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Substitution of Gabapentin Therapy with Pregabalin Therapy in Neuropathic Pain due to Peripheral Neuropathy

Cory Toth BSc, MD, FRCPC
DOI: http://dx.doi.org/10.1111/j.1526-4637.2009.00796.x 456-465 First published online: 1 March 2010


Objective. To determine the utility of substitution of pregabalin (PGB) for gabapentin (GBP) therapy in the relief of neuropathic pain (NeP) in patients with peripheral neuropathy (PN).

Design. A cohort study was performed examining PGB substitution in patients who were GBP responders (≥30% NeP relief on a visual analog scale [VAS]) or GBP nonresponders after prolonged GBP use, with further comparison to patients receiving continuous GBP therapy.

Setting. Patients with PN and related NeP requiring GBP therapy were evaluated in a tertiary care neurological clinic at 0, 6, and 12 months.

Outcome Measures. Pain severity (Visual Analog Score [VAS]) was the primary outcome measure, while quality of life (European Quality of Life - 5 Domains [EQ-5D] and EQ-5D VAS) and occurrence of adverse events were secondary outcome measures.

Results. Both GBP responder and nonresponder groups had additional NeP relief of about 25% following substitution of PGB after 6 and 12 months, while improved EQ-5D VAS was identified in the GBP nonresponder group. There were no serious adverse events for either medication, while GBP nonresponders discontinued PGB in more than 30% of cases due to inefficacy or adverse events.

Conclusions. Randomized, controlled, blinded head-to-head studies of GBP and PGB have not been published. The results of this open-label assessment of PGB substitution for GBP suggest that PGB may provide additional pain relief and possible improvement in quality of life above that received by GBP use in patients with NeP due to PN.

  • Peripheral Neuropathy
  • Neuropathic Pain
  • Gabapentin
  • Pregabalin


Peripheral neuropathy (PN) is a common condition [1] found in about 2.4% of the population, and in up to 8% in the elderly population (older than 80 years of age) [2]. Patients with PN frequently present with a variety of symptoms that may include numbness, paresthesias, tingling, incoordination, motor deficit, and also neuropathic pain (NeP) [1]. Other significant symptoms may accompany NeP such as allodynia, dysthesia, or hyperesthesia [3]. The prevalence of NeP may be as high as 50% of all patients with PN, making this an under-recognized and possibly undertreated feature of PN [4–7]. Regardless of its cause, NeP is associated with disability, depressed quality of life (QOL), and other associated conditions such as sleep disturbance and mood disorders [8–12].

In greater than 85% of patients presenting with NeP due to PN, pharmacotherapy is necessary for pain management [7]. Despite the heterogeneous availability of pharmacotherapies [13], the selection of one medication to assist with NeP relief is difficult and can only be supported by using existing guidelines for management of NeP due to the paucity of head-to-head agent studies available [13,14]. The anticonvulsants gabapentin (GBP) and pregabalin (PGB) are often considered first-line agents for the management of NeP irrespective of cause [13]. Both agents modulate the alpha-2-delta subunit of the voltage-gated calcium channel in order to relieve NeP [15]. However, the newer agent, PGB, may be easier to administer, may have a faster onset of action, has nonsaturable linear intestinal uptake, and may be a more potent inhibitor of neurotransmitter release at the calcium channel than GBP [16]. Unfortunately, in the absence of expensive head-to-head comparison studies, comparisons between the efficacy and tolerability of GBP and PGB are difficult to achieve.

The aim of this study was to determine the potential role of replacing GBP use with PGB therapy for NeP due to PN, both in patients considered to have responded to GBP therapy or those who did not. I hypothesized that PGB therapy would improve NeP relief and permit better tolerability than GBP in the management of NeP due to PN.

Materials and Methods

Patient Assessment

From September 2005 until June 2008, patients with a primary diagnosis of PN and related NeP referred to the Neuromuscular and Neuropathic Pain Clinics at the University of Calgary were prospectively identified. All patients enrolled within these clinics provide informed consent for ethically approved assessment of their clinical outcomes during all management conducted at these clinics (Centre for Advancement of Health, University of Calgary), but there was no specific consent obtained for switching of medications, which was considered as standard medical care. Patients with PN and associated NeP were asked, “Do you have pain or discomfort over your feet and legs on a near-daily basis for more than 6 months?” All patients who responded positively with a clinical picture consistent with NeP and presence of PN were deemed to have NeP as a complicating feature of their PN. The douleur neuropathique 4 questions [DN4] questionnaire [6], with good sensitivity (83%) and specificity (90%), was used to identify clinical likelihood of NeP presence—only those patients with a score of ≥4 were considered eligible.

