Oxcarbazepine for neuropathic pain

  • Review
  • Intervention

Authors


Abstract

Background

Neuropathic pain is difficult to treat. Oxcarbazepine is an anticonvulsant drug closely related to carbamazepine and is reportedly better tolerated. Oxcarbazepine has been reported to be efficacious in the treatment of neuropathic pain.

Objectives

To determine the benefits and harms of oxcarbazepine for different forms of neuropathic pain.

Search methods

We searched the Cochrane Neuromuscular Disease Group Specialized Register (30 October 2012), CENTRAL (2012, Issue 10), MEDLINE (January 1966 to October 2012), EMBASE (January 1980 to October 2012) and the Chinese Biomedical Retrieval System (January 1978 to October 2012) for trials. We also searched the National Institutes of Health (NIH) databases and the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing trials, and wrote to the companies who make oxcarbazepine and to pain experts asking for additional information.

Selection criteria

All randomised controlled trials and cross-over studies of oxcarbazepine for the treatment of people of any age or sex with any neuropathic pain were eligible. We planned to include trials of oxcarbazepine compared with placebo or any other intervention, regardless of administration route, dosage or length of treatment.

Data collection and analysis

Two review authors independently selected the studies for inclusion, assessed their risk of bias, extracted data and typed the data onto forms. The authors resolved any disagreements through discussion.

Main results

Four multicentre, randomised, placebo-controlled, double-blind trials with a total of 779 participants were eligible for inclusion. These were from a series of studies funded by the manufacturer. Three of them investigated oxcarbazepine in people with painful diabetic neuropathy (634 participants) and one was a trial of oxcarbazepine for neuropathic pain due to radiculopathy (145 participants). Although these trials were well designed, the imbalanced and large amount of incomplete outcome data led to a risk of bias in the results. Results for painful diabetic neuropathy showed that compared to the baseline the proportion of participants who reported a 50% or 30% reduction of pain scores after 16 weeks of treatment was significantly higher in the oxcarbazepine group than the placebo group (50% reduction: risk ratio (RR) 1.91, 95% confidence interval (CI) 1.08 to 3.39, number of people needed to treat for an additional beneficial outcome (NNTB) 6.0, 95% CI 3.3 to 41.0; 30% reduction: RR 1.57, 95% CI 1.01 to 2.44, NNTB 6.1, 95% CI 3.1 to 113.6). However, both results were based on data from the single positive trial (146 participants) since the two negative trials did not provide data that could be included in a meta-analysis. For participants with neuropathic pain due to radiculopathy, the trial demonstrated no significant efficacy for oxcarbazepine. Although trial reports stated that most side effects were mild to moderate in severity, more people experienced serious adverse events with oxcarbazepine than with placebo (RR 3.65, 95% CI 1.45 to 9.20, number needed to treat for an additional harmful outcome (NNTH) 17.4, 95% CI 11.0 to 42.0) in the three painful diabetic neuropathy trials. The proportion of people with adverse events leading to withdrawals was statistically higher in the oxcarbazepine group than in the placebo group (RR 3.83, 95% CI 2.29 to 6.40). For radiculopathy the difference between oxcarbazepine and placebo did not reach significance for serious adverse events, but more people had adverse events leading to withdrawal with oxcarbazepine than with placebo (RR 2.84, 95% CI 1.55 to 5.23).

Authors' conclusions

On the basis of moderate quality evidence from one trial in diabetic peripheral neuropathy, oxcarbazepine is effective in reducing pain for this condition. However, this conclusion does not take into account negative results from other trials in diabetic peripheral neuropathy that could not be included in our meta-analysis. We did not find any evidence from randomised controlled trials to determine the efficacy or safety of oxcarbazepine for other kinds of neuropathic pain, other than one low quality trial in people with radiculopathy. Most adverse effects related to oxcarbazepine are rated as mild to moderate in severity, but adverse events leading to discontinuation of drug administration or serious adverse events are not uncommon. More well designed randomised controlled trials investigating oxcarbazepine for various types of neuropathic pain are needed.

Résumé scientifique

L'oxcarbazépine contre la douleur neuropathique

Contexte

La douleur neuropathique est difficile à traiter. L'oxcarbazépine est un anticonvulsivant étroitement lié à la carbamazépine et qui serait mieux toléré. Il a été rapporté que l'oxcarbazépine était efficace dans le traitement de la douleur neuropathique.

Objectifs

Déterminer les avantages et les inconvénients de l'oxcarbazépine pour différentes formes de douleur neuropathique.

