Newer Isn’t Always Better! Gabapentin vs. Pregabalin for Chronic Sciatica

Author(s)
Austin Morgan, PharmD
Frank Fanizza, PharmD

Reviewed By
Dale Dong, PharmD
Michael Petrick, PharmD, BCACP
Patricia L. Poole, PharmD, BCPS

Citation
Robertson K, Marshman LAG, Plummer D, Downs E. Effect of Gabapentin vs Pregabalin on Pain Intensity in Adults With Chronic Sciatica: A Randomized Clinical Trial. JAMA Neurol. 2019; 76: 28-34.

The Problem

 

“I can’t live with this pain.” “I don’t want to get addicted to one of those opioids.” “I have a high deductible insurance plan so I need something affordable.” Sound familiar? Sciatica is a subset of neuropathic pain which can be particularly frustrating for patients and difficult to manage. With a lack of evidence to guide treatment and opioid use becoming increasingly under the microscope, data supporting the use of alternative pain regimens are needed. Gabapentin (GBP) and pregablin (PGB) are GABA analogs often used to treat sciatic pain, but is one superior to the other? Pregabalin is newer and available as a branded product only, but is it more effective than generically available GBP?

 

What’s Known

 

While acute pain syndromes have relatively well-defined treatment guidelines, chronic pain management remains something of an art form. During our lifetime, a majority of us (up to 84% of the population in some estimates) will experience low back pain and this results in significant personal and societal burden.¹ Sciatica, a lumbosacral radiculopathy with sciatic nerve involvement, is the cause of approximately five percent of low back pain cases, but the lifetime incidence ranges from 13-40%.² Sciatica is characterized by pain originating in the lower back and radiating down the posterior portion of one leg causing a burning, stinging, or sharp pain sensation.  Some patients also experience paraesthesias and numbness.³ Patient with chronic sciatica (CS) have persistent symptoms despite treatment for at least three months.

 

Limited data exist and evidence-based treatment recommendations for CS are lacking. The American Pain Society recommends non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen first-line for lower back pain. They also provide a grade B recommendation for GBP in chronic radicular pain, but not for sciatica specifically.⁴ The NICE-UK guideline recommends antidepressants or anticonvulsants, including GBP and PGB as first-line, albeit off-label, treatments for neuropathic pain syndromes based on a systematic review and meta-analysis.^5-7 Opioid analgesics, topical products including capsaicin and lidocaine, botulinum toxin, and other anticonvulsants such as topiramate are alternatives and might be considered by specialty settings, like pain clinics.

 

Despite these guideline recommendations, a 2012 systematic review evaluating trials solely involving sciatica found the evidence to be of low-quality for all treatment modalities, including anticonvulsants and antidepressants.⁸ More recently, a 2018 review of anticonvulsants used for radicular pain found moderate- to high-quality evidence that they were ineffective and increased risk of adverse events. Although GBP and PGB are commonly prescribed medications in the United States to treat conditions like CS, to date, there have been no head-to-head trials comparing their efficacy or safety.⁹

 

What’s New

 

Investigators at a single neurosurgery clinic in Australia conducted a prospective, double-blind, randomized, crossover study. Eligible patients were 18 years or older with unilateral CS. Patients could not have prior exposure to GBP or PGB byt were permitted to continue their home medication regimens, including OTC and prescription analgesics.

 

Participants were randomized to one of two treatment sequences for a total follow-up of 17 weeks (Table 1). Pregabalin was dosed twice daily whereas GBP was dosed three times daily. In order to maintain blinding, patients taking PGB received a placebo once daily. The primary outcome of the study was leg pain intensity using the visual analog scale (VAS). A change of 1.5 on the 10 point scale was considered clinically important. The secondary outcome was disability measured by the Oswestry Disability Index (ODI) questionnaire. A change of 10 on the 100 point scale was considered clinically important.

Table 1: Treatment Schedule and Dosing

 

Schedule	Arm A (n=8)	Arm B (n=10)
Week 1-4	Gabapentin (GBP) initiation and titration*	Pregabalin (PGB) initiation and titration^
Week 5-8	Maintenance of maximally tolerated GBP dose	Maintenance of maximally tolerated PGB dose
Week 9	Washout	Washout
Week 10-13	PGB initiation and titration^	GBP initiation and titration*
Week 14-17	Maintenance of maximally tolerated PGB dose	Maintenance of maximally tolerated GBP dose

^{* The starting dose of GBP was 400 mg once daily for one week. Gabapentin was titrated to a maximum of 800 mg three times daily}

^{^ The starting dose of PGB was 150 mg once daily for one week. Pregabalin was titrated to a maximum of 300 mg twice daily}

 

Twenty patients were randomly assigned to one of the treatment sequences and 18 were included in the final analysis. The mean age of study participants was 57 years old and a slight majority were male. The use of other analgesics was common with many patients taking acetaminophen + codeine (56%), an opioid (33%), and/or an NSAID (17%). All 18 participants reached the maximum target dose for the study medications.  Only one patient requiring a dose reduction due to an adverse drug event (ADE).

