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Keywords:

  • Epilepsy;
  • Antiepileptic drugs;
  • Pregabalin;
  • Adverse effects;
  • Side effects;
  • Meta-analysis

Summary

  1. Top of page
  2. Summary
  3. Study end points
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. References
  11. Supporting Information

Purpose: Despite the widespread use of antiepileptic drugs (AEDs) across different neurologic and psychiatric disorders, no study has systematically reviewed all available randomized controlled trials (RCTs) of a given AED to fully uncover its tolerability profile.

We aimed at identifying treatment emergent adverse events (AEs) associated with pregabalin through a systematic review and meta-analysis of all available RCTs. We also assessed the association between serious AEs and pregabalin, and investigated whether pregabalin AEs display a dose–response relationship.

Methods: We searched MEDLINE, EMBASE, and Cochrane CENTRAL to February 2010 for RCTs. Additional studies were identified from reference lists of retrieved papers and from online clinical databases. We selected placebo-controlled, double-blind RCTs investigating the therapeutic effects of pregabalin in adults with any condition. Studies had to include at least 20 subjects per arm and have a duration of at least 4 weeks. AEs were assessed for their association with pregabalin after identification/exclusion of synonyms, rare AEs, and nonassessable AEs due to methodologic limitations. We used relative risks (RRs) to assess the association of any [99% confidence intervals (CIs)] or serious AEs (95% CIs) with pregabalin, and risk differences (RDs, 95% CIs) to investigate dose–response relationships of pregabalin AEs.

Key findings: Thirty-eight RCTs were included in our study. Of 39 AEs, 20 (51%) were significantly associated with pregabalin (dizziness, vertigo, incoordination, balance disorder, ataxia, diplopia, blurred vision, amblyopia, tremor, somnolence, confusional state, disturbance in attention, thinking abnormal, euphoria, asthenia, fatigue, edema, peripheral edema, dry mouth, constipation). The highest RRs were found for cognition/coordination AEs. There was no significant association between serious AEs and pregabalin. There was a selective dose–response pattern in the onset of pregabalin AEs, with certain AEs appearing at lower doses than others.

Significance: Individuals starting treatment with pregabalin are at increased risk for several AEs, particularly those affecting cognition/coordination. Pregabalin AEs appear according to a selective dose–response pattern, possibly reflecting the severity of dysfunction of distinct anatomic structures. These findings may aid clinicians in providing better patient management, and support the value of including in meta-analyses of AED tolerability profiles RCTs performed in different conditions.

In addition to their traditional indication in epilepsy, antiepileptic drugs (AEDs) have been used extensively over the last few years to treat a wide range of neurologic and psychiatric disorders (Johannessen Landmark, 2008). In a recent U.S. Food and Drug Administration (FDA) meta-analysis of 199 randomized controlled trials (RCTs) of 11 AEDs, less than one third were performed in epilepsy. Neuropathic pain, bipolar disorder, migraine, and anxiety accounted for almost one-half of the trials (U.S. Food and Drug Administration, 2010). Moreover, the number of indications and off-label utilizations of common AEDs is continuously growing (Rosenberg & Salzman, 2007). Therefore, providing reliable information on the tolerability and safety profiles of these agents has a broad clinical relevance.

Meta-analyses of RCTs have attempted to provide such data for several AEDs (Marson et al., 1997, 2000; Chadwick & Marson, 2000; Jette et al., 2000; Ramaratnam et al., 2000; Chaisewikul et al., 2001; Marson et al., 2001; Chadwick & Marson, 2002; Jette et al., 2002; Leach et al., 2002; Pereira et al., 2002; Chadwick & Marson 2005; Hemming et al., 2008; Jette et al., 2008; Lozsadi et al., 2008; Michael & Marson, 2008). However, due to the exclusion of any RCT performed outside of a selected disorder (in most cases epilepsy), none of these investigations had a sufficiently large sample size to reveal the adverse event (AE) profile of any AED. In one study, for instance, assessment was restricted to the five most commonly observed AEs (Marson et al., 1997). Including all available trials in which a certain AED was investigated would lead to a more comprehensive evaluation of the drug’s tolerability and safety profiles. Moreover, considering that most of these studies include fixed-dose regimens, it would allow a better ascertainment of dose-response relationships for any AE.

Pregabalin is a suitable candidate for this type of analysis, for two main reasons: (1) it has been investigated in a large variety of conditions (e.g. pharmacoresistant epilepsy, neuropathic pain, fibromyalgia, and generalized anxiety disorder); (2) it does not display clinically significant interactions with other drugs, thereby avoiding the confounding effect of AEs due to drug–drug interactions (Ryvlin et al., 2008).

Study end points

  1. Top of page
  2. Summary
  3. Study end points
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. References
  11. Supporting Information

The primary aim of this study was to identify any AEs associated with pregabalin treatment, through a systematic review and meta-analysis of available RCTs.

We additionally investigated the association between serious AEs and pregabalin treatment, and assessed whether pregabalin AEs exhibit a dose–response relationship.

Methods

  1. Top of page
  2. Summary
  3. Study end points
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. References
  11. Supporting Information

Criteria for considering studies for this review

Types of studies

We included only randomized, placebo-controlled, double-blind trials investigating the therapeutic effects of pregabalin in adults with different neurologic and psychiatric disorders. We further limited our analysis to studies that recruited at least 20 subjects per arm and had a duration of at least 4 weeks. Full journal publication or summary clinical trial reports were required, with brief abstracts not included. All other study types, including nonrandomized trials, case reports, or clinical observations, were excluded.

Types of participants

Subjects were aged 18 years or older and affected by different neurologic or psychiatric conditions, including epilepsy, neuropathic pain, fibromyalgia, and generalized anxiety disorder.

Types of interventions

Oral treatment with pregabalin at any dose was the intervention. Studies had to include a placebo arm.