Each patient was assessed clinically using the Toronto Clinical Scoring System (TCSS) [17,18], a simple validated screening tool for diabetic PN (DPN) based upon history and examination emphasizing sensory deficits as compared with other measurements of PN severity; a higher TCSS score indicating greater clinical severity is significantly associated with greater pathological abnormality of sural nerve fiber density [17]. Although designed for studies of DPN, the TCSS has been used to quantify more generalized forms of neuropathy [7]. PN was defined to be present if the patient was found to have a TCSS score of ≥3 along with the mandatory presence of sensory abnormalities on distal leg examination. Patients were excluded from further consideration if another condition other than PN such as a rheumatological disorder or peripheral vascular disease was present in the lower extremities. Likewise, patients with symptoms of pain only present during exertion were excluded due to confounding peripheral vascular disease, or the possibility of neurogenic claudication. In cases of more than one pain syndrome, patients were allowed to participate only when they could discriminate between sources of overall chronic pain, otherwise they were excluded from further assessment.

PN Assessment

During the assessment of their PN, investigation for the most likely etiology of PN was performed using a combination of clinical assessment with a neuromuscular neurologist, laboratory investigations, and electrophysiological testing in all cases. Complete standardized neurological and electrophysiological examinations were carried out in all patients. All patients had routine and standard blood work to examine for possible causes of their PN (complete blood count, electrolytes, urea, creatinine, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltranspeptidase, alkaline phosphatase albumin, total bilirubin, international normalized ratio, thyroid stimulating hormone, 2 hours glucose tolerance test, hemoglobin A1C, cobalamin, erythrocyte sedimentation rate, antinuclear antibody, extracted nuclear antibody testing, serum protein electrophoresis, rheumatoid factor, vitamin B12 levels, fasting methylmalonic acid, and fasting homocysteine levels).

Substitution of PGB for GBP and Follow-Up

Following their assessment, patients were offered pharmacotherapy as part of their pain management protocol. All patients starting on GBP during that time were assessed as a part of this clinical care study. During follow-up visits after the availability of PGB in Canada (starting approximately September 2005), all patients already using GBP as monotherapy were offered the choice of replacing their GBP with PGB. It was necessary that each patient use their maximum tolerated dose of GBP for a minimum of 2 weeks, with overall GBP use for a minimum of 4 weeks, before substitution would be considered as part of this study. Adverse events were not considered as a reason to switch to PGB use; only perceived inefficacy was permitted as a reason for switching. Due to limitations of medical insurance coverage, not all patients have the option to change their pharmacological management to PGB, and these patients were excluded (even though some patients chose to pay for PGB outside of their insurance coverage) due to the possibility of other financial decisions acting as a confounder in this study. All patients using multiple therapies for NeP including GBP were also excluded. At this initial time point (0 months), immediately before switching to PGB, pain visual analog scales (VASs) and QOL scores were obtained.

Comparison was made between the groups switched to PGB and a a cohort group of patients with PN and related NeP receiving only GBP without a switch to PGB, the GBP continuous group, which was followed in identical manner. This cohort consisted of patients who were unable to switch their GBP therapy to PGB therapy due to financial constraints or patients who chose to not switch GBP therapy for personal reasons.

For those patients choosing to substitute PGB for GBP, a direct switch was performed overnight, with the GBP stopped after the nighttime dose, followed by commencement of PGB the following morning using a conversion table of the author's creation, listed in Table 1. All patients were contacted via telephone 1 week after the substitution of medication to determine the presence of any new or intolerable adverse events. Additional clinical follow-up visits occurred after 6 and 12 months for each patient. For every patient visit, the primary outcome consisting of the degree of NeP was evaluated using VAS provided by a line bisection score with a undenoted 10 cm line between anchors of “no pain” on the left and “worst possible pain” at the right, making values between 0 and 10 with nonintegers eligible. It was requested that each patient provide the VAS based only upon their NeP as a mean value over the last 24 hours, excluding other sources of pain, if present. The VAS was scored by line measurement in each case to the nearest millimeter. The last available data points were used for calculation of VAS in the case of patient withdrawal from the study.

