Pain Medicine 2011; 12: 1112–1116 Wiley Periodicals, Inc.
Brief Research Report Replacement of Gabapentin with Pregabalin in Postherpetic Neuralgia Therapy pme_1162
Masataka Ifuku, MD, Masako Iseki, MD, Ikuhiro Hidaka, MD, Yoshihito Morita, MD, Syuji Komatus, MD, and Eiichi Inada, MD Department of Anesthesiology & Pain Medicine, Juntendo University School of Medicine, Tokyo, Japan Reprint requests to: Masataka Ifuku, MD, Department of Anesthesiology & Pain Medicine, Juntendo University School of Medicine, 3-1-3 Hongo, Tokyo 113-0033, Japan. Tel: 81 3 3813 3111; Fax 03-5689-3820; E-mail:
[email protected].
Abstract Purpose. Although both gabapentin and pregabalin are first-line drugs for neuropathic pain including postherpetic neuralgia (PHN), no report has directly compared the magnitude of pain relief and the incidence of side effects of both drugs. By substituting gabapentin with pregabalin in postherpetic neuralgia therapy, we can compare the two drugs. Methods. In 32 PHN patients being administered gabapentin, without changing the frequency of dosing, the drug was substituted with pregabalin at one-sixth dosage of gabapentin. After 2 weeks, an interview was conducted about the visual analog scale (VAS) pain score, changes in the time of onset of action and duration of action after the substitution of drug and side effects (such as somnolence, dizziness, and peripheral edema). In addition, the dosage was increased while paying careful attention to the side effects (titration) in 22 patients who requested a dosage increase among those whom VAS pain score of ⱖ25 mm remained even after the substitution. Results. No significant changes were observed in VAS pain scores after the substitution of gabapentin with pregabalin. Regarding the time of onset of action and the duration of action after the substitution, the highest number of patients answered that no change occurred compared with the previous drug, followed by the patients who answered that the time of onset of action became quicker, and the duration of action became longer. The incidence of somnolence and dizziness showed no significant difference before and after the substitution, but peripheral edema showed a significant increase
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after the substitution. The level of side effects of both drugs was mild, and continued medication was possible. In the patient group where pregabalin dosage was increased, the VAS pain score decreased significantly compared with that before and after increase the dosage (P < 0.05). On the other hand, in nine out of 22 patients in the group where the dosage was increased, side effects appeared or were exacerbated. In two out of nine patients, it was necessary to reduce the dosage to the initial volume. Conclusion. It was suggested that the analgesic action of pregabalin in PHN was six times that of gabapentin in terms of effectiveness in dosage conversion. Regarding the side effects, although the incidence of the peripheral edema was higher with pregabalin compared with gabapentin, this finding is not conclusive because the present study was conducted in a small number of subjects. Although pain reduction can be expected to increase with pregabalin dosage, it is necessary to increase the dosage gradually and carefully because of exacerbation of side effects. Key Words. Gabapentin; Pregabalin; Postherpetic Neuralgia
Introduction Herpes zoster-associated pain continues for a long duration in about 20% patients even if antiviral drugs are used at the initial stage of onset, and often progresses to postherpetic neuralgia (PHN) [1]. After progression to PHN, invasive treatments such as nerve block are often unsuccessful and, generally, pharmacological treatments become the first choice of therapy [2]. Gabapentin and pregabalin both act on the a2d subunit of the calcium ion (Ca2+) channel; both drugs have been reported as a medicine with an analgesic action on neuropathic pain [3–6]. It is a first-line drug in the guidelines for treatment of PHN in Europe as well as in the United States [7–10]. Gabapentin has a low oral bioavailability (42–57%), and since the oral bioavailability decreases with dosage increase, it shows nonlinear pharmacokinetics [11]. On the other hand, pregabalin has a very high oral bioavailability (83.9–97.7%) and shows linear pharmacokinetics [12]. Pregabalin is considered to be better in relieving PHN pain. There is no accurate data regarding the effect of pain relief on neuropathic pain between the two drugs; based on the
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Replacement of Gabapentin with Pregabalin maximum dose, it is assumed that pregabalin has six times greater pharmacological effect against neuropathic pain than gabapentin [13]. However, there is no published report that directly compares the two drugs [14]. Because pregabalin therapy is accompanied by higher onset rate of side effects in proportion to the dosage increase [15], when substituting gabapentin with pregabalin, it is necessary to alter the first dosage so that both drugs have similar dosage titers. Therefore, it is important to compare the dosage titers of both drugs. In Japan, amitriptyline hydrochloride, an antidepressant, as well as gabapentin, an antiepileptic drug, have been used for the pharmacological treatment of PHN to date. Pregabalin became available for prescription in Japan as a therapeutic drug for PHN in June 2010. We substituted gabapentin with pregabalin so that the dosage of pregabalin was one-sixth the dosage of gabapentin.