Search methods for identification of studies

Studies were identified by several methods. RCTs of pregabalin (and key brand name: Lyrica) were identified using: MEDLINE (PubMed) from 1990 to February 2010; EMBASE (Ovid), from 1990 to February 2010; and Cochrane CENTRAL issue 2, 2010. Additional studies were sought in reference lists of retrieved papers, and by searching the Internet for summary clinical trial reports not available as full publications. The National Institutes of Health (NIH) clinical trial registry (http://www.clinicaltrial.gov) and the PhRMA clinical study results database (http://www.clinicalstudyresults.org) were also interrogated for trial results of pregabalin (Lyrica) in all conditions. Search strategies for MEDLINE, EMBASE, and Cochrane CENTRAL are available in Appendix S1.

Eligibility was determined by reading each study identified by the search. All studies were read independently by two authors (GZ and LS) and agreement was reached after discussion.

Strategy for the analysis of adverse events

Selection of adverse events

Relevant AEs were selected by using the following three-step strategy: (1) identification of synonyms, which were grouped under one main term; (2) identification and subsequent exclusion of treatment emergent AEs not frequently signaled in clinical studies, that is, AEs observed in <10 subjects among those treated with pregabalin or placebo; and (3) identification and subsequent exclusion of any other AEs the assessment of which was impeded by a nonuniform acquisition of data in clinical trials.

After selecting those AEs to be included in our analyses, we extracted the frequency of each AE from the pregabalin and placebo groups of each study that met inclusion criteria. This information was recorded into a separate data extraction sheet.

Statistical analysis

All analyses were performed using RevMan (2008).

Statistical heterogeneity was assessed using the I2 test, with an I2 > 70% indicating heterogeneity. A chi-square test for heterogeneity was also used. Provided no significant clinical or statistical heterogeneity was present, the analyses used a fixed-effect model. In cases where I2 was >70%, random-effect model was used.

We estimated: (1) relative risks (RRs) to assess the association of any or serious AEs with pregabalin treatment; and (2) risk differences (RDs) to investigate dose–response relationships of pregabalin AEs. For the latter analysis, we selected only those studies in which subjects were randomized to fixed-dose regimens (150, 300, 450, and 600 mg/day), and excluded studies or study arms using flexible-dose regimens, since in these studies it is not possible to assign the appearance of an AE to a precise drug dose.

To ease interpretation of dose–response relationships, each RD estimate was complemented by the computation of the number needed to harm (NNH).

When assessing the association of any AE with pregabalin treatment, the confidence intervals (CIs) of RRs were set at 99%. This conservative approach was aimed at minimizing the error rate without reducing the probability of an adequate individualization of AEs. For all other analyses, 95% CIs were used.

Results

  1. Top of page
  2. Summary
  3. Study end points
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. References
  11. Supporting Information

Description of studies

Results of the search

Our search yielded 86 potentially eligible RCTs, 19 of which were unpublished studies identified in the PhRMA clinical study results database. From this initial screening, we excluded non–double-blind studies, abstracts, active-controlled studies, double-blind studies in which pregabalin was administered only for a few days in subjects undergoing surgery, and studies performed on healthy volunteers. Fifty-three randomized, placebo-controlled, double-blind studies in which pregabalin was administered to subjects with various conditions were carefully evaluated (Fig. 1), and 38 were ultimately selected for our analysis on the criteria stated (see Types of studies). Main clinical characteristics of selected studies are reported in Table 1.

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Figure 1.   Flow diagram of randomized controlled trials (RCTs).

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Table 1.   Characteristics of studies included in our analysis
AuthorDiseaseStudy duration (weeks)Titration phaseDrug regimen150 mg (n)300 mg (n)450 mg (n)600 mg (n)Flexible dose (n)
  1. aOn 200 mg/day.

  2. bOn 400 mg/day.

  3. cVaried according to treatment arm.

  4. dUp to 600 mg/day according to creatinine values.

  5. eIncluded an arm treated with 50 mg/day (data not shown).

  6. fIncluded an arm treated with 75 mg/day (data not shown).

  7. GAD, generalized anxiety disorder; SAD, social anxiety disorder; w, weeks; d, days.

Anon. 2005aPanic disorder101–2 wBID90a 85b  
Anon. 2005bPartial epilepsy171 wBID    152
Anon. 2007aDiabetic neuropathy92 wTID   86 
Anon. 2007bGAD91 wBID-TID    177
Anon. 2007cDiabetic neuropathy131 wBID 153 152 
Anon. 2007dDiabetic neuropathy146 wBID    271
Anon. 2008bFibromyalgia142 wBID 183182186 
Anon. 2008dHIV neuropathy151–2 wBID    151
Anon. 2009aNeuropathic pain84 wBID    127
Anon. 2009bCentral poststroke pain124 wBID    110
Anon. 2009ePostherpetic neuralgia131 wBID8689 97 
Arezzo 2008Diabetic neuropathy131 wBID   82 
Arnold 2008Fibromyalgia141–2 wcBID 183190188 
Arroyo 2004Partial epilepsy124–8 dTID99  92 
Beydoun 2005Partial epilepsy128 dBID-TID   103 111 
Crofford 2005Fibromyalgia80–3 dTID132134132  
Dworkin 2003Postherpetic neuralgia91 wdTID   89 
Elger 2005Partial epilepsy120–1 wBID   137131
Feltner 2003GAD41 wTID70  67 
French 2003ePartial epilepsy120 dBID8690 89 
Freynhagen 2005Neuropathic pain121 wBID   132141
Lee 2009Partial epilepsy12Up to 8 wBID    119
Lesser 2004fDiabetic neuropathy50–1 wTID 81 82 
Mease 2008Fibromyalgia131 wBID 185183190 
Montgomery 2006GAD85–7 dBID  97b110 
Montgomery 2008GAD8Up to 6 wBID-TID    177
Pande 2004SAD106 dTID42  47 
Pande 2003GAD46 dTID69  70 
Pohl 2005GAD64 dBID TID78a 89b 88  
Richter 2005Diabetic neuropathy62 wBID79  82 
Rickels 2005GAD4Up to 7 dTID 919089 
Rosenstock 2004Diabetic neuropathy80TID 76   
Sabatoski 2004Postherpetic neuralgia71 wTID8176   
Siddall 2006Central neuropathic pain12FlexibleBID    70
Stacey 2008Postherpetic neuralgia4Fixed 0 flexible 2 wBID 88  91
Tölle 2008Diabetic neuropathy121 wBID9999 101 
van Seventer 2006Postherpetic neuralgia131 wBID8798 90 
Vranken 2008Central neuropathic pain44 wBID    20

For a detailed description of included and excluded studies see Appendix S2.