View this table:
Table 1

Dose equivalencies of Gabapentin and Pregabalin for the substitution protocol

Daily Dose of Gabapentin Pre-Switch (mg/day)Daily Dose of Pregabalin (mg/day) Post-Switch (Using Twice Daily Dosing)
2,700 or higher600
  • All substitutions were performed using an overnight switch of the medications. Doses of 150, 300, and 600 mg were prescribed as daily dosing with half in the morning and half in the evening. For 225 mg dosing, 75 mg was prescribed in the morning and 225 mg was prescribed in the evening. For 450 mg, 150 mg was prescribed in the morning and 300 mg was prescribed in the evening.

Secondary outcomes consisted of health status and QOL assessments using the European Quality of Life - 5 Domains (EQ-5D), which were completed before the start of GBP treatment, at the completion (or continuation) of GBP treatment, and following 6 and 12 months of PGB or monitored GBP treatment. The EQ-5D has two sections, with the first section examining the health state in five dimensions: mobility, self-care, usual activities, pain/complaints, and anxiety/depression. The health status profile is converted into a single utility score using a scoring algorithm based upon interviews performed with general public members from a UK population [19] with utility scores ranging from −0.594, indicating serious problems in all dimensions, to 1, indicating no problems at all. The second section, the EQ-5D VAS measures the perception of the patient for their overall health on a 100-mm VAS, with zero indicating worst imaginable health state and 100 indicating the best imaginable health.

Tolerability and Adverse Events

Standardized forms listing potential adverse events were used to identify both tolerable and intolerable adverse events during or prior to follow-up visits; all adverse events leading to discontinuation of medication were recorded. An adverse event was defined as any noxious, unintended, and unexpected response suspected to have a causal relationship with the medication used. A serious adverse event was defined as any life-threatening reaction to pharmacotherapy that required in-patient hospitalization, additional urgent physician assessment, or resulted in persistent or significant disability. Patients were asked to identify any side events felt to be related to their medication. If pain relief was felt to be insufficient or if intolerable adverse events were felt to be limiting everyday activities, then patients were asked to consider a discontinuation or substitution to another medication, an increase in medication dose, or addition of a second medication for combination therapy. Adverse events were identified at each of the 0, 6, and 12 months follow-up time points. Clinical end points were continuance of PGB until the last follow-up time (12 months), or discontinuation/replacement of PGB, with similar time points used for patients receiving GBP.

Data Analysis and Ethical Considerations

The use of pharmacotherapy in this study was not performed using consent, but instead followed anticipated best possible clinical care, with the accumulated data examined based upon ethically approved follow-up procedures. Data were analyzed using unmatched analysis of variance (anova) testing between intervention groups and between time points. The baseline pain score prior to PGB substitution for GBP was used for comparison to later pain scores for patients using either GBP or PGB. Bonferroni corrections were applied for multiple comparisons between the three clinical groups. An “intent to treat” analysis was performed once patients were seen for follow-up at 6 months, with last observations carried forward in the case of lost follow-up, or discontinuation/replacement of PGB.


A total of 146 patients initiated and continued GBP as monotherapy and were prospectively identified as potential participants for this clinical care study (Figure 1), with a total of 77 patients that were either unable or unwilling to perform a switch to PGB, leading to a cohort group of patients receiving GBP consisting of 47 patients. Those patients with insufficient data who were lost to follow-up before their 6 months follow-up after PGB initiation were not known to discontinue PGB use and their response to PGB was unknown—therefore, no data were collected for these specific patients other than baseline data. A total of 17 patients who declined participation due to personal decision later elected to use PGB on their own outside of this study, without their data collected.

Figure 1

Summary of patient flow throughout study. PGB = pregabalin; GBP = gabapentin.

A total of 33 patients were deemed GBP responders based upon the relief of NeP they had achieved with its prior use for at least 4 weeks as monotherapy. An additional 36 patients were deemed GBP nonresponders based upon their inability to achieve at least 30% pain relief with its prior use as monotherapy for at least 4 weeks. In all cases, the reason for switching to PGB was a perceived inefficacy of GBP for pain relief. All of these 69 patients were switched to PGB in overnight fashion as described and these patients were followed clinically at 6- and 12-month intervals. A cohort group of 47 patients with PN and NeP consisting of patients receiving continuous GBP who were either unable or unwilling to switch to PGB therapy were monitored in identical fashion throughout the 12 months follow-up period. These cohort patients had similar clinical parameters as with GBP responders and GBP nonresponders (Table 2). There were withdrawal rates ranging from 3% to 19% in each group, highest in GBP nonresponders (Figure 1), while no withdrawals occurred after 6 months of follow-up in any of the three cohorts.