Subjects and Methods Subjects Subjects were PHN patients who were being administered gabapentin, and whose pain had continued for 3 months or more after being infected with herpes zoster. The following patients were, however, excluded from the subjects: PHN patients to whom a nerve block was administered to at the time of substituting drugs, patients with an estimated glomerular filtration rate of ⱕ30 mL/min/ 1.73 m2 and who had advanced renal damages, and patients who had other painful conditions that influenced pain assessment. At the end of June 2010, pregabalin became available as a prescription drug. The substitution to pregabalin was implemented under the situation where gabapentin dosage was neither increased nor decreased for at least the previous month, because the side effects were not severe enough to require a change in dosage, the doctor did not increase the dosage, or the patients did not request for a dosage increase. Written informed consent were obtained from individual patients regarding the use of resulting data.
Evaluation Methods At the time of drug substitution, a prescription that substituted the dosage of gabapentin with that of pregabalin at one-sixth dosage of gabapentin, with an unchanged frequency of intake, was given to patients; the evaluation was performed 2 weeks later. Next, while evaluating pain after the substitution, if a visual analog scale (VAS) pain score of ⱖ25 mm was maintained and interfered with daily life, the dose was increased every 2 weeks only when the patient made the request (titration group) to the extent that side effects did not develop. The evaluation was performed after the dosage increase was at the rate of 1.5 times of the daily dosage up to a
moderate level when side effects were observed, or up to the dosage where the patients themselves did not request for further increase. Evaluation Items VAS The state when the pain was most severe in a day was evaluated by a VAS pain score of 100 mm at each point before pregabalin was substituted, after it was substituted, and after the dosage was increased. Presence and Change in Side Effects Regarding the three side effects, i.e., somnolence, dizziness, and peripheral edema, which occur with a high frequency with both drugs, yes/no answers were obtained regarding the presence of these side effects during the administration of either gabapentin or pregabalin. Moreover, in patients for whom pregabalin dosage was increased after drug substitution, confirmation was made about the three side effects on whether any of them was exacerbated or developed anew. Statistical Analysis Regarding VAS pain scores, which was the primary end point of this study, after the normal distribution was confirmed by the Shapiro–Wilk test for normality, a corresponding paired t-test was performed before and after drug substitution. Patients with increased dosage were divided into three groups for comparison (before the substitution, after the substitution, and after the dosage increase), and multiple comparisons were made using one-way analysis of variance. The comparison of incidences of somnolence, dizziness, and edema as side effects was performed by the Wilcoxon Matched-Pairs signed-rank test. The significance level was assumed to be 0.05. Results There were 32 patients (15 males and 17 females). The average age was 73.3 ⫾ 9.0 years and the average VAS pain score was 49.1 ⫾ 24.1 mm (Table 1). During evaluation after 2 weeks, the VAS pain score (mean ⫾ SD) was 46.9 ⫾ 22.5 mm. Thus, no significant difference was observed in the score before and after the substitution (P > 0.05) (Figure 1). However, the score varied greatly among individuals. Regarding changes in individual VAS pain scores, the score in the patient with most pain relief was -18 mm and that in the patient with maximum pain exacerbation was +30 mm (Table 2). Regarding the presence of side effects after drug substitution, although no significant difference was observed in the number of patients with somnolence and dizziness 1113
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Ifuku et al.
Table 1 Baseline characteristics of participants at entry (N = 32) Sex—no (%) Male Female Region—no (%) Cranial Cervical Thoracic Below lumber Concomitant medication—no (%) None TCA SSRI Opioid Kanpo Antiarhythmic NSAIDs Age—year Median Range Length from onset—Month Median Range Pain VAS—mm Mean Range Daily dose of Gabapentin—mg Median Range Gabapentin administration period—Month Median Range eGFR*—mL/min/1.73 m2 Mean Range
Table 2 Mean patient assessment of pain and side effects during gabapentin and pregabalin phases (N = 32)
15 (47) 17 (53) 5 4 20 3
(17) (12) (62) (9)
13 13 3 3 3 2 1
(40.6) (40) (9) (9) (9) (6) (3)
73 46–96 28.2 3.1–132 49.1 16–96 600 150–1350 7.75 2.0–33.5 66.1 32.3–106.7
* Estimate glomerular filtration rate. TCA = tricyclic antidepressant; SSRI = selective serotoninreuptake inhibitor; Opioid = fentanyl and codeine; Kanpo = yokukansan and keishikajyutubuto; Antiarhythmic = mexiletine hydeochloride; NSAIDs = nonsteroidal anti-inflammatory drug.