Included studies

The 38 studies included a total of 11,918 subjects, 8,235 of whom were randomized to pregabalin and 3,683 to placebo. Nineteen studies were performed in neuropathic pain, four in fibromyalgia, six in pharmacoresistant epilepsy, six in generalized anxiety disorder, two in social anxiety disorder, and one in panic disorder. Ten studies used flexible-dose regimens, with pregabalin doses usually increased up to 600 mg/day. In 25 studies, after a titration phase of variable duration, pregabalin doses were fixed. Three studies included both flexible and fixed-dose arms. Study duration varied from 4–14 weeks.

Excluded studies

From 53 potentially eligible RCTs, 15 studies (Anon, 2005c,d; Arnold et al., 2007; De Haas et al., 2007; Houghton et al., 2007; Zesiewicz et al., 2007; Anon., 2008a,c; Crofford et al., 2008; Feltner et al., 2008; Anon., 2009c,d,f; Ferrara et al., 2009; Kasper et al., 2009) were excluded from our analysis due to additional limitations (see Fig. 1). Reasons for exclusion included: lack of AE data, nonsuitable study designs for AE analysis, ≤20 subjects on pregabalin treatment, nonstable doses of other concomitant drugs during the double-blind phase, and short study duration (Appendix S2).

Risk of bias in included studies

Although all studies were reported to be randomized, placebo-controlled, and double-blind, no full details were generally given on the randomization generation scheme, allocation concealment, and blinding. However, the risk of bias in the analysis of treatment-emergent AEs was considered to be very low because many studies were multicenter and performed in a relatively large population of patients.

Description of adverse events in included studies

Results of the search

In the 38 studies included in our analysis, we found 87 AEs occurring with pregabalin treatment. After identification of synonyms, rare AEs, and other nonassessable AEs, 39 AEs (45% of the initial sample) were investigated in fixed-effect meta-analyses for their association with pregabalin (Fig. 2).

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Figure 2.   Flow diagram of the selection process of adverse events (AEs).

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Synonyms

Of the 87 AEs, 11 (12.6%) were considered as synonyms of an another AE: accidental injury as a synonym of contusion; abnormal gait of ataxia; confusion of confusional state; coordination abnormal of incoordination; euphoric mood of euphoria; generalized edema of edema; myasthenia of asthenia; and flu syndrome, pharyngitis, nasopharyngitis, and rhinitis of upper respiratory tract infection (RTI). These synonyms were merged with their corresponding AEs in all analyses.

Nonfrequently observed adverse events

Thirty-four AEs (enlarged abdomen, abdominal pain, anorgasmia, anxiety, blood glucose increase, creatinine clearance decrease, cognitive performance, conjunctivitis, convulsion, decreased libido, depersonalization, depressed level of consciousness, depression, disorientation, dyspepsia, eczema, feeling drunk, feeling abnormal, flatulence, hyperglycemia, hypertension, hyperthermia, joint swelling, insomnia, lethargy, malaise, neuralgia, overdose, decreased reflexes, sleep disorder, speech disorder, sweating, thirst, and urinary incontinence), 39.1% of the initial sample, occurred in <10 subjects assigned to pregabalin or placebo, and were, therefore, excluded from our analysis.

Other adverse events

Weight gain is an established AE of pregabalin, occurring in about one fourth of treated patients (Ryvlin et al., 2008). However, weight gain assessment varies considerably across studies. In the 38 studies included in our analysis, some reported the proportion of subjects who gained weight throughout the study. Others calculated the mean weight increase of enrolled subjects. Because these methodologic discrepancies seriously impeded an accurate assessment of this AE, we decided to disregard in our analysis the following items: weight gain, increased weight, and weight change.

Meta-analyses results

Adverse events associated with pregabalin

Analysis of data showed no evidence of heterogeneity (I2 between 0% and 60%). Therefore, a fixed-effect model was used in all cases.

As illustrated in Fig. 3, 20 of the 39 (51%) analyzed AEs were significantly associated with pregabalin treatment. The highest RR (95% CI) was found for balance disorder 8.22 (1.75 to 38.57), followed by euphoria 6.18 (2.76 to 13.87), incoordination 4.88 (2.18 to 10.95), ataxia 4.77 (2.77 to 8.20), and edema 4.63 (2.15 to 9.95). A detailed description of these results is available in Appendix S3.

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Figure 3.   Relative risks (99% CI) of adverse events (n = 39) eligible for assessment of the association with pregabalin treatment.

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Serious adverse events associated with pregabalin

Serious AEs were reported in 21 (55%) of the 38 studies, resulting in a total of 6,588 subjects, 4,382 of whom randomized to pregabalin and 2,206 to placebo. The RR (95% CI) for experiencing a serious AE on pregabalin compared to placebo was 1.02 (0.77 to 1.36). In the majority of cases, reported serious AEs were a heterogeneous number of events, and only in 16 studies was it clearly specified whether the observed serious AE was considered associated or not associated with the experimental drug. When specified, serious AEs considered related with pregabalin were: somnolence in three patients, ataxia, peripheral edema, ventricular extrasystoles, accidental injury or fall in two, spasticity due to drug withdrawal, increased anxiety, fractured arm secondary to a fall, chest pain, subacute myocardial infarction, hypotension, transient loss of consciousness, asthenia, and encephalopathy in one patient, respectively. One further patient had edema, hypervolemia, and reduced platelet count. In patients treated with placebo, serious AEs that were considered related to the treatment were: coronary artery disorder, ventricular extrasystoles, attack of unconsciousness, manic reaction, and prostate cancer.