View this table:
Table 2

Clinical features of the cohorts of patients deemed to be gabapentin responders or nonresponders, or receiving gabapentin continuously

Clinical FeatureGabapentin Responders (n = 32)Gabapentin Nonresponders (n = 29)Gabapentin Continuous Use Cohort Group (n = 40)
Age of diagnosis of PN (years), mean ± SD57.3 ± 9.254.4 ± 9.858.4 ± 11.1
Sex of patients (female)21 (66%)20 (69%)27 (68%)
Age of onset of NeP symptoms (years), mean ± SD57.8 ± 8.353.8 ± 10.057.7 ± 10.2
Age of initiation for gabapentin (years), mean ± SD59.5 ± 11.057.0 ± 11.260.1 ± 10.3
Etiology of PN
  Diabetic PN111215
  Monoclonal gammopathy of uncertain significance434
  Cobalamin (Vitamin B12) deficiency123
  Idiopathic PN101014
  Autoimmune conditions523
  Multiple myeloma101
TCSS (mean ± SD)11.8 ± 3.212.2 ± 2.712.3 ± 2.5
Pain VAS pre-gabapentin7.9 ± 1.17.8 ± 0.87.7 ± 0.7
EQ-5D utility score pre-gabapentin0.17 ± 0.170.12 ± 0.140.13 ± 0.11
EQ-5D VAS pre-gabapentin39.1 ± 13.238.5 ± 12.738.0 ± 12.2
VAS post-gabapentin4.9 ± 0.9 *6.6 ± 1.05.7 ± 0.8 *
% Improvement in VAS post-gabapentin38% ± 7% *†‡15% ± 9%26% ± 8%
Gabapentin dose prior to substitution of pregabalin (mg/day)2,135 ± 7222,246 ± 6252,195 ± 565
Adverse effects of gabapentin use
  Sedation6 (19%)16 (55%)13 (33%)
  Dizziness (light-headedness)6 (19%)12 (41%)10 (25%)
  Peripheral edema4 (13%)4 (14%)4 (10%)
  Fatigue1 (3%)02 (5%)
  Dry mouth02 (6%)2 (5%)
  Other001 (3%)
  Number of patients with adverse effects due to gabapentin12 (38%) 24 (83%)18 (45%)
Serious adverse effects due to gabapentin000
Duration of time using gabapentin (months)11.6 ± 5.0 4.6 ± 1.510.9 ± 3.4
TCSS prior to pregabalin switch12.4 ± 3.912.3 ± 4.711.7 ± 3.9
EQ-5D utility score prior to pregabalin switch0.27 ± 0.110.19 ± 0.130.26 ± 0.11
EQ-5D VAS prior to pregabalin switch57.8 ± 13.2 *39.2 ± 11.648.1 ± 12.8
  • * Indicates that a significant difference using anova testing when comparing characteristics between pre-gabapentin use and post-gabapentin use time points.

  • Indicates that a significant difference upon anova testing for comparison between the gabapentin responder and gabapentin nonresponder groups.

  • Indicates that a significant difference upon anova testing for comparison between the gabapentin responder and gabapentin continuous use groups.

  • Bold type indicates a significant difference between groups in that row (P < 0.025). Data are represented as means ± SD.

  • TCSS = Toronto clinical neuropathy score; PN = peripheral neuropathy; VAS = visual analog scale; EQ-5D = European Quality of Life - 5 Domains.

GBP responders, GBP nonresponders, and continuous GBP patients were similar with respect to age, sex, severity of neuropathy, and the dose of GBP achieved (Table 2). Prior to GBP use, there were no differences between subsequent GBP responders and nonresponders with respect to VAS, TCSS, and EQ-5D scores (Table 2). However, GBP responders had a significant improvement of 38% in their VAS compared with 15% for nonresponders (Table 2) with initiation of GBP, as compared with 26% with continuous GBP patients. A greater EQ-5D VAS score was identified in GBP responders when compared with GBP nonresponders as well as the cohort group, although the EQ-5D health state scores were similar (Table 2). The duration of time for the use of GBP was significantly longer for GBP responders, but there was no difference in the maximum dose used for GBP (Table 2). GBP nonresponders had greater likelihood of adverse events related to GBP (Table 2). There was no significant difference between groups with respect to PGB dosage after substitution (Table 3). The dose of GBP in the cohort patients did not change significantly over time (Tables 3 and 4).