Stratégie de recherche documentaire

Nous avons recherché des essais dans le registre spécialisé du groupe Cochrane sur les affections neuro-musculaires (30 octobre 2012), CENTRAL (2012, numéro 10), MEDLINE (de janvier 1966 à octobre 2012), EMBASE (de janvier 1980 à octobre 2012) et le Chinese Biomedical Retrieval System (de janvier 1978 à octobre 2012). Nous avons également cherché des essais cliniques en cours dans les bases de données du National Institutes of Health (NIH) et dans le système d’enregistrement international des essais cliniques de l’Organisation mondiale de la Santé (OMS), et nous avons écrit aux fabricants de l'oxcarbazépine et à des spécialistes de la douleur pour leur demander des informations supplémentaires.

Critères de sélection

Était éligible tout essai clinique randomisé et toute étude croisée sur l'oxcarbazépine pour le traitement de personnes de tout âge et tout sexe atteintes de douleurs neuropathiques. Nous avions prévu d'inclure des essais sur l'oxcarbazépine comparée à un placebo ou à toute autre intervention, quelle que soit la voie d'administration, la posologie et la durée du traitement.

Recueil et analyse des données

Deux auteurs de la revue ont, de manière indépendante, sélectionné les études à inclure, évalué leurs risques de biais, extrait les données et saisi celles-ci sur des formulaires. Les auteurs ont résolu tous les désaccords par la discussion.

Résultats principaux

Quatre essais randomisés, en double aveugle, contrôlés par placebo et multicentriques, avec un total de 779 participants, étaient éligibles à l'inclusion. Ils faisaient partie d'une série d'études financées par le fabricant. Trois d'entre eux avaient étudié l'oxcarbazépine chez les personnes souffrant de neuropathie diabétique douloureuse (634 participants) et le quatrième était un essai sur l'oxcarbazépine pour la douleur neuropathique due à une radiculopathie (145 participants). Bien que ces essais aient été bien conçus, la quantité importante et déséquilibrée de données de résultat incomplètes conduisait à un risque de biais dans les résultats. Les résultats pour la neuropathie diabétique douloureuse ont montré que la proportion de participants ayant fait état d'une baisse de 50 % ou de 30 % des scores de douleur après 16 semaines de traitement était significativement plus élevée dans le groupe à oxcarbazépine que dans le groupe à placebo (baisse de 50 % : risque relatif (RR) 1,91 , intervalle de confiance (IC) à 95% 1,08 à 3,39 , nombre de sujets à traiter pour observer un résultat bénéfique supplémentaire (NSTb) 6,0 , IC à 95% 3,3 à 41,0 ; baisse de 30 % : RR 1,57 , IC à 95% 1,01 à 2,44 , NSTb 6,1 , IC à 95% 3,1 à 113,6). Ces deux résultats sont toutefois basés sur des données provenant du seul essai positif (146 participants) puisque les deux essais négatifs n'ont pas fourni de données pouvant être incluses dans une méta-analyse. Pour les participants souffrant de douleurs neuropathiques dues à une radiculopathie, l'essai n'avait pas mis en évidence d'efficacité significative pour l'oxcarbazépine. Bien que les rapports des essais indiquaient que la plupart des effets indésirables étaient légers à modérés, la proportion d'événements conduisant à des retraits était statistiquement plus élevée dans le groupe à oxcarbazépine que dans le groupe à placebo, tant pour la neuropathie diabétique douloureuse (RR 3,86 ; IC à 95% 2,29 à 6,40) que pour la radiculopathie (RR 2,84 ; IC à 95% 1,55 à 5,23).

Conclusions des auteurs

D'après les données de qualité moyenne issues d'un essai concernant la neuropathie diabétique périphérique, l'oxcarbazépine est efficace pour réduire la douleur dans cette maladie. Toutefois, cette conclusion ne prend pas en compte les résultats négatifs d'autres essais dans le domaine de la neuropathie diabétique périphérique qui ne pouvaient pas être inclus dans notre méta-analyse. Nous n'avons pas trouvé de données issues d'essais contrôlés randomisés permettant de déterminer l'efficacité ou l'innocuité de l'oxcarbazépine pour d'autres types de douleur neuropathique. La plupart des effets indésirables liés à l'oxcarbazépine sont classés comme légers à modérés, mais les événements indésirables ayant conduit à l'arrêt de l'administration du médicament ou à des effets indésirables graves ne sont pas rares. Il sera nécessaire d'effectuer de nouveaux essais contrôlés randomisés bien conçus sur l'oxcarbazépine pour différents types de douleur neuropathique.