Analysis of dose–effect responses for pregabalin adverse events

Of the 38 studies, 10 were excluded from this part of the analysis due to utilization of flexible-dose regimens. Three other studies included both flexible- and fixed-dose arms, and we excluded the flexible-dose groups. Two studies included 200 and 400 mg/day arms, which were merged for the purposes of this analysis with the 150 and 450 mg/day arms, respectively. Therefore, the sample eligible for this analysis amounted to 28 studies. In these analyses, heterogeneity (I2 > 70%) was found in some cases and a random effect model was adopted for euphoria at 150 mg/day, ataxia and edema at 300 mg/day, fatigue at 450 mg/day, and somnolence and edema at 600 mg/day.

RDs (95% Cis) for the 20 pregabalin AEs at different doses are shown in Table 2. There was a selective dose-dependent pattern in the onset of AEs, with five AEs first presenting at 150 mg/day (dizziness, ataxia, somnolence, edema, and dry mouth), 11 at 300 mg/day (vertigo, incoordination, blurred vision, amblyopia, confusional state, disturbance in attention, thinking abnormal, euphoria, asthenia, peripheral edema, and constipation), 2 at 450 mg/day (balance disorder and fatigue), and 2 at 600 mg/day (diplopia and tremor). Further details are given in Appendix S4.

Table 2.   Adverse effects significantly associated with pregabalin
Adverse effect150 mg/day 150 mg300 mg/day 300 mg450 mg/day 450 mg600 mg/day 600 mg
  1. Risk difference (CI 95%) at various pregabalin dosages. Fixed effect model has been used otherwise differently specified.

  2. aOnly one study nv, not evaluable (no data available for that dose).

  3. bRandom effect model used.

Dizziness0.08 (0.05 to 0.10)0.21 (0.19 to 0.24)0.29 (0.25 to 0.32)0.30 (0.27 to 0.32)
Vertigo0.02 (−0.01 to 0.05)a0.05 (0.02 to 0.07)0.03 (0.00 to 0.07)0.06 (0.04 to 0.08)
Incoordination0.00 (−0.01 to 0.02)0.03 (0.01 to 0.04)0.07 (0.05 to 0.09)0.07 (0.05 to 0.10)
Balance disordernv0.01 (−0.00 to 0.03)0.09 (0.05 to 0.13)a0.06 (0.03 to 0.09)
Ataxia0.03 (0.00 to 0.05)0.04 (0.00 to 0.08)b0.04 (0.01 to 0.07)a0.11 (0.09 to 0.13)
Diplopia0.00 (−0.02 to 0.03)0.02 (−0.00 to 0.04)nv0.07 (0.05 to 0.10)
Blurred vision0.02 (−0.02 to 0.05)0.04 (0.02 to 0.05)0.06 (0.04 to 0.08)0.07 (0.05 to 0.09)
Amblyopia0.01 (−0.01 to 0.03)0.03 (0.00 to 0.06)0.05 (−0.00 to 0.10)a0.07 (0.05 to 0.09)
Tremor0.00 (−0.03 to 0.04)0.02 (−0.01 to 0.06)nv0.06 (0.02 to 0.10)
Somnolence0.07 (0.04 to 0.10)0.14 (0.12 to 0.16)0.16 (0.14 to 0.19)0.17 (0.13 to 0.21)b
Confusional state0.01 (−0.01 to 0.03)0.03 (0.01 to 0.05)0.05 (0.01 to 0.09)a0.04 (0.01 to 0.07)
Disturb attentionnv0.04 (0.01 to 0.06)0.05 (0.02 to 0.08)0.06 (0.03 to 0.09)
Thinking abnormal0.02 (−0.01 to 0.04)0.04 (0.01 to 0.06)0.06 (0.04 to 0.09)0.08 (0.05 to 0.10)
Euphoria0.05 (−0.06 to 0.15)b0.04 (0.02 to 0.06)0.07 (0.05 to 0.09)0.06 (0.03 to 0.08)
Edema0.05 (0.01 to 0.08)0.08 (−0.02 to 0.18)bnv0.07 (0.01 to 0.13)b
Peripheral edema0.02 (−0.00 to 0.05)0.05 (0.03 to 0.07)0.04 (0.02 to 0.06)0.08 (0.06 to 0.10)
Asthenia0.01 (−0.02 to 0.03)0.02 (0.00 to 0.04)0.03 (0.01 to 0.06)0.04 (0.02 to 0.06)
Fatiguenv0.02 (−0.00 to 0.05)0.05 (0.03 to 0.12)b0.03 (0.00 to 0.06)
Dry mouth0.04 (0.02 to 0.06)0.05 (0.03 to 0.06)0.08 (0.06 to 0.10)0.07 (0.05 to 0.08)
Constipation0.02 (−0.01 to 0.05)0.03 (0.01 to 0.04)0.04 (0.02 to 0.06)0.04 (0.03 to 0.06)

NNH values for each AE at different pregabalin doses are illustrated in Figs 4–6. Most AEs displayed a clear dose–response relationship, this being particularly evident for balance disorder, amblyopia, confusional state, disturbance in attention, asthenia, and constipation.

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Figure 4.   NNH values for pregabalin vestibulocerebellar adverse events at different drug doses. NNH values calculated from a single study are omitted.

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Figure 5.   NNH values for pregabalin CNS adverse events at different drug doses. NNH values calculated from a single study are omitted.

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Figure 6.   NNH values for gastrointestinal/metabolic adverse events at different drug doses. NNH values calculated from a single study are omitted.