View this table:
Table 3

Clinical features of patients using pregabalin after 6 months of therapy who were considered to be gabapentin reponders or nonresponders

Clinical FeatureGBP Responders (n = 32)GBP Nonresponders (n = 29)GBP Continuous Use Cohort Group (n = 40)
PGB/GBP dose after substitution for GBP (mg/day) at 6 months389 ± 124405 ± 129N/A (GBP Dose 2235 ± 552)
Pain VAS3.4 ± 0.7 *†‡4.9 ± 0.95.8 ± 1.0
% Improvement in VAS since PGB initiation31% ± 12% *26% ± 10% *§−4% ± 9%
Adverse effects of PGB/GBP use after 6 months
  Sedation3 (9%)14 (48%)10 (25%)
  Dizziness (light-headedness)3 (9%)5 (17%)3 (8%)
  Peripheral edema2 (6%)2 (7%)5 (13%)
  Fatigue2 (6%)8 (28%)7 (18%)
  Dry mouth3 (9%)4 (14%)2 (5%)
  Other02 (7%)1 (3%)
  Number of patients with adverse effects due to PGB/GBP8 (25%) 22 (76%)12 (30%)
Serious adverse effects due to PGB/GBP000
  Number of patients discontinuing PGB/GBP06 (21%)4 (10%) Discontinued GBP
Reasons for discontinuing PGB/GBP use
  Sedation04 (14%)2 (5%)
  Dizziness (light-headedness)01 (3%)1 (3%)
  Inefficacy01 (3%)1 (3%)
TCSS12.7 ± 4.512.4 ± 5.012.0 ± 4.8
EQ-5D utility score0.39 ± 0.11 *0.32 ± 0.12 *0.25 ± 0.08
Change in EQ-5D utility score since PGB initiation+0.12 ± 0.14 +0.13 ± 0.10 §−0.01 ± 0.06
EQ-5D VAS64.1 ± 11.8 *†‡53.2 ± 10.7 *47.3 ± 10.1
Change in EQ-5D VAS since PGB initiation+6.3 ± 6.8 *+14.0 ± 10.6 *§−0.8 ± 5.8
  • * Indicates that a significant difference with anova testing when compared with the pre-PGB time point.

  • Indicates that a significant difference upon anova testing for comparison between the GBP responder and GBP nonresponder groups.

  • Indicates that a significant difference upon anova testing for comparison between the GBP responder and GBP continuous use groups.

  • § Indicates that a significant difference upon anova testing for comparison between the GBP non responder and GBP continuous use groups.

  • Bold type identifies significance within that category (P < 0.025). Data are represented as mean ± SD.

  • PGB = pregabalin; GBP = gabapentin; TCSS = Toronto clinical neuropathy score; VAS = visual analog scale; EQ-5D = European Quality of Life - 5 Domains; N/A = not available.

View this table:
Table 4

Clinical features of patients using pregabalin after 12 months of therapy who were considered to be gabapentin reponders or nonresponders

Clinical FeatureGBP Responders (n = 32)GBP Nonresponders (n = 29)GBP Cohort Group (n = 40)
PGB/GBP after substitution for GBP (mg/day) at 12 months426 ± 116434 ± 126N/A (GBP Dose 2280 ± 554)
Pain VAS3.6 ± 1.0 †‡5.0 ± 1.35.9 ± 1.1
% Improvement in VAS since PGB initiation27% ± 13% 24% ± 11% §−4% ± 7%
Adverse effects of PGB use
  Sedation3 (9%)15 (52%)10 (25%)
  Dizziness (light-headedness)3 (9%)6 (21%)3 (8%)
  Peripheral edema3 (9%)3 (10%)6 (15%)
  Fatigue3 (9%)8 (28%)7 (18%)
  Dry mouth4 (13%)4 (14%)2 (5%)
  Other02 (7%)1 (3%)
  Number of patients with adverse effects due to PGB/GBP9 (28%)24 (83%)13 (33%)
Serious adverse effects due to PGB/GBP000
Total number of patients discontinuing PGB/GBP0 8 (28%)5 Discontinued GBP
Reasons for discontinuing PGB/GBP use
  Sedation04 (14%)1 (3%)
  Dizziness (light-headedness)01 (3%)1 (3%)
  Peripheral edema01 (3%)0
  Fatigue001 (3%)
  Dry mouth000
  Inefficacy01 (3%)2 (5%)
TCSS12.8 ± 4.412.5 ± 5.212.4 ± 4.8
EQ-5D utility score0.37 ± 0.10 *†‡0.31 ± 0.16 *§0.23 ± 0.09
Change in EQ-5D utility score since PGB initiation+0.10 ± 0.06+0.12 ± 0.08−0.03 ± 0.05
Change in EQ-5D utility score since 6 months follow-up−0.02 ± 0.05−0.01 ± 0.06−0.02 ± 0.05
EQ-5D VAS60.5 ± 11.7 *†‡51.8 ± 10.6 *§45.1 ± 10.0
Change in EQ-5D VAS since PGB initiation+2.7 ± 6.5 †‡+12.6 ± 10.0 *§−3.0 ± 7.0
Change in EQ-5D VAS since 6 months follow-up−3.6 ± 5.1−1.4 ± 5.7−2.2 ± 5.5
  • * Indicates that a significant difference with anova testing when compared with the pre-PGB time point.

