al Associations between gabapentinoids and suicidal behaviour, unintentional overdoses, injuries, road traffic incidents, and violent crime: population based cohort study in Sweden. BMJ 2019;365:l2147 PMID: 31189556 Free PMC Article https://www.bmj.com/content/365/bmj.l2147 - Tracy DK Gabapentinoids linked to new risks, including suicidal behaviour. BMJ 2019;365:l4021 PMID: 31189536 https://www.bmj.com/content/365/bmj.l4021
  27. FDA News Release> Jyly 22, 2019 FDA approves first generics of Lyrica. https://www.fda.gov/news-events/press-announcements/fda-approves-first-generics-lyrica
  28. FDA Drug Safety Communication. Dec 19, 2019 FDA warns about serious breathing problems with seizure and nerve pain medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR). When used with CNS depressants or in patients with lung problems https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-serious-breathing-problems-seizure-and-nerve-pain-medicines-gabapentin-neurontin
  29. NEJM Knowledge+ Pain Management and Opioids: Recharge