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Discussion

  1. Top of page
  2. Summary
  3. Study end points
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. References
  11. Supporting Information

We found 20 AEs significantly associated with pregabalin treatment. Most (16 of 20; 80%) were cognition/coordination AEs, which a recent study found to be the strongest determinant of impaired health-related quality of life in people taking AEDs (Perucca et al., 2009). Of these 16 AEs, 9 indicate involvement of vestibulocerebellar/brainstem structures (dizziness, vertigo, incoordination, balance disorder, ataxia, tremor, diplopia, blurred vision, and amblyopia), whereas 7 are related to higher cortical functions (euphoria, disturbance in attention, thinking abnormal, somnolence, confusional state, asthenia, and fatigue). A cause–effect relationship between cognition/coordination AEs and pregabalin treatment was further supported by inspection of the 10 highest RRs, nine of which were found to belong to this AE class (Appendix S3). Finally, all these AEs shared a clear dose–response relationship. The occurrence of this AE class may be attributed directly to the primary mode of action of pregabalin. Pregabalin inhibits the depolarization-dependent calcium influx at P-, Q-, and N-type voltage-gated calcium channels, resulting in decreased neurotransmitters release (Ben-Menachem, 2004). The highest level of expression of these channels has been found in the cerebellum and in the hippocampus, and their dysfunction or decreased activity has been linked to ataxia (Zhuchenko et al., 1997; Liao et al., 2008) and cognitive impairment (Nakagawasai et al., 2010).

The remaining four AEs indicate gastrointestinal/metabolic dysfunction (edema, peripheral edema, dry mouth, and constipation). As opposed to the cognition/coordination class, these AEs were slightly less common and did not display a clear dose–response relationship (except for constipation). The pathogenesis of these AEs is unclear and should be elucidated in future studies.

There was a dose-dependent pattern in the onset of pregabalin AEs, with certain AEs appearing at lower doses than others. An example is provided by amblyopia, blurred vision, and diplopia. As discussed previously, these AEs are likely to result from brainstem involvement and displayed a clear dose–response relationship. However, amblyopia and blurred vision appeared at 300 mg/day, and were accompanied by diplopia only at 600 mg/day. It is possible that the onset of the two former AEs corresponds to a milder brainstem dysfunction than that observed with higher doses, particularly with the occurrence of diplopia. Similar considerations can be extended to other AEs, and suggest that different AEs can be clinically significant biomarkers of the severity of dysfunction of distinct anatomic structures.

In this study, serious AEs were not more frequent with pregabalin compared to placebo. Although randomized, double-blind, placebo-controlled trials are not the optimal design to evaluate these AEs, our findings nevertheless corroborate the results of other investigations of the safety profile of pregabalin (Ryvlin et al., 2010).

Our study has several limitations. Although RCTs allow direct comparisons of AE rates between an investigated compound and placebo, as well as an accurate analysis of dose–response relationships for any identified AE, their short duration hampers the assessment of long-term toxicity. Moreover, different terms may be used in different RCTs to describe a given AE, which may result in its exclusion from all analyses, as in our case with weight gain. Collective efforts should be made to develop a single standardized terminology for RCTs of AEDs.

We have already noted that pregabalin seems to be devoid of pharmacokinetic interactions. However pharmacodynamic interactions may still influence drug tolerability and appearance of some AEs, and their relation with the experimental drug dose may also be modified by total drug load. In the examined RCTs, most often pregabalin was administered on monotherapy (patients with anxiety disorders, neuropathic pain, or fibromyalgia), whereas patients with epilepsy received this drug as add-on treatment. Finally, in the present meta-analysis, we did not control for the underlying disease, which might have altered drug’s toxicity profile; however, these effects will be evaluated in a subsequent study.

Disclosure

  1. Top of page
  2. Summary
  3. Study end points
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. References
  11. Supporting Information