Plain language summary

Oxcarbazepine for neuropathic pain

Neuropathic pain is pain that arises from damage to the part of the nervous system that carries sensory information to the brain. It is difficult to treat because of its severity, duration and resistance to simple painkillers. Some studies have suggested that oxcarbazepine, when given on its own, can relieve pain from nerve damage. To investigate the benefits and harms of oxcarbazepine in different forms of neuropathic pain, we performed a comprehensive search for randomised controlled trials and found four trials, involving 634 participants with painful diabetic neuropathy and 145 with neuropathic pain due to radiculopathy. All were funded by the manufacturer. The results showed that oxcarbazepine produced pain relief and an improved global impression of change in pain at 16 weeks for people with diabetic neuropathy. This evidence, which was of moderate quality, only included data from the single positive trial, and did not take into account negative results from other diabetic peripheral neuropathy trials that could not be included in our analysis. For painful radiculopathy, data from the only included trial showed no significant efficacy of oxcarbazepine. Although trial reports stated that most side effects were mild to moderate in severity, the number of any kind of event and those leading to participants' dropping out of the trials were both higher in the oxcarbazepine group than in the placebo group, and serious events were not uncommon. In the radiculopathy trial, numbers with serious adverse events were similar with oxcarbazepine and placebo, but with oxcarbazepine more people experienced adverse events that led them to stop treatment. We did not find studies of oxcarbazepine for other types of neuropathic pain that met our inclusion criteria. More well designed randomised controlled trials of oxcarbazepine for various types of neuropathic pain are needed, with large numbers of participants spread over different centres. Such studies should also compare the effect of different dosages on pain relief.

Résumé simplifié

L'oxcarbazépine contre la douleur neuropathique

La douleur neuropathique est une douleur qui résulte d'atteintes à la partie du système nerveux qui transporte l'information sensorielle vers le cerveau. Elle est difficile à traiter en raison de son intensité, de sa durée et de sa résistance aux simples analgésiques. Certaines études ont suggéré que l'oxcarbazépine, lorsqu'administrée seule, peut soulager la douleur causée par des atteintes nerveuses. Afin d'étudier les avantages et les inconvénients de l'oxcarbazépine dans différentes formes de douleur neuropathique, nous avons effectué une recherche exhaustive d'essais contrôlés randomisés et avons trouvé quatre essais impliquant 634 participants souffrant de neuropathie diabétique douloureuse et 145 participants souffrant de douleurs neuropathiques dues à une radiculopathie. Tous avaient été financés par le fabricant. Les résultats montraient que l'oxcarbazépine produit un soulagement de la douleur ainsi qu'une meilleure impression globale de changement de la douleur après 16 semaines chez les personnes atteintes de neuropathie diabétique. Ce résultat, qui était de qualité moyenne, ne reposait que sur les données du seul essai positif et ne prenait pas en compte les résultats négatifs d'autres essais sur la neuropathie diabétique périphérique que nous ne pouvions pas inclure dans notre analyse. Pour la radiculopathie douloureuse, les données du seul essai inclus ne mettaient pas en évidence une efficacité significative de l'oxcarbazépine. Bien que les rapports des essais indiquaient que la plupart des effets indésirables étaient légers à modérés, les nombres de tous les types d'événements ainsi que de ceux ayant conduit à l'abandon de participants étaient significativement plus élevés dans le groupe à oxcarbazépine que dans le groupe à placebo, et les événements graves n'étaient pas rares. Nous n'avons pas trouvé d'études sur l'oxcarbazépine pour d'autres types de douleur neuropathique qui répondent à nos critères d'inclusion. Il sera nécessaire d'effectuer de nouveaux essais contrôlés randomisés bien conçus sur l'oxcarbazépine pour différents types de douleur neuropathique, avec de nombreux participants provenant de différentes populations et répartis sur plusieurs centres. Ces études devraient également comparer l'effet de différentes posologies sur le soulagement de la douleur et les effets indésirables.

Notes de traduction

Traduit par: French Cochrane Centre 22nd March, 2013
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux pour la France: Minist�re en charge de la Sant�

