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Q&A 408.1

How do you switch between and for , and vice versa?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals Date prepared: 5th November 2012

Background

Both gabapentin and pregabalin were originally developed as antiepileptic drugs. Both agents are also licensed for use in neuropathic pain1,2.

The mechanism of action is similar for pregabalin and gabapentin. Both drugs bind to the α2δ subunit of voltage-gated calcium channels1,2. Gabapentin has nonlinear , meaning careful titration of dose is required, whereas pregabalin possesses linear pharmacokinetics, which mean dosing regimes are more straightforward3.

Pregabalin is recommended as a first-line treatment option for neuropathic pain by the National Institute for Health and Clinical Excellence4. This recommendation was seen as controversial at the time of publication of the guideline, as gabapentin was in common use prior to this time5.

Answer

There have been no clinically relevant pharmacokinetic interactions found between pregabalin and gabapentin6, although pregabalin displaces gabapentin from receptors7.

The manufacturer of both pregabalin and gabapentin advises that if they are to be discontinued, or the dose reduced or substituted with an alternative , the dose should be tapered gradually over a minimum of a week1,2. However, this withdrawal is to minimise the risk of increased frequency where they are being used for patients with seizure disorders8. The clinical importance of a slow withdrawal in patients with neuropathic pain remains unknown.

Literature Search There is very limited evidence in the medical literature with regards to managing a switch between the two agents.

A conference abstract of a small study included 26 patients who were directly switched from gabapentin to pregabalin. The focus of the study was looking at unlicensed doses of pregabalin and gabapentin for the treatment of pain models outside of the pregabalin license. Patients were switched directly to pregabalin after stopping gabapentin with no dose tapering or wash out period. Most patients were switched to 150mg twice daily of pregabalin (above the recommended licensed starting dose in the UK). Unfortunately, there was no reported information on tolerability of this switching regime9.

An open label study substituted gabapentin with pregabalin in patients with neuropathic pain due to . The author describes an overnight switch from gabapentin to pregabalin, based on a conversion table which is described in the paper as “of the author’s creation” (table 1). No serious adverse effects appeared to have been caused by the switch. Patients who had not responded to gabapentin therapy appeared to have a higher likelihood of adverse effects such as sedation and , although these did not lead to treatment discontinuation after one week10.

Daily Dose of Daily dose of pregabalin per day Dosing schedule of pregabalin gabapentin pre-switch post switch (mg/day) (mg/day) 0-900 150 75mg twice daily

From the National Electronic Library for Medicines. www.nelm.nhs.uk 1

Medicines Q&As

901-1500 225 75mg in the morning and 150mg in the evening* 1501-2100 300 150mg twice daily 2101-2700 450 150mg in the morning and 300mg in the evening 2700 or higher 600 300mg twice daily Table 1: Dose conversion of gabapentin to pregabalin used in the Toth study. *the table in the published study actually reads 75mg in the morning and 225mg in the evening. This error has been corrected in the above table.

Yilmaz et al conducted a cross-over study design in which patients with neuropathic pain due to spinal cord injury were randomised into either the pregabalin or gabapentin group. Patients were titrated up to the highest tolerated dose up to 1800mg per day for gabapentin and 300mg per day for pregabalin for a total of 8 weeks. After a washout period of 2 weeks, they were switched to the other medication. Tolerability of this switching regime was not reported.11

A small (n=32) study of patients with post-herpetic saw patients switched from gabapentin to pregabalin at one sixth of the gabapentin dose. No serious side effects occurred, and no significant difference was found before and after substitution in the number of patients with and dizziness. A significant (p<0.05) increase in the number of patients with peripheral oedema was found after the switch12.

Manufacturer’s Information , the manufacturer of both Lyrica® (pregabalin) and Neurontin® (gabapentin), advise that in the absence of clinical studies, licensed dosage information for both gabapentin and pregabalin should be consulted. They are unable to make any recommendations regarding initiating or switching13.

An in-house pharmacokinetic simulation suggests that a regime of halving the original gabapentin dose, and introducing half the intended dose of pregabalin on day 0, then stopping gabapentin and doubling the pregabalin dose on day 4 leads to fairly stable drug levels of pregabalin equivalents. However, the efficacy and safety of this switching regime has not been established, and use in this way would fall out with the licenses of the products13.