  • Indicates that a significant difference upon anova testing for comparison between the GBP responder and GBP nonresponder groups.

  • Indicates that a significant difference upon anova testing for comparison between the GBP responder and GBP continuous use groups.

  • § Indicates that a significant difference upon anova testing for comparison between the GBP non responder and GBP continuous use groups.

  • Bold type identifies significance within that category (P < 0.025). Data are represented as mean ± SD.

  • PGB = pregabalin; GBP = gabapentin; TCSS = Toronto clinical neuropathy score; VAS = visual analog scale; EQ-5D = European Quality of Life - 5 Domains; N/A = not available.

At 1 week after substitution of PGB for GBP, there were no intolerable adverse events noted in any of the GBP responders. Excessive sedation (3/29) and dizziness described as light-headedness (4/29) occurred in a minority of patients who were GBP nonresponders. There were no other noted difficulties in the week after medication substitution and the early occurring adverse effects did not lead to discontinuation in any patients.

Both GBP responders and GBP nonresponders had significant improvements in VAS for NeP after the substitution for both 6 and 12 months follow-up periods (Tables 3 and 4). There were no significant differences in the EQ-5D utility scores between GBP responders or GBP nonresponders, but GBP responders had an improved EQ-5D utility score when compared with GBP continuous group at both 6 and 12 months, while GBP nonresponders' EQ-5D utility score bested GBP continuous group at the 12 months period (Tables 3 and 4). The EQ-5D VAS improved for GBP nonresponders at 6 and 12 months after PGB initiation (Tables 3 and 4). GBP responders, who started with a higher EQ-5D VAS prior to switching to PGB, did not demonstrate benefit for the EQ-5D VAS (Tables 3 and 4). At 6 months, the PGB doses increased minimally in both GBP nonresponders and GBP responders, with a minimal change to GBP dosing also performed in the cohort group. At 12 months, there were slight declines in the EQ-5D VAS and utility scores for both GBP nonresponders and GBP responders when compared with the 6 months follow-up period.

Adverse events occurred in both groups of patients, as well as in cohorts, as identified during clinical follow-up after PGB substitution (Tables 3 and 4). Patients experiencing adverse effects due to PGB use were more common in the GBP nonresponder group, who also had a higher number of adverse effects due to GBP use than GBP responders (Tables 2–4). Of the 83% of GBP nonresponders who noted adverse events due to GBP, 23/24 (96%) of these patients also experienced adverse events due to PGB at final follow-up. There were no serious adverse effects noted in any group. After several months of use, GBP nonresponder group patients were more likely to discontinue their use of PGB, while no patients in the GBP responder group discontinued PGB (Tables 3 and 4).


In patients with PN and related NeP, further relief of NeP may be the most beneficial intervention to improve overall well-being and QOL. In this prospective study, the substitution of PGB for GBP was associated with improved pain relief and fewer adverse effects, particularly in the patient population that had already responded positively to GBP. Further improvements in NeP severity were accomplished in both groups of patients, although those patients who were GBP nonresponders may have had relatively better responses. Moreover, PGB use in either the GBP responder or nonresponder groups led to improved pain relief when compared with the GBP continuous group. Furthermore, improvements in EQ-5D VAS were identified for GBP nonresponders who switched to PGB. Even with discontinuation of PGB occuring in some patients in the GBP nonresponder group, there were still improvements in the EQ-5D VAS and utility scores. Finally, those patients noting adverse events or intolerabilty due to GBP (GBP nonresponders) also tended to have more adverse events with PGB, suggesting either heightened predisposition for adverse effects or genetic predispositions for adverse events with use of either or both of GBP and PGB. The reasons for this abundance of adverse events in the GBP nonresponder group are otherwise not obvious.