Laički sažetak

Lijek okskarbazepin za liječenje neuropatske boli

Neuropatska bol je bol koja nastaje zbog oštećenja dijela živčanog sustava koji prenosi osjetne informacije do mozga. Teško ju je liječiti zbog njene ozbiljnosti, trajanja i otpornosti na jednostavne lijekove protiv bolova. Neke studije sugerirale su da okskarbazepin, kada se daje samostalno, može smanjiti bol nastalu zbog oštećenja živaca. Kako bi se ispitale prednosti i nedostatke korištenja okskarbazepina u liječenju različitih oblika neuropatske boli, proveden je Cochrane sustavni pregled u kojem je napravljeno opsežno pretraživanje literature kako bi se našli randomizirani klinički pokusi na tu temu. Pronađena su četiri takva pokusa koja su uključivala 634 sudionika sa bolnom dijabetičkom neuropatijom i 145 sudionika kod kojih je neuropatska bol nastala zbog radikulopatije. Sva istraživanja su bila financirana od strane proizvođača. Rezultati su pokazali da okskarbazepin, nakon 16 tjedana tretmana, djeluje na ublažavanje boli i poboljšani globalni dojam promjene u boli kod osoba oboljelih od dijabetičke neuropatije. Ovi dokazi, koji su umjerene kvalitete, uključuju samo podatke dobivene iz jednog pozitivnog istraživanja i nisu uzeti u obzir negativni rezultati iz ostalih istraživanja dijabetičke periferne neuropatije koji nisu mogli biti uključeni u ovu analizu. Kod osoba oboljelih od radikulopatije, podaci iz jedinog istraživanja uključenog u analizu nisu pokazivali značajnu učinkovitost okskarbazepina. Iako su prikazi istraživanja navodili da je većina nuspojava bila blage do umjerene težine, broj bilo koje vrste događaja, kao i onih događaja koji su doveli do odustajanja sudionika iz istraživanja, su bili veći u skupini koja je uzimala okskarbazepin nego u skupini koja je uzimala placebo, a ozbiljni štetni učinci nisu bili rijetkost. U istraživanju koje je uključivalo osobe oboljele od radikulopatije, broj štetnih nuspojava je bio sličan u skupini koja je primala okskarbazepin i skupini koja je primala placebo, ali u skupini koja je primala okskarbazepin više osoba je osjetilo nuspojave koje su ih navele da prekinu liječenje. Osim navedenih istraživanja nismo pronašli istraživanja koja bi zadovoljila naše kriterije, a koja bi pratila učinke okskarbazepina na druge vrste neuropatske boli. Stoga je potrebno provesti više dobro osmišljenih randomiziranih kliničkih pokusa koji bi istražili učinak okskarbazepina na druge vrste neuropatske boli, te uključili velik broj sudionika iz više istraživačkih centara. Takva istraživanja trebala bi također uspoređivati utjecaj različitih doza okskarbazepina na ublažavanje boli.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Tihana Repić
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Summary of findings(Explanation)

Summary of findings for the main comparison. Oxcarbazepine versus placebo for painful diabetic neuropathy
  1. 1 The numbers of withdrawal were not balanced across groups, especially those due to adverse events.
    2 The placebo responses of included trials showed considerable inconsistency.
    3 Results of each daily dose group suggested trends of dose-effect relationships both for global recovery and adverse events: the highest daily dose (1800 mg/day) of oxcarbazepine had the best effect on pain relief but also led to the most adverse events, especially serious ones.

Oxcarbazepine versus placebo for painful diabetic neuropathy
Patient or population: people with painful diabetic neuropathy
Settings: hospitals and clinics
Intervention: oxcarbazepine
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Placebo oxcarbazepine
Reduction in patient-reported pain scores by 50% from the baseline
Visual Analogue Scale
Follow-up: mean 16 weeks
182 per 1000 348 per 1000
(197 to 617)
RR 1.91
(1.08 to 3.39)
146
(1 study)
⊕⊕⊕⊝
moderate 1
NNTB 6.0 (95% CI 3.3 to 41.0)
Reduction in patient-reported pain scores by 30% from the baseline
Visual Analogue Scale
Follow-up: mean 16 weeks
286 per 1000 449 per 1000
(289 to 698)
RR 1.57
(1.01 to 2.44)
146
(1 study)
⊕⊕⊕⊝
moderate 1
NNTB 6.1 (95% CI 3.1 to 113.6)
Patients with obvious or significant improvement after 16 weeks treatment
the patient's global assessment of therapeutic effect
Follow-up: mean 16 weeks
301 per 1000 439 per 1000
(340 to 566)
RR 1.46
(1.13 to 1.88)
493
(2 studies)
⊕⊕⊕⊝
moderate 1,2,3
NNTB 6.4 (95% CI 4.1to 14.4)
Serious adverse events
clinical manifestation
Follow-up: mean 16 weeks
25 per 1000 91 per 1000
(36 to 230)
RR 3.65
(1.45 to 9.2)
634
(3 studies)
⊕⊕⊕⊝
moderate 1,2,3
NNTH 17.4 (95% CI 11.0 to 42.0).
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harmful outcome.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Neuropathic pain is defined as "pain initiated or caused by a primary lesion or dysfunction of the nervous system" (Merskey 1994) or more recently as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system" (Treede 2008). Neuropathic pain is difficult to treat because of its severity, chronicity and resistance to simple analgesics. Neuropathic pain may have its genesis in the brain, spinal cord or peripheral nerves and arises from conditions including radiculopathy (cervical or lumbar), malignancy, infection (for example postherpetic neuralgia and human immunodeficiency virus (HIV) related neuropathy), injury to the spinal cord, diabetic neuropathy, trigeminal neuralgia and complex regional pain syndrome type II (Jensen 2001). The epidemiology of neuropathic pain has not been well described, at least in part because the underlying conditions are so diverse. Current pooled estimates suggest that as much as 3% of the population may be affected by neuropathic pain (Davis 2004; Foley 2003; Heliovaara 1987; Schmader 2002; Verma 2005; Werhagen 2004).