GZ has received speaker’s or consultancy fees from EISAI, Jansen-Cilag, Novartis, Sanofi-Aventis, and UCB Pharma. LS received speaker’s or consultancy fees and/or support for congress participation from Bial, Cyberonics, Eisai, GSK, Johnson & Johnson, Novartis, Pfizer, Sanofi-Aventis, Schwarz Pharma, and UCB Pharma; in the past 3 years, he received research grants from Bial, Eisai, Novartis, Pfizer, and UCB Pharma. PP and PG report no disclosures. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Study end points
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. References
  11. Supporting Information
  • Anon. (2005a) A 10-week, randomized, double-blind, multicenter, placebo-controlled study of pregabalin and paroxetine in the treatment of panic disorder. Protocol No. 1008-091 PhRMA Clinical study Synopsis 6 July 2005.
  • Anon. (2005b) A randomized, double-blind, parallel group, placebo and lamotrigine controlled, multicenter study in patients with partial seizures. Protocol No.1008-112 Clinical study Synopsis 14 July 2005.
  • Anon. (2005c) Sustained efficacy study of pregabalin in patients with panic disorder with or without agoraphobia. Protocol No. 1008-093 PhRMA Clinical study Synopsis 14 July 2005.
  • Anon. (2005d) Pregabalin BID add-on trial: a randomized, double-blind, placebo-controlled parallel-group single-center sleep EEG study in patients with partial seizures and sleep disturbance. Protocol 1008-000-167 Part B PhRMA Clinical Study Synopsis - 7 September 2005.
  • Anon. (2007a) A placebo-controlled trial of pregabalin and amitriptyline for treatment of painful diabetic peripheral neuropathy. Protocol No. 1008-040 PhRMA Clinical study Synopsis 14 July 2007.
  • Anon. (2007b) A placebo-controlled study of pregabalin in elderly patients with generalized anxiety disorder. Protocols 1008-0090, 1008-0152. PhRMA Clinical study Synopsis 12 September 2007.
  • Anon. (2007c) A randomized, double-blind, placebo-controlled, parallel-group, multi-center trial of pregabalin versus placebo in the treatment of neuropathic pain associated with diabetic peripheral neuropathy. Protocol No. A0081071 Clinical study Synopsis 19 December 2007.
  • Anon. (2007d) A 14-week, double-blind, randomized, placebo-controlled, multicenter study to evaluate the safety and efficacy of pregabalin (150mg-600mg/day) using a flexible optimal dose schedule in patients with painful Diabetic Peripheral Neuropathy (DPN). Protocol No. A0081030 Clinical study Synopsis 28 December 2007.
  • Anon. (2008a) An 8 week multi-center, randomized, double blind, placebo-controlled study to evaluate the efficacy, safety and tolerability of pregabalin (150mg-600mg/day) using a flexible dosing schedule in the treatment of subjects with symptoms of neuropathic pain. Protocol No. 1008-1081 PhRMA Clinical study Synopsis 17 January 2008.
  • Anon. (2008b) A 14 week, randomized, double-blind, placebo-controlled trial of pregabalin twice daily in patients with fibromyalgia. Protocol No. A0081100 Clinical study Synopsis 7 March 2008.
  • Anon. (2008c) A 10-week, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of pregabalin (150mg–600mg/Day) using a flexible, optimized dose schedule in subjects with peripheral neuropathic pain. Protocol No A008-1037 PhRMA Clinical study Synopsis 06 August 2008.
  • Anon. (2008d) A randomized, double-blind, placebo-controlled, parallel group, multi-center trial of pregabalin versus placebo in the treatment of neuropathic pain associated with HIV neuropathy. Protocol No. A0081066 Clinical study Synopsis 7 October 2008.
  • Anon. (2009a) A 9-week, randomized, double-blind, placebo-controlled, multicenter, study of pregabalin (BID) in subjects with post traumatic peripheral neuropathic pain. Protocol No. A0081064 Clinical study Synopsis 7 January 2009.
  • Anon. (2009b) A 13-week, randomized, multicenter, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety and tolerability of pregabalin (150-600 mg/day) using a flexible dosing schedule in the treatment of subjects with Central Post-Stroke Pain (CPSP). Protocol No. A0081063 Clinical study Synopsis 10 March 2009.
  • Anon. (2009c) A multicenter, randomized, double-blind, placebo-controlled study of pregabalin in subjects with Generalized Anxiety Disorder (GAD) switching from benzodiazepine therapy. Protocol No. A008-1092 PhRMA Clinical study Synopsis 16 April 2009.
  • Anon. (2009d) A multicenter, double-blind randomized, placebo-controlled study of the efficacy and safety of pregabalin in the treatment of subjects with post-operative pain following Total Knee Arthroplasty (TKA). Protocol No. 1008-1133 PhRMA Clinical study Synopsis 17 July 2009-d.
  • Anon. (2009e) A 13-week, randomized, double-blind, multicenter, placebo-controlled study to evaluate efficacy and safety of pregabalin (CI-1008) in the treatment of postherpetic neuralgia. Protocol No. A0081120 Clinical study Synopsis 19 August 2009.
  • Anon. (2009f) Randomized, double-blind, 6-week study of pregabalin in subjects with restless legs syndrome. Protocol No. A0081183 PhRMA Clinical study Synopsis 4 October 2009.
  • Arezzo JC, Rosenstock J, Lamoreaux L, Pauer L. (2008) Efficacy and safety of pregabalin 600 mg/d for treating painful diabetic peripheral neuropathy: a double-blind placebo-controlled trial. BMC Neurol 8:33.
  • Arnold LM, Crofford LJ, Martin SA, Young JP, Sharma U. (2007) The effect of anxiety and depression on improvements in pain in a randomized, controlled trial of pregabalin for treatment of fibromyalgia. Pain Med 8:634638.
  • Arnold LM, Russell IJ, Diri EW, Duan WR, Young JP Jr, Sharma U, Martin SA, Barrett JA, Haig G. (2008) A 14-week, randomized, double-blinded, placebo-controlled monotherapy trial of pregabalin in patients with fibromyalgia. J Pain 9:792805.
  • Arroyo S, Anhut H, Kugler AR, Lee CM, Knapp LE, Garofalo EA, Messmer S. (2004) Pregabalin 1008-011 International Study Group. Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures. Epilepsia 45:2027.
  • Ben-Menachem E. (2004) Pregabalin pharmacology and its relevance to clinical practice. Epilepsia 45(suppl 6):1318.
