Disclaimer statement: Managing neuropathic pain is a very complex topic and should encompass using different approaches including pharmacological and non-pharmacological options. This article focuses on the use of gabapentinoids given their very wide use.
Authors
Anthony Lau, BSc(Pharm), ACPR, PharmD, BCPS (biography, no disclosures), Hans Haag, BSc, BSc(Pharm), ACPR, PharmD (biography, no disclosures), Katherine Daley, ACPR, PharmD (biography, no disclosures), Dr. Martha Ignaszewski, MD, FRCPC (biography and disclosures)
Disclosures: Martha Ignaszewski: Honoraria for educational lecture (Indivior) and attendance at a regional advisory meeting (Otsuka/Lundbeck). Mitigating potential bias: Only published trial data are included. Recommendations are consistent with published guidelines (CPS, CFP). Recommendations are consistent with current practice patterns. All potential conflicts are disclosed. Treatments or recommendations in this article are unrelated to products/services/treatments involved in disclosure statements.
What I did before
Chronic neuropathic pain significantly impacts patients’ quality of life as well as causes reduced daily activity, sleep disturbances, and heightened rates of anxiety and depression.1 Its far-reaching impact results in decreased productivity and increased healthcare utilization.2 Many individuals with chronic neuropathic pain require medications to manage symptoms and the use of gabapentinoids, including gabapentin and pregabalin, have been recommended as first-line treatment over opioid analgesics in the current Canadian Pain Society and Canadian Family Physician guidelines.3-5 Despite the growing number of Health Canada and FDA-approved indications for pregabalin, such as diabetic neuropathy, post-herpetic neuralgia, fibromyalgia, and spinal cord injury-related pain, gabapentin has received more extensive research attention.6,7 This substantial body of research may be a contributing factor to the comfort and widespread utilization of gabapentin among clinicians.
When managing patients with neuropathic pain inadequately controlled on gabapentin, I previously recommended dose escalations beyond 1800 mg per day over switching to an alternate agent if gabapentin did not cause intolerable adverse effects. This practice was based on the findings of a Cochrane systematic review, which suggested that doses up to 3600 mg per day were effective and safe for patients with normal renal function.6 However, if dose intensification with gabapentin did not improve the clinical response, I would then consider rotating to pregabalin due to its increased potency and more convenient dosing regimen. Concerns about drug cost and coverage in British Columbia limited my use of pregabalin as a first-line treatment option. The approximate drug cost for a 300 mg dosage of gabapentin is $0.11 per pill, whereas a 75 mg dosage of pregabalin amounts to $0.33 per pill.
What changed my practice
Seeing gabapentin commonly being titrated to high doses in clinical practice with anecdotally little benefit prompted me to compare the therapeutic differences between gabapentin and pregabalin and learn more about the ceiling effect of gabapentin. Evidence suggests that gabapentin, but not pregabalin, exhibits a ceiling dose effect that argues against conventional dose escalation approaches.
Gabapentinoids are thought to exert their analgesic effects by reducing the release of excitatory neurotransmitters (e.g. glutamate, norepinephrine, and substance P) through binding and inhibiting presynaptic voltage-gated calcium channels.8 Gabapentin’s bioavailability decreases with an increase in dose and its absorption becomes saturable at 600 mg per dose (approximately 1800 mg per day divided every eight hours). Particularly, its bioavailability drops from 60% to 33% when the dosage is escalated from 900 to 3600 mg per day, divided every eight hours. In contrast, pregabalin maintains consistent bioavailability of 90% across all therapeutic dose ranges.9 As a result of these differences in bioavailability, pregabalin has a faster onset of action at around 1.5 hours compared to gabapentin at around 4-5 hours. Pregabalin is also absorbed in the small intestine and proximal colon, whereas gabapentin is solely absorbed in the small intestine. These pharmacokinetic differences contribute to gabapentin’s lack of effect above 600 mg per dose (1800 mg per day divided every eight hours), also known as the ceiling dose, while pregabalin’s efficacy is not limited by any ceiling or plateau effect.10 Increasing the dose of gabapentin beyond this ceiling dose is unlikely to produce any additional meaningful pain relief.6,11 The overall adverse effect profile of both agents and dosing considerations are similar, but achieving 600 mg per day of pregabalin is associated with an increased risk of adverse effects such as somnolence and dizziness.12