PGB, and its replacement of GBP in an acute manner, was generally well tolerated in these populations. Acute adverse events within a week of substitution were not identified in GBP responders, but were present in a minority of GBP nonresponders. Over time, PGB use was associated with more tolerable adverse effects in GBP responders, but was associated with intolerability and even discontinuation in a number of GBP nonresponders.

PGB has several potential advantages over GBP in patients experiencing NeP. The newer anticonvulsants, such as GBP and PGB, have fewer associated drug interactions; this is particularly important for more elderly patients with medical co-morbidities and other medication use [20]. One of the biggest problems with GBP use among clinicians is underdosing, although this was not a problem in the current study [21]. Suboptimal dosing of GBP below recommended dosing [20,22–25] can lead to inappropriate levels of pain relief and misconceptions of medication failure. The nonlinear pharmacokinetic profile of GBP may also contribute to potential difficulties with titration of a drug to an effective level while attempting to minimize adverse effects. The newer agent PGB has greater bioavailability and a linear pharmacokinetic profile when provided at dosages of 150–600 mg/day, making PGB an effective analgesic agent for the management of NeP associated with DPN and PHN [26–31]. Finally, PGB may have greater potency at the alpha-2-delta subunit protein of voltage-gated calcium channels than GBP [32].

There are definite limitations associated with this study. The main limitations are the inability to perform head-to-head comparisons for first-time therapy, and the unblinded status of patient assessments. Next, there is no optimal control group to compare with given the absence of placebo. A cohort group receiving continuous GBP dosing was used for comparison, but this group was unable to switch to PGB, and may have had negative perceptions about GBP's continued use given the lack of ability to switch to a “newer” medication. Those patients deemed GBP nonresponders may have had heightened expectations of pain relief with their “newer” and potentially improved medication. It is not possible to control for such variables without performing a randomized, double-blind, controlled study. Also, GBP responders had a longer duration of use of GBP than GBP nonresponders, likely due to positive response to efficacy of the therapy for pain relief in GBP responders; such longer duration of use may have influenced their later response to PGB in an uncertain manner. Although all patients were encouraged to use conservative measures to assist with NeP relief including aerobic forms of exercise, there was no ability to control for other nonpharmaceutical or over-the-counter pharmaceutical interventions. It must be considered that patients referred to and followed at our tertiary care clinic may have not been representative of the general population of patients with PN. Finally, further data to capture mood disorders, impression of change, and sleep dysfunction were not collected in this study. There was no confirmation of the pathological type of PN obtained in some patients (leading to a diagnosis of idiopathic peripheral neuropathy). This is, in part, due to the low yield of nerve biopsy in most of these conditions, and it is common for idiopathic PN to represent about 40% of a population of PN [33]. Overall, the data presented here cannot compare with the value of a randomized, double-blind, controlled head-to-head study of GBP and PGB, but the likelihood of such a study being performed is extremely low.

Ideal future studies would include head-to-head comparison studies between the two agents PGB and GBP. As well, future studies should also examine important features such as QOL, impression of change, and the impact of pain relief upon mood and sleep. Studies of combination therapy that have included GBP use [34,35], may also examine the ability to use PGB as an adjuvant therapy for NeP relief.


In this patient population, PGB may provide greater pain relief and contribute to fewer adverse events than GBP. Those patients felt to be GBP responders achieved further relief from NeP without additional adverse events once converted to PGB use, while GBP nonresponders were able to achieve improved pain relief with PGB. A switch from GBP to PGB therapy needs to be considered in the context of the patient with NeP, as patients with very good clinical responses to GBP may have less room for benefit from substitution of PGB. I advocate that switching from GBP to PGB use should be considered in patients with dissatisfaction with their GBP therapy regardless of GBP's initial efficacy.


No funding from any source was received in the performance of this study or the construction of this manuscript. The author has received clinical and scientific research support from Alberta Heritage Foundation Medical Research, the University of Calgary, Pfizer Canada, and Valeant Canada.


  • The author has no financial interests to disclose.


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