Pain VAS—mm Somnolence—% (N) Dizziness—% (N) Peripheral edema— % (N)
Gabapentin Phase
Pregabalin Phase
P Value
49.1 21.9 (7) 18.8 (6) 18.8 (6)
46.9 15.6 (5) 25.0 (8) 31.3 (10)
0.211 0.317 0.157 0.046*
* Significant at 95% level (P < 0.05).
Pregabalin dosage increased from median 100 mg (minimum 50 mg, maximum 225 mg) to median 175 mg (minimum 75 mg, maximum 300 mg). Regarding the changes in individual VAS pain scores, while there was a patient in whom prominent pain relief was observed (maximum change in VAS pain score of -53 [82 → 29]) mm compared with that before the dosage increase, there was also a patient in whom almost no pain relief was observed; this patient had a change in VAS pain score of -2 (74 → 72) mm, and there was an exacerbation of side effects. Nine patients (28.1%) had exacerbation of side effects after the pregabalin dosage increase, followed by five patients (15.6%) who had exacerbation of somnolence, five patients (15.6%) who had dizziness, and two patients (6.2%) who had exacerbation of edema (multiple answers). Among these, two patients (6.2%) required a dosage decrease of pregabalin to the amount before substitution. Discussion No significant difference was observed in VAS pain scores before and after the drug substitution. Therefore, this
before and after the substitution, the number of patients with peripheral edema increased significantly in the group where gabapentin was substituted with pregabalin (P < 0.05). Serious side effects interfering with daily life were not observed before and after the substitution. Twenty-two patients had increased dosage to improve the analgesic effect after the substitution (titration group). Although no significant difference was observed in VAS pain scores after substitution of gabapentin with pregabalin in the titration group, where the scores increased from 51.5 ⫾ 23.0 mm to 52.1 ⫾ 20.3 mm (P > 0.05), regarding the judgment of the effect of action after the dosage increase, VAS pain scores significantly decreased from 52.1 ⫾ 20.3 mm to 35.5 ⫾ 21.2 mm (P < 0.05) (Figure 2).
Figure 1 The VAS pain score before and after the substitution (N = 32).
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Replacement of Gabapentin with Pregabalin of gabapentin for neuropathic pain. The amount of substitution of gabapentin with pregabalin, however, varied in the study’s protocol and was not strictly one-sixth. In the present study, we targeted patients with the same disease (PHN), and comparisons were made by substituting gabapentin with pregabalin at one-sixth the dosage of gabapentin without changing the number of dosages. It is therefore believed that the dosage titers of both drugs can be calculated accurately. As described in the introduction, oral bioavailability of gabapentin varies according to dosage but that of pregabalin is not dependent on the dosage, and a high oral bioavailability of ⱖ90% is maintained. Therefore, it is considered that individual differences appeared under the uniform change to one-sixth dosage. This is the reason why one patient had exacerbation of pain after the substitution of drug while another patient showed alleviation of pain before and after the substitution.