Furthermore, when comparing the pharmacodynamic profiles of pregabalin and gabapentin, they possess notable differences in their binding affinity and potency. Pregabalin exhibits a six-fold higher binding affinity for the α2δ-1 calcium channel subunit compared to gabapentin.10,13 The increased binding affinity explains the greater potency and subsequent analgesic effect of pregabalin.10 These pharmacodynamic and aforementioned pharmacokinetic characteristics of pregabalin translate into clinical benefits such as faster onset of pain score reduction compared to gabapentin.14
Recent meta-analyses comparing gabapentin and pregabalin in the treatment of various neuropathic pain conditions have shown superior pain control with pregabalin. A Cochrane review from 2015 demonstrated a comparable number needed to treat (NNT) for a 50% reduction in pain intensity for both medications, independent of the etiology of pain. The particular NNTs for pregabalin and gabapentin were 7.71 and 7.16, respectively.10 A more recent meta-analysis in 2022 specifically focused on post-herpetic neuralgia and found greater efficacy with pregabalin in alleviating pain and improving global perception of pain and sleep.15 Another meta-analysis published in 2021 reported similar results in patients with spinal cord injury, with pregabalin reducing pain to a greater extent compared to gabapentin, carbamazepine, amitriptyline, and placebo.16 When compared to placebo, both pregabalin and gabapentin were associated with a greater incidence of adverse effects. However, there was no significant difference in rates of adverse reactions between pregabalin and gabapentin. Despite the similarities in the safety profile of both gabapentinoids, careful monitoring should still be exercised given their increasingly recognized risk of respiratory depression, particularly when combined with opioids. The absolute risk for respiratory depression is low when gabapentin or pregabalin is given without concurrent CNS depressants.17 Similarly, clinicians should remain up to date with the potential risks of gabapentinoids given recent observational data suggesting increased cardiovascular and thromboembolic risks associated with gabapentinoid use.18
What I do now
Considering the pharmacokinetic and pharmacodynamic differences between gabapentin and pregabalin, I now advocate for deprescribing gabapentin when patients do not achieve adequate pain relief at 600 mg per dose, cumulating to a daily dose of 1800 mg. Evidence suggests that doses beyond 1800 mg per day do not provide additional benefit and carry an increased risk of adverse effects. Instead, I consider pregabalin as a substitute for gabapentin in patients with inadequate pain control rather than further dose escalations. Studies suggest using a 6:1 conversion ratio when converting gabapentin to pregabalin.19 With regards to drug costs, the availability of generic brand formulations of pregabalin offers ways to circumvent its higher costs relative to gabapentin. Understanding the ceiling dose of gabapentin allows me to more effectively treat my patients’ pain by switching to pregabalin or an alternate agent, when dose escalation is unlikely to provide any additional benefit.
Figure 1. Algorithm for assessment and approach to utilizing gabapentin and pregabalin in chronic neuropathic pain
AED = antiepileptic drug; Botox = Botulinum toxin A; SNRI = serotonin-norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant
Additional resources on the management of neuropathic pain
- This reference explores non-pharmacological options for neuropathic pain management: British Columbia Ministry of Health. Managing patients with pain in primary care – part 1. BC Guidelines. 2022. Accessed March 27, 2024. (View PDF)
- This reference explores pharmacological agents for neuropathic pain management: British Columbia Ministry of Health. Managing patients with pain in primary care – part 2. BC Guidelines. 2022. Accessed March 27, 2024. (View PDF)
- This summary provides NNTs for diabetic neuropathy and postherpetic neuralgia, suggesting slight benefit for pregabalin over gabapentin. However, pregabalin had a lower NNH compared to gabapentin with regards to adverse reactions: British Columbia Ministry of Health. Medications for neuropathic pain newsletter. Government of British Columbia. December 2018. Accessed March 27, 2024. (View PDF)
- This clinical guideline supports the use of gabapentinoids as well as explores other pharmacological and non-pharmacological modalities for neuropathic pain management: Korownyk CS, Montgomery L, Young J, et al. PEER simplified chronic pain guideline: management of chronic low back, osteoarthritic, and neuropathic pain in primary care. Can Fam Physician. 2022;68(3):179-190. doi:10.46747/cfp.6803179. (View)
References