  • Beydoun A, Uthman BM, Kugler AR, Greiner MJ, Knapp LE, Garofalo EA, Pregabalin 1008-009 Study Group. (2005) Safety and efficacy of two pregabalin regimens for add-on treatment of partial epilepsy. Neurology 64:475480.
  • Chadwick DW, Marson AG. (2000) Zonisamide for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2:CD001416. Review. Update in: Cochrane Database Syst Rev 2002;2:CD001416.
  • Chadwick DW, Marson AG. (2002) Zonisamide add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 4:CD001416. Review. Update in: Cochran Database Syst Rev 2005;4:CD001416.
  • Chadwick DW, Marson AG. (2005) Zonisamide add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 4:CD001416.
  • Chaisewikul R, Privitera MD, Hutton JL, Marson AG. (2001) Levetiracetam add-on for drug-resistant localization related (partial) epilepsy. Cochrane Database Syst Rev 1:CD001901.
  • Crofford LJ, Rowbotham MC, Mease PJ, Russell IJ, Dworkin RH, Corbin AE, Young JP Jr, LaMoreaux LK, Martin SA, Sharma U, Pregabalin 1008-105 Study Group. (2005) Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 52:12641273.
  • Crofford LJ, Mease PJ, Simpson SL, Young JP Jr, Martin SA, Haig GM, Sharma U. (2008) Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief (FREEDOM): a 6-month, double-blind, placebo-controlled trial with pregabalin. Pain 136:419431.
  • de Haas S, Otte A, de Weerd A, van Erp G, Cohen A, van Gerven J. (2007) Exploratory polysomnographic evaluation of pregabalin on sleep disturbance in patients with epilepsy. J Clin Sleep Med 3:473478.
  • Dworkin RH, Corbin AE, Young JP Jr, Sharma U, LaMoreaux L, Bockbrader H, Garofalo EA, Poole RM. (2003) Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 60:12741283.
  • Elger CE, Brodie MJ, Anhut H, Lee CM, Barrett JA. (2005) Pregabalin add-on treatment in patients with partial seizures: a novel evaluation of flexible-dose and fixed-dose treatment in a double-blind, placebo-controlled study. Epilepsia 46:19261936.
  • Feltner DE, Crockatt JG, Dubovsky SJ, Cohn CK, Shrivastava RK, Targum SD, Liu-Dumaw M, Carter CM, Pande AC. (2003) A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder. J Clin Psychopharmacol 23:240249.
  • Feltner D, Wittchen HU, Kavoussi R, Brock J, Baldinetti F, Pande AC. (2008) Long-term efficacy of pregabalin in generalized anxiety disorder. Int Clin Psychopharmacol 23:1828.
  • Ferrara JM, Kenney C, Davidson AL, Shinawi L, Kissel AM, Jankovic J. (2009) Efficacy and tolerability of pregabalin in essential tremor: a randomized, double-blind, placebo-controlled, crossover trial. J Neurol Sci 285:195197.
  • French JA, Kugler AR, Robbins JL, Knapp LE, Garofalo EA. (2003) Dose-response trial of pregabalin adjunctive therapy in patients with partial seizures. Neurology 60:16311637.
  • Freynhagen R, Strojek K, Griesing T, Whalen E, Balkenohl M. (2005) Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Pain 115:254263.
  • Hemming K, Maguire MJ, Hutton JL, Marson AG. (2008) Vigabatrin for refractory partial epilepsy. Cochrane Database Syst Rev 3:CD007302.
  • Houghton LA, Fell C, Whorwell PJ, Jones I, Sudworth DP, Gale JD. (2007) Effect of a second-generation alpha2delta ligand (pregabalin) on visceral sensation in hypersensitive patients with irritable bowel syndrome. Gut 56:12181225.
  • Jette NJ, Marson AG, Kadir ZA, Hutton JL. (2000) Topiramate for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2:CD001417. Review. Update in: Cochran Database Syst Rev 2002;3:CD001417.
  • Jette NJ, Marson AG, Hutton JL. (2002) Topiramate add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 3:CD001417. Review. Update in: Cochran Database Syst Rev 2008;3:CD001417.
  • Jette N, Hemming K, Hutton JL, Marson AG. (2008) Topiramate add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 3:CD001417.
  • Johannessen Landmark C. (2008) Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy. CNS Drugs 22:2747.
  • Kasper S, Herman B, Nivoli G, Ameringen MV, Petralia A, Mandel FS, Baldinetti F, Bandelow B. (2009) Effitcacy of pregabalin and venlafaxine-XR in generalized anxiety disorder: results of a double-blind, placebo-controlled 8-week trial. Int Clin Psychopharmacol 24:8796.
  • Leach JP, Marson AG, Hutton JL. (2002) Remacemide for drug-resistant localization related epilepsy. Cochrane Database Syst Rev 4:CD001900.
  • Lee BI, Yi S, Hong SB, Kim MK, Lee SA, Lee SK, Shin DJ, Kim JM, Song HK, Heo K, Lowe W, Leon T. (2009) Pregabalin add-on therapy using a flexible, optimized dose schedule in refractory partial epilepsies: a double-blind, randomized, placebo-controlled, multicenter trial. Epilepsia 50:464474. Erratum in: Epilepsia. 2009 Aug;50(8):2010.
  • Lesser H, Sharma U, LaMoreaux L, Poole RM. (2004) Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology 63:21042110.
  • Liao YJ, Safa P, Chen YR, Sobel RA, Boyden ES, Tsien RW. (2008) Anti-Ca2+ channel antibody attenuates Ca2+ currents and mimics cerebellar ataxia in vivo. Proc Natl Acad Sci U S A 105:27052710.
  • Lozsadi D, Hemming K, Marson AG. (2008) Pregabalin add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 1:CD005612.
  • Marson AG, Kadir ZA, Hutton JL, Chadwick DW. (1997) The new antiepileptic drugs: a systematic review of their efficacy and tolerability. Epilepsia 38:859880.
  • Marson AG, Kadir ZA, Hutton JL, Chadwick DW. (2000) Gabapentin for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2:CD001415. Review. Update in: Cochran Database Syst Rev 2000;3:CD001415.
  • Marson AG, Hutton JL, Leach JP, Castillo S, Schmidt D, White S, Chaisewikul R, Privitera M, Chadwick DW. (2001) Levetiracetam, oxcarbazepine, remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review. Epilepsy Res 46:259270.
  • Mease PJ, Russell IJ, Arnold LM, Florian H, Young JP Jr, Martin SA, Sharma U. (2008) A randomized, double-blind, placebo-controlled, phase III trial of pregabalin in the treatment of patients with fibromyalgia. J Rheumatol 35:502514.