Figure 2 The VAS pain score (mean ⫾ SD) in titration group (N = 22). GBP = gabapentin phase; PGB = pre-titration pregabalin phase; titPGB = after titration phase. *Significant decrease in each group (P < 0.05). study supported the hypothesis that the dosage titer of pregabalin in PHN was six times that of gabapentin. In this study, some patients receiving gabapentin continued to experience intense pain, the VAS score being more than 90 mm. Consequently, one can assume that the pain intensity did not change because neither gabapentin nor pregabalin possessed a pain-relief effect. However, for the purpose of titration, the dosage was increased in 22 patients out of 32 undergoing this substitution, and VAS pain scores after the dosage increase improved significantly. From this observation, pregabalin was believed to have pain-relieving effects in the patients in the present study, and we believe the hypothesis that the dosage titer of both drugs 1:6 can be justified. In the Cochran library [16], the number needed to treat (NNT) for PHN was reported to be 3.9 (95% confidence interval [CI], 3–5.7) for gabapentin and 3.9 (95% CI, 3.1– 5.1) for pregabalin. However, their actions vary between different subjects, and it is difficult to decide the merits of pregabalin and gabapentin in a rigorous sense by comparing NNT alone. In 2010, Toth conducted a study in which substitution to pregabalin was implemented in patients taking gabapentin for neuropathic pain [17], and classified the patients into those who showed pain relief with pregabalin, those who did not show pain relief with pregabalin, and a cohort group (continuance of gabapentin). This study suggested that the effectiveness of pregabalin was higher than that
The side effect whose incidence increased significantly at the time of substitution from gabapentin to pregabalin was edema. In the study by Rice et al. performed in the United Kingdom [3], the major side effects of gabapentin were dizziness (28.8%), somnolence (18.8%), and edema (8.1%). The incidence of edema after taking gabapentin in the present study is 18.8%, which is high (Table 2). In a multicenter, double-blind, randomized, controlled trial [15] of pregabalin therapy in PHN patients conducted in Japan, the side effects were dizziness (31.1%), somnolence (28.6%), and edema (11.7%). The incidence of edema after taking pregabalin in this study was also 31.3%, which is high. Although an assertive conclusion cannot be made from the results of this study alone— which shows a high incidence of edema with pregabalin therapy compared with other reports—the incidence of edema is believed to be higher than that with gabapentin therapy. The possible causes for the higher incidence of peripheral edema in our study compared to that in other studies remain unclear. However, because we only asked the participants if they experienced side effects, they may have answered “yes” to the question regarding the presence of peripheral edema, although they may have had mild subjective symptoms due to other factors (e.g., aging). Although the onset mechanism of edema has not been clarified accurately, it is believed that the angiotensin-converting enzyme inhibitor function disrupts the mechanism that controls the inflow of water and electrolytes from blood vessels into tissues, and that angioedema resulting from the storage of the transuded water in the tissues in the intercellular space is the cause [18]. Therefore, it can be concluded that gabapentin and pregabalin affect the electrolyte control mechanism in the vessel wall through the Ca2+ channel [19]. In this study, the increase in pregabalin dosage after the substitution significantly decreased VAS pain scores in PHN patients. It is already known that the oral bioavailability of pregabalin is high, and Cmax and area under the curve increases are linearly proportional to the dosage increase. Therefore, it can be considered that the 1115
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Ifuku et al. enhancement of efficacy in pain relief proportional to the increase in pregabalin dosage has been proven in actual medical practice. The gabapentin dose could not be increased during gabapentin administration in patients belonging to the titration group because only 300-mg gabapentin tablets were used as the in-hospital standard, and most of the patients were taking the 300-mg tablet as a single dose. Thus, increasing the dose meant making it twice the original single dose. One can therefore assume that physicians were concerned about manifestations of side effects and disease exacerbation. Conversely, the in-hospital standard for pregabalin was a 25-mg capsule and the single dose was 50 mg, thus enabling a 1.5-fold increase. On the other hand, an explanation as to why the 10 patients in the non-titration group did not request the increase, the fact that the VAS pain score was comparatively lower than that of the titration group (no significant difference) and the possibility of apprehension regarding the occurrence and potential of side effects can be considered. Until now, no study has reported statistical significance tests on analgesic effects of dosages in the same population similar to this study. However, among patients with increased pregabalin dosage in this study, one patient had insignificant pain relief. Thus, the analgesic effect of pregabalin will not apply to all PHN patients. Moreover, because the occurrence rate of adverse events will increase because of dosage increases, it is essential to accurately perform the assessment of side effects along with the effectiveness of pain relief for titration of pregabalin dosages. References 1 Beutner KR, Friedman DJ, Forszpaniak C, et al. Valaciclovir compared with acyclovir for improved therapy for herpes zoster immunocompetent adult. Antimicrob Agents Chemother 1995;39:1546–53. 2 Benzon HT, Chekka K, Darnule A, et al. The prevention and management of postherpetic neuralgia with emphasis on interventional procedures. Reg Anesth Pain Med 2009;34:514–21. 3 Rice AS, Maton S. Gabapentin in postherpetic neuralgia: A randomized, double blind, placebo controlled study. Pain 2001;94:215–24. 4 Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: A randomized controlled trial. JAMA 1998;280:1837–42. 5 Dworkin RH, Corbin AE, Young JP Jr, et al. Pregabalin for treatment of postherpetic neuralgia: A randomized, placebo-controlled trial. Neurology 2003;60:1274–83. 6 Sabatowski R, Galvez R, Cherry DA, et al. Pregabalin reduces pain and improves sleep and mood distur-
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