Therapeutic considerations of gabapentin versus pregabalin in treating chronic neuropathic pain

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

1. 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)
2. 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)
3. 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)
4. 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

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3. 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)
4. 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)
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6. 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)
7. Health Canada. Summary basis of decision – Lyrica – Health Canada. Government of Canada. 2016. Updated July 14, 2021. Accessed March 26, 2024. (View)
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Therapeutic Considerations of Gabapentin Versus Pregabalin in Treating Chronic Neuropathic Pain

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