 

When compared to baseline, a statistically significant mean reduction in leg pain intensity based on the VAS was observed for GBP (-1.72; p<0.001) and PGB (-0.94; p=0.002) over the 8 week treatment periods. Regardless of treatment sequence, GBP was significantly more effective at reducing leg pain intensity when compared to PGB (-0.78; p=0.035) (Table 2). Both GBP and PGB led to statistically significant mean reductions in disability based on the ODI questionnaire (-10.66; p<0.001, -8.78; p<0.001 respectively). A significant difference for disability reduction was not observed between GBP and PGB (p=0.63). However, gabapentin was the only treatment to result in both statistically and clinically significant reductions for both outcomes measured.

 

Twelve of 18 patients (67%) experienced an ADE during the study. Pregabalin was associated with a significantly higher number of ADEs compared to GBP (31 vs 7, p=0.002). Nausea, vomiting, and headache were the most common side effects of PGB (39% of patients) while drowsiness and sedation were the most common side effects of GBP (17% of patients). Treatment sequence had an effect on ADEs with respect to PGB, as ADEs occurred twice as frequently when PGB was prescribed first (Table 2).

 

Table 2: Treatment Period Comparisons: Gabapentin (GBP) and Pregabalin (PGB)

 

Description	GBP to PGB (n=8)	PGB to GBP (n=10)	P-value*
Visual Analog Scale, mean reduction (range)
Drug 1 x 8 weeks	1.35 (0.5-2.9)	1.43 (0.1-4.2)	0.62
Drug 2 x 8 weeks	0.33 (0-0.7)	2.01 (0.6-5.5)	0.01
P-value*	<0.01	0.34	NA^
Oswestry Disability Index, mean reduction (range)
Drug 1 x 8 weeks	11.25 (0-30)	12.4 (2-28)	0.31
Drug 2 x 8 weeks	4.25 (0-12)	10.2 (0-30)	0.24
P-value*	0.14	0.36	NA
Adverse Events, no.
Drug 1 x 8 weeks	3	21	NA
Drug 2 x 8 weeks	10	4	NA

^{* P-value <0.05 considered statistically significant}

^{^ NA=not available}

 

Our Critical Appraisal

 

A strength of this study included its randomize crossover design with two (blinded) active treatments. Based on the half-lives of GBP and PGB, a one-week washout period was appropriate before starting the second medication in the treatment sequence. The study utilized a single center, which can be seen as both a strength and a limitation. Since one neurosurgeon was involved in the screening and evaluation process, there was consistency in patient recruitment. However, the use of a single center limits its generalizability. The outcome measures used in the study were appropriate.  Both the VAS and ODI are validated for chronic pain, although not specifically validated in patients with CS.^10,11 Furthermore, thresholds for clinically important differences for the primary and secondary outcomes were established a priori.  This strengthens the authors’ claim that GBP led to clinically important reductions in leg pain intensity as well as disability.

 

During the prespecified interim analysis, GBP was found to be superior to PGB, resulting in the early termination of the study. Thus, the sample size was rather small and increases the risk of a type 1 error. Additionally, long term efficacy of these agents cannot be determined as patients were treated for a total of eight weeks and only four weeks at maximum tolerated dose. Confounding is also a problem as patients were allowed to continue pre-study medications, including opioid analgesics. While this is likely what occurs in “real life”, it’s harder to attribute improvements in pain and disability solely to GBP or PGB. Moreover, the authors do not provide information regarding the continued use or dosages of the background analgesics.

 

The doses of GBP and PGB used in this study are not consistent with the maximum recommended doses. The maximum recommended dose of pregabalin is 600 mg per day – and this was the target dose in this study.¹² However, the target dose of GBP in this study was 2.4 g, which is below the maximum recommended daily dose of 3.6 g.¹³ Thus the selected doses may have reduced the efficacy of GBP but may also explain the higher rate of ADEs with PGB. 

 

The efficacy of GBP in this study is similar to previous reports. In two prior open-label studies assessing GBP as monotherapy and as an add-on to amitriptyline, GBP was found to have a clinically significant benefit on leg pain intensity and disability in patients with CS. Daily doses of GBP in these studies ranged from 900 mg to 1800 mg.^14,15 In the presented study, PGB resulted in statistically, but not clinically, significant reductions in leg pain intensity and disability. These results differ from a previously reported randomized controlled trial of 207 patients in which PGB did not significantly improve leg pain intensity when compared to placebo over an eight-week treatment period. However, it should be noted that the majority of patients in the study had acute sciatica, not CS.¹⁶

 

The Bottom Line

These data are the most compelling evidence published to day. We recommend the use of GBP as the preferred add-on agent to background analgesia in patients with CS. Not only is it less expensive, GBP appears to be superior to PGB in terms of efficacy and safety.

 

The Key Points

1. Lifetime incidence of sciatica approaches 40% but there is limited data regarding the effectiveness of commonly prescribed treatments.
2. A recently published 17-week single-center, blinded, crossover study found that gabapentin was superior to pregabalin in terms of reducing leg pain intensity and had fewer adverse effects.
3. Study limitations hinder broad application of these findings but represent the best available evidence regarding the treatment of chronic sciatica.
4. For patients with chronic sciatica not optimally managed on other analgesics, gabapentin at moderate doses is a better choice than pregabalin.