- McCarberg BH, Billington R. Consequences of neuropathic pain: quality-of-life issues and associated costs. Am J Manag Care. 2006;12(9 Suppl):S263-S268. (View PDF)
- daCosta DiBonaventura M, Cappelleri JC, Joshi AV. A longitudinal assessment of painful diabetic peripheral neuropathy on health status, productivity, and health care utilization and cost. Pain Med. 2011;12(1):118-126. doi:10.1111/j.1526-4637.2010.01012.x (View PDF)
- van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies [published correction appears in Pain. 2014 Sep;155(9):1907]. Pain. 2014;155(4):654-662. doi:10.1016/j.pain.2013.11.013. (View article with UBC or view correction with UBC)
- Moulin D, Boulanger A, Clark AJ, et al. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res Manag. 2014;19(6):328-335. doi:10.1155/2014/754693. (View PDF)
- Mu A, Weinberg E, Moulin DE, Clarke H. Pharmacologic management of chronic neuropathic pain: review of the Canadian Pain Society consensus statement. Can Fam Physician. 2017;63(11):844-852. (View PDF)
- Wiffen PJ, Derry S, Bell RF, Rice ASC, Tölle TR, Phillips T, et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6(6):CD007938. doi:10.1002/14651858.CD007938. (View PDF)
- Health Canada. Summary basis of decision – Lyrica – Health Canada. Government of Canada. 2016. Updated July 14, 2021. Accessed March 26, 2024. (View)
- Taylor CP. The biology and pharmacology of calcium channel alpha2-delta proteins Pfizer Satellite Symposium to the 2003 Society for Neuroscience Meeting. Sheraton New Orleans Hotel, New Orleans, LA November 10, 2003. CNS Drug Rev. 2004;10(2):183-188. doi:10.1111/j.1527-3458.2004.tb00012.x. (View)
- Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010;49(10):661-669. doi:10.2165/11536200-000000000-00000. (View with UBC)
- Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-173. doi:10.1016/S1474-4422(14)70251-0. (View PDF)
- Neurontin (gabapentin). US Food and Drug Administration. Updated October 2017. Accessed March 27, 2024. (View PDF)
- Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev. 2009;(3):CD007076. doi:10.1002/14651858.CD007076.pub2. (View PDF)
- Ghayur MN. Potential adverse consequences of combination therapy with gabapentin and pregabalin. Case Rep Med. 2021;2021:1-4. doi:10.1155/2021/5559981. (View PDF)
- Devi P, Madhu K, Ganapathy B, Sarma G, John L, Kulkarni C. Evaluation of efficacy and safety of gabapentin, duloxetine, and pregabalin in patients with painful diabetic peripheral neuropathy. Indian J Pharmacol. 2012;44(1):51-56. doi:10.4103/0253-7613.91867. (View)
- Cao X, Shen Z, Wang X, Zhao J, Liu W, Jiang G. A meta-analysis of randomized controlled trials comparing the efficacy and safety of pregabalin and gabapentin in the treatment of postherpetic neuralgia. Pain Ther. 2023;12(1):1-18. doi:10.1007/s40122-022-00451-4. (View PDF)
- Tong C, Zhengyao Z, Mei L, Dongpo S, Qian H, Fengqun M. Pregabalin and gabapentin in patients with spinal cord injury-related neuropathic pain: a network meta-analysis. Pain Ther. 2021;10(2):1497-1509. doi:10.1007/s40122-021-00302-8. (View PDF)
- Bykov K, Bateman BT, Franklin JM, Vine SM, Patorno E. Association of gabapentinoids with the risk of opioid-related adverse events in surgical patients in the United States. JAMA Netw Open. 2020;3(12):e2031647. doi:10.1001/jamanetworkopen.2020.31647. (View)
- Pan Y, Davis PB, Kaebler DC, Blankfield RP, Xu R. Cardiovascular risk of gabapentin and pregabalin in patients with diabetic neuropathy. Cardiovasc Diabetol. 2022;21(1):170. doi: 10.1186/s12933-022-01610-9. (View PDF)
- Toth C. Substitution of gabapentin therapy with pregabalin therapy in neuropathic pain due to peripheral neuropathy. Pain Med. 2010;11(3):456-465. doi:10.1111/j.1526-4637.2009.00796.x (View)
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What is the relative cost differential between gabapentin and pregabalin? Is there a difference between adverse effects relative to acetaminophen or other less toxic medications? Anticonvulsants increase suicidality as does chronic pain. What are the risks of suicide with use of an anticonvulsant in this setting?
The Tmax (maximum plasma concentration) of gabapentin occurs about 2-3 hours after a dose. (https://pdf.hres.ca/dpd_pm/00047015.PDF)
The Tmax for pregabalin varies from about 1-3 hours after a dose, depending on it is delayed by food. (https://pdf.hres.ca/dpd_pm/00070660.PDF)
By 2005, it was shown that the peak effect of a single dose of gabapentin for pain from singles occurs by about 2-3 hours. (https://pubmed.ncbi.nlm.nih.gov/16087911/; doi: 10.1212/01.wnl.0000168259.94991.8a.)
Both drugs have a small probability of benefit, but it’s a shame that we don’t know from randomized clinical trials the probability that a person who is not helped meaningfully by gabapentin could be helped meaningfully by pregabalin or any other drug.