The underlying mechanisms of neuropathic pain are complicated and unclear (Finnerup 2007). It is known that the peripheral and central nervous systems are capable of both structural and functional plastic changes in response to injury and experience. Peripheral changes include the sensitisation of nociceptors, which results in decreased activation thresholds and increased pain in response to a given stimulus, and abnormal neuronal sprouting that leads to expansion of nociceptive receptive fields and ectopic firing of dorsal root ganglia cells. Changes in expression of abnormal sodium and calcium channels are considered to be instrumental in the generation of spontaneous discharges from injured neurons (Callin 2008).

Central changes following peripheral nerve injury include loss of inhibitory effects in the central nervous system and heightened sensitivity of neurons in the spinal cord, which occurs in spite of reduced peripheral input. Moreover, N-methyl-D-aspartic acid (NMDA) receptors are upregulated and activated and play an important role in central sensitisation in neuropathic pain. Other important findings include facilitatory descending pathways and the potential relevance of genetic differences between individuals (Callin 2008; Carpenter 2002; Suzuki 2004).

Neuropathic pain has a profound effect on quality of life and expenditure on health care (Schmader 2002). It remains a major therapeutic challenge despite considerable research efforts during the past few decades. The shared pathophysiology of neuropathic pain and epilepsy supports the rationale for using certain antiepileptic drugs (AEDs) in the treatment of neuropathic pain (Dickenson 2002; Jensen 2002). A number of Cochrane reviews assess the effects of individual AEDs in neuropathic pain, including lamotrigine (Wiffen 2011a), carbamazepine (Wifffen 2011b), gabapentin (Moore 2011), pregabalin (Moore 2009), valproic acid (Gill 2011), phenytoin (Birse 2012) and clonazepam (Corrigan 2012). These replace an original review of AEDs for neuropathic pain (Wiffen 2010), first published in 2005 and now withdrawn.

Oxcarbazepine (10,11-dihydro-10-oxo-5H,dibenz[b,f]azepine-5-carboxamide) is the keto analogue of carbamazepine, a sodium channel modulator used primarily in the treatment of epilepsy as well as trigeminal neuralgia. It has previously been reported to be better tolerated and safer than carbamazepine, with a lower risk of allergic reactions and drug-drug interactions (Beydoun 2002a; Dam 1989). Three double-blind, placebo-controlled trials have evaluated oxcarbazepine in painful diabetic neuropathy. Two of them (Beydoun 2006; Dogra 2005) showed statistically significant pain reduction in participants treated with oxcarbazepine compared with placebo, while the other (Grosskopf 2006) showed no difference in efficacy between oxcarbazepine-treated and placebo-treated participants.

Data on the potential efficacy of oxcarbazepine for treating the pain associated with trigeminal neuralgia were derived from an active-control double-blind trial (Lindstrom 1987) and meta-analyses (Beydoun 2002a; Beydoun 2002b) of three double-blind comparative trials. These showed that oxcarbazepine produced substantial pain relief in the great majority of people suffering from trigeminal neuralgia and that there was no significant difference in pain relief between oxcarbazepine and carbamazepine. Additionally, a pooled analysis was performed of seven open-label clinical trials, sharing the same protocol, of oxcarbazepine in different neuropathic pain conditions (Magenta 2005). The results of this analysis suggest that oxcarbazepine administered as monotherapy can relieve pain associated with neuropathies. We undertook this Cochrane review to systematically gather and assess the evidence from randomised controlled trials (RCTs) on the use of oxcarbazepine for all forms of neuropathic pain.

Objectives

To determine the benefits and harms of oxcarbazepine for different forms of neuropathic pain.

Methods

Criteria for considering studies for this review

Types of studies

We included RCTs or cross-over studies of oxcarbazepine for the treatment of neuropathic pain. Trials were eligible whether published or unpublished. There was no language restriction. We interviewed the study authors