  • Michael B, Marson AG. (2008) Clobazam as an add-on in the management of refractory epilepsy. Cochrane Database Syst Rev 2:CD004154.
  • Montgomery SA, Tobias K, Zornberg GL, Kasper S, Pande AC. (2006) Efficacy and safety of pregabalin in the treatment of generalized anxiety disorder: a 6-week, multicenter, randomized, double-blind, placebo-controlled comparison of pregabalin and venlafaxine. J Clin Psychiatry 67:771782.
  • Montgomery S, Chatamra K, Pauer L, Whalen E, Baldinetti F. (2008) Efficacy and safety of pregabalin in elderly people with generalised anxiety disorder. Br J Psychiatry 193:389394.
  • Nakagawasai O, Onogi H, Mitazaki S, Sato A, Watanabe K, Saito H, Murai S, Nakaya K, Murakami M, Takahashi E, Tan-No K, Tadano T. (2010) Behavioral and neurochemical characterization of mice deficient in the N-type Ca2+ channel alpha1B subunit. Behav Brain Res 208:224230.
  • Pande AC, Crockatt JG, Feltner DE, Janney CA, Smith WT, Weisler R, Londborg PD, Bielski RJ, Zimbroff DL, Davidson JR, Liu-Dumaw M. (2003) Pregabalin in generalized anxiety disorder: a placebo-controlled trial. Am J Psychiatry 160:533540.
  • Pande AC, Feltner DE, Jefferson JW, Davidson JR, Pollack M, Stein MB, Lydiard RB, Futterer R, Robinson P, Slomkowski M, DuBoff E, Phelps M, Janney CA, Werth JL. (2004) Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo-controlled, multicenter study. J Clin Psychopharmacol 24:141149.
  • Pereira J, Marson AG, Hutton JL. (2002) Tiagabine add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 3:CD001908.
  • Perucca P, Carter J, Vahle V, Gilliam FG. (2009) Adverse antiepileptic drug effects: toward a clinically and neurobiologically relevant taxonomy. Neurology 72:12231229.
  • Pohl RB, Feltner DE, Fieve RR, Pande AC. (2005) Efficacy of pregabalin in the treatment of generalized anxiety disorder: double-blind, placebo-controlled comparison of BID versus TID dosing. J Clin Psychopharmacol 25:151158.
  • Ramaratnam S, Marson AG, Baker GA. (2000) Lamotrigine add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 3:CD001909. Review. Update in: Cochrane Database Syst Rev 2001;3:CD001909
  • RevMan. (2008) Review Manager (RevMan) [Computer program]. Version 5.0. The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen.
  • Richter RW, Portenoy R, Sharma U, Lamoreaux L, Bockbrader H, Knapp LE. (2005) Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. J Pain 6:253260.
  • Rickels K, Pollack MH, Feltner DE, Lydiard RB, Zimbroff DL, Bielski RJ, Tobias K, Brock JD, Zornberg GL, Pande AC. (2005) Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam. Arch Gen Psychiatry 62:10221030.
  • Rosenberg JM, Salzman C. (2007) Update: new uses for lithium and anticonvulsants. CNS Spectr 12:831841.
  • Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. (2004) Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain 110:628638.
  • Ryvlin P, Perucca E, Rheims S. (2008) Pregabalin for the management of partial epilepsy. Neuropsychiatr Dis Treat 4:12111224.
  • Ryvlin P, Kälviäinen R, Von Raison F, Giordano S, Emir B, Chatamra K. (2010) Pregabalin in partial seizures: a pragmatic 21-week, open-label study (PREPS). Eur J Neurol 17:726732.
  • Sabatowski R, Gálvez R, Cherry DA, Jacquot F, Vincent E, Maisonobe P, Versavel M, 1008-045 Study Group. (2004) Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain 109:2635.
  • Siddall PJ, Cousins MJ, Otte A, Griesing T, Chambers R, Murphy TK. (2006) Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Neurology 67:17921800.
  • Stacey BR, Barrett JA, Whalen E, Phillips KF, Rowbotham MC. (2008) Pregabalin for postherpetic neuralgia: placebo-controlled trial of fixed and flexible dosing regimens on allodynia and time to onset of pain relief. J Pain 9:10061017.
  • Tölle T, Freynhagen R, Versavel M, Trostmann U, Young JP Jr. (2008) Pregabalin for relief of neuropathic pain associated with diabetic neuropathy: a randomized, double-blind study. Eur J Pain 12:203213.
  • U.S. Food and Drug Administration. (2010) Joint meeting of the Peripheral and Central Nervous Drugs Advisory Committee and the Psychopharmacologic Drugs Advisory Committee: briefing material, July 10, 2008. http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4372b1-00-index.html. Accessed May 20, 2010.
  • van Seventer R, Feister HA, Young JP Jr, Stoker M, Versavel M, Rigaudy L. (2006) Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13-week, randomized trial. Curr Med Res Opin 22:375384.
  • Vranken JH, Dijkgraaf MG, Kruis MR, van der Vegt MH, Hollmann MW, Heesen M. (2008) Pregabalin in patients with central neuropathic pain: a randomized, double-blind, placebo-controlled trial of a flexible-dose regimen. Pain 136:150157.
  • Zesiewicz TA, Ward CL, Hauser RA, Salemi JL, Siraj S, Wilson MC, Sullivan KL. (2007) A pilot, double-blind, placebo-controlled trial of pregabalin (Lyrica) in the treatment of essential tremor. Mov Disord 22:16611663.
  • Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC. (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet 15:6269.

Supporting Information

  1. Top of page
  2. Summary
  3. Study end points
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. References
  11. Supporting Information

Appendix S1. MEDLINE (PubMed), EMBASE (OVID), and Cochrane CENTRAL search strategies.

Appendix S2. Characteristics of studies identified trough a search in MEDLINE, EMBASE, Cochrane CENTRAL issue 2 2010, ClinicalStudyResults.org, ClinicalTrials.gov, reference lists of retrieved papers, and the Internet.

Appendix S3. Fixed-effects meta-analyses to assess the association of any adverse event with pregabalin treatment.

Appendix S4. Adverse effects significantly associated with pregabalin at different doses.

Data S1. Brief summary.

FilenameFormatSizeDescription
EPI_2966_sm_AppendixS1.doc22KSupporting info item
EPI_2966_sm_AppendixS2.doc247KSupporting info item
EPI_2966_sm_AppendixS3.doc682KSupporting info item
EPI_2966_sm_AppendixS4.doc948KSupporting info item
EPI_2966_sm_Briefsummary.doc23KSupporting info item

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