Can the authors comment on the their experience getting special authority exemption for pregabalin in similar clinical scenarios? Cost/drug coverage will be the largest barrier to changing my practice.
The Therapeutics Initiative has spent time working through the evidence for gabapentin and pregabalin and tackling the issue of the presence/absence of a dose response. We agree with some of your points (e.g. ceiling dose for gabapentin) but have different opinions on others (e.g. we do believe there is a ceiling dose for pregabalin whereas you suggest there isn’t).
If you are interested, here are links to our work in this area:
https://www.ti.ubc.ca/2022/02/27/134-finding-the-lowest-effective-dose-for-non-opioid-analgesics/
https://www.ti.ubc.ca/2019/02/19/117-gabapentin-and-pregabalin-are-high-doses-justified/
BC prescribers can also register for our Portrait to get information on their prescribing habits for these medications compared to their colleagues and compared to our interpretation of what is best evidence:
https://www.ti.ubc.ca/2023/01/13/portrait-pain/
Thanks for bringing attention to an important issue.
Regarding resource #3 from the BC Provincial Academic Detailing Service (PAD) mentioned above: “This summary provides NNTs for diabetic neuropathy and postherpetic neuralgia, suggesting slight benefit for pregabalin over gabapentin. However, pregabalin had a lower NNH compared to gabapentin with regards to adverse reactions”
Please note, that the intent of our document was not to suggest that pregabalin had a slight benefit over gabapentin, since the NNT’s quoted were from 2 separate Cochrane reviews – each comparing drug (gabapentin or pregabalin) to placebo, not each other (references: Cochrane systematic reviews CD007938 and CD007076). Also, the pregabalin 2009 Cochrane review (CD007076) was updated in 2019, and so we published an appendix with the updated NNT’s: https://www2.gov.bc.ca/assets/gov/health/practitioner-pro/provincial-academic-detailing-service/medications-neuropathic-pain-appendix.pdf. “Compared to the 2009 Cochrane review, the NNTs and NNHs for painful diabetic neuropathy reflect a decrease in the estimate of the numbers of responders to pregabalin 300 mg as well as fewer people discontinuing due to adverse events. Compared to the 2009 review, NNTs and NNHs remain similar for post herpetic neuralgia. Estimates for patient’s impression of change (much or very much improved) are relatively unchanged (NNTs range from 4 to 6 across doses and indications).”
The Therapeutics Initiative released a review of gabapentin and if I recall correctly it came to the conclusion that Gabapentin doses greater than 900mg/day seldom have increased benefit, but more side effects on higher doses. They recommend a usual ceiling dose of 900mg/day rather than this review that suggested an 1800mg ceiling dose. Same message overall, more doesn’t equal “better”, but clarity around the 900mg vs 1800mg would be beneficial.
Thank you.
Some good advice based on new evidence that I am not familiar with.
Response to Barry Campbell:
Thank you for your comment, Barry. The approximate drug cost for a 300 mg dosage of gabapentin is $0.11 per pill, whereas a 75 mg dosage of pregabalin is $0.33 per pill. Regarding the adverse effects of other analgesics like acetaminophen and NSAIDs, it is difficult to comment definitively because different medications have different side effect profiles. Safety considerations also depend on patient-specific factors such as age and comorbidities. Therefore, this would be very individual-dependent, even more so within something as intricate as chronic pain, suicidality, and medication use.
Response to Thomas L. Perry:
Thank you for your comment, Thomas. We agree that there is currently a lack of data comparing gabapentin and pregabalin head-to-head. We can only extrapolate and make an educated clinical assessment and decision based on clinical response, as well as on what we know about the pharmacology, pharmacokinetics, and pharmacodynamics of these drugs. A RCT examining pregabalin versus gabapentin would be very helpful.
Response to Oona Hayes:
Thank you for your comment, Oona. Special authority is very patient-specific since for these indications, approval is assessed on a case-by-case basis. Therefore, we have provided suggestions in our article to help address the costs of pregabalin. Regarding drug costs, the availability of generic formulations of pregabalin offers ways to circumvent its higher costs relative to gabapentin.
Response to Aaron M Tejani:
Thank you for your comment and great discussion, Aaron. We appreciate and value the TI’s work in examining the evidence for gabapentin and pregabalin. It is great to see that we agree on many important clinical points.
Response to Cristi Froyman:
Thank you for clarifying and providing an update to the PAD resources used, Cristi!
Response to Randy Holmes:
Thank you for your comment, Randy. We agree with the TI on the message that more is not necessarily better, but we also acknowledge that there are other views and opinions on where this threshold may be.
Response to Kelly Chu:
Thank you for your comment, Kelly. We hope you found our article helpful and insightful.