Summary

In the absence of more detailed data, recommendations cannot be made about initiating or switching to gabapentin following pregabalin treatment or vice versa. The individual SPCs suggest that both agents should be discontinued over the course of a week, although whether this is relevant for patients with neuropathic pain remains unclear.

Any decisions made will need to be based on a clinical judgement, in partnership with the patient. Pain clinics or individual Primary Care Trusts may have developed local switching guidance which should be consulted where possible.

Limitations This Medicines Q&A does not consider the potential for differences in efficacy of pregabalin and gabapentin but merely considers how to manage a switch.

Disclaimer • Medicines Q&As are intended for healthcare professionals and reflect UK practice. • Each Q&A relates only to the clinical scenario described. • Q&As are believed to accurately reflect the medical literature at the time of writing. • The authors of Medicines Q&As are not responsible for the content of external websites and links are made available solely to indicate their potential usefulness to users of NeLM. You must use your judgement to determine the accuracy and relevance of the information they contain.

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Medicines Q&As

• This document is intended for use by NHS healthcare professionals and cannot be used for commercial or marketing purposes. • See NeLM for full disclaimer.

References

Quality Assurance

Prepared by Hayley Johnson, Regional Drug & Therapeutics Centre

Date Prepared 5th November 2012

Checked by Nancy Kane, Regional Drug & Therapeutics Centre

Date of check 29th November 2012

Search strategy

Embase PREGABALIN* AND GABAPENTIN* AND NEUROPATHIC PAIN*

Medline Pregabalin.af AND gabapentin.af AND NEURALGIA* eMC NICE PRODIGY Micromedex Manufacturer’s medical information department

References

1 Summary of Product Characteristics- Neurontin (gabapentin). Pfizer Ltd. Accessed via http://www.medicines.org.uk/EMC/printfriendlydocument.aspx?documentid=17095 on 05/11/2012. [date of revision of the text 04/2012] 2 Summary of Product Characteristics- Lyrica (pregabalin). Pfizer Ltd. Accessed via http://www.medicines.org.uk/EMC/medicine/14651/SPC/Lyrica+Capsules/ on 05/11/2012. [date of revision of the text 07/2009 3 Dworkin r, O’Connor A, Audette J et al. Recommendations for the pharmacological management of neuropathic pain: An overview and literature update. Mayo Clinical Proceedings 2010; 85(3): S3-S14 4 National Institute of Health and Clinical Excellence. NICE CG96. Neuropathic Pain: the pharmacological management of neuropathic pain in adults in non-specialist settings. 2010. Accessed via http://publications.nice.org.uk/neuropathic-pain-cg96/guidance on 05/11/2012 5 Why q pregabalin ? DTB 2010;48:61 doi:10.1136/dtb.2010.04.0029. Accessed via http://dtb.bmj.com/content/48/6/61.extract on 05/11/2012 6 Baxter K, Preston C (Eds), Stockley’s Drug Interactions. [online] London: Pharmaceutical Press. Accessed via www.medicinescomplete.com on 05/11/2012. 7 Bazire S. Pregabalin. In: Psychotropic Drug Directory 2009, page 356 8 Gajraj N. Pregabalin: its pharmacology and use in . Anasethesia and alangesia 2007; 105(6) 1805-1815 9 Allen S. Pregabalin- is it any better than gabapentin? Presented at the IASP’s 11th World Congres on Pain: Sydney, Australia 2005, cited in: Personal Communication with Medical Information- Pfizer Ltd 27/11/2012

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Medicines Q&As

10 Toth C. Substitution of gabapentin therapy with pregabalin therapy in neuropathic pain due to peripheral neuropathy. Pain 2010; 11: 456-465 11 Yilmaz B, Yasar E, Koroglu Omac O et al. Gabapentin vs pregabalin for the treatment of neuropathic pain in patients with spinal cord injury: a cross over study. European Journal of Pain Supplements. 2011; 5(1): 239 12 Ifuku M, Iseki M, Hidaka I et al. Replacement of gabapentin with pregabalin in therapy. Pain medicine 2011; 12: 1112-1116. 13 Personal Communication with Medical Information- Pfizer Ltd 27/11/2012

From the National Electronic Library for Medicines. www.nelm.nhs.uk 4