Q&A 408.3
How do you switch between pregabalin and gabapentin for neuropathic pain, and vice versa?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: March 2015
Background
Both gabapentin and pregabalin were originally developed as antiepileptic drugs. Gabapentin, along with the originator brand of pregabalin (Lyrica) are also licensed for neuropathic pain. In March 2015, NHS England released guidance on prescribing pregabalin for neuropathic pain: “Pregabalin should only be prescribed for the treatment of neuropathic pain under the brand name Lyrica® (unless there are clinical contra-indications or other special clinical needs e.g. patient allergic to an excipient, branded product unavailable etc which apply to Lyrica®, when you should not prescribe Lyrica® or pregabalin).”[1],[2],[3],[4]
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 pharmacokinetics, meaning careful titration of dose is required, whereas pregabalin possesses linear pharmacokinetics, which mean dosing regimes are more straightforward[5].
Pregabalin is recommended as one of the first-line treatment options for neuropathic pain (alongside amitriptyline, duloxetine and gabapentin), by the National Institute for Health and Clinical Excellence[6]. This recommendation was seen as controversial at the time of publication of the guideline, as gabapentin was in common use prior to this time[7].
Answer
There have been no clinically relevant pharmacokinetic interactions found between pregabalin and gabapentin[8], although pregabalin displaces gabapentin from receptors[9].
The manufacturer of both pregabalin and gabapentin advises that if they are to be discontinued, or the dose reduced or substituted with an alternative medication, the dose should be tapered gradually over a minimum of a week1,2. However, this withdrawal is to minimise the risk of increased seizure frequency where they are being used for patients with seizure disorders[10]. 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 regime[11].
An open label study substituted gabapentin with pregabalin in patients with neuropathic pain due to peripheral neuropathy. 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 dizziness, although these did not lead to treatment discontinuation after one week[12].
Daily Dose of gabapentin pre-switch (mg/day) / Daily dose of pregabalin per day post switch (mg/day) / Dosing schedule of pregabalin0-900 / 150 / 75mg twice daily
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.[13]
A small (n=32) study of patients with post-herpetic neuralgia 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 somnolence and dizziness. A significant (p<0.05) increase in the number of patients with peripheral oedema was found after the switch[14].
Manufacturer’s Information
Pfizer, 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 products[15].
Another unpublished pharmacokinetic simulation study was conducted in 14 healthy patients. Four different switching scenarios were simulated. Based on these simulations, comparable therapeutic effect would be expected using daily doses of gabapentin 3600 mg/day and pregabalin 450 mg/day.[16]
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 Clinical Commissioning Groups 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.
Quality Assurance
Prepared by
Vincent Cassidy, Regional Drug & Therapeutics Centre
(Amended by Hayley Johnson, Regional Drug & Therapeutics Centre)
Date Prepared
3rd November 2014
(Amended 17th March 2015)
Checked by
Hayley Johnson, Regional Drug & Therapeutics Centre
(Amendments checked by: Sue Dickinson, Regional Drug & Therapeutics Centre)
Date of check
20th January 2015
Amendments checked on: 17th March 2015
Search strategy
Embase
1. EMBASE; PREGABALIN/ [Limit to: Human and Publication Year 2012-2014]; 2594 results.
2. EMBASE; GABAPENTIN/ [Limit to: Human and Publication Year 2012-2014]; 3924 results.
3. EMBASE; NEUROPATHIC PAIN/ [Limit to: Human and Publication Year 2012-2014]; 4523 results.
4. EMBASE; 1 AND 2 AND 3 [Limit to: Human and Publication Year 2012-2014]; 463 results.
Medline
5. MEDLINE; Pregabalin.ti,ab; 1806 results.
6. MEDLINE; gabapentin.ti,ab [Limit to: Publication Year 2012-2014]; 860 results.
7. MEDLINE; NEURALGIA/ [Limit to: Publication Year 2012-2014]; 1887 results.
8. MEDLINE; 5 AND 6 AND 7 [Limit to: Publication Year 2012-2014]; 34 results.
eMC
NICE
Micromedex
Manufacturer’s medical information department
References
3
Available through NICE Evidence Search at www.evidence.nhs.uk
[1] Summary of Product Characteristics- Neurontin 100 mg Hard Capsules (gabapentin). Pfizer Ltd. Accessed via http://www.medicines.org.uk/emc/medicine/17095 on 21/10/2014. [date of revision of the text 26/06/13]
[2] Summary of Product Characteristics- Lyrica Capsules (pregabalin). Pfizer Ltd. Accessed via http://www.medicines.org.uk/emc/medicine/14651 on 21/10/2014. [date of revision of the text 06/08/2014]
[3] Summary of Product Characteristics- Alzain Capsules (pregabalin). Dr Reddy’s Laboratories Ltd. Accessed via http://www.medicines.org.uk/emc/medicine/30054 on 17/03/2015. [date of revision of the text: 10/02/2015]
[4] NHS England Pregabalin Guidance, March 2015. Accessed via http://www.england.nhs.uk/wp-content/uploads/2015/03/pregabalin-guidance.pdf
[5] 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
[6] National Institute of Health and Clinical Excellence. NICE CG173. Neuropathic Pain: the pharmacological management of neuropathic pain in adults in non-specialist settings. 2013. Accessed via http://www.nice.org.uk/guidance/cg173 on 05/11/2014
[7] 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
[8] Baxter K, Preston C (Eds), Stockley’s Drug Interactions. [online] London: Pharmaceutical Press. Accessed via www.medicinescomplete.com on 05/11/2012.
[9] Bazire S. Pregabalin. In: Psychotropic Drug Directory 2009, page 356
[10] Gajraj N. Pregabalin: its pharmacology and use in pain management. Anasethesia and alangesia 2007; 105(6) 1805-1815
[11] 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
[12] Toth C. Substitution of gabapentin therapy with pregabalin therapy in neuropathic pain due to peripheral neuropathy. Pain Medicine 2010; 11: 456-465
[13] 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
[14] Ifuku M, Iseki M, Hidaka I et al. Replacement of gabapentin with pregabalin in postherpetic neuralgia therapy. Pain medicine 2011; 12: 1112-1116.
[15] Personal Communication with Medical Information- Pfizer Ltd 27/11/2012
[16] Personal Communication with Medical Information- Pfizer Ltd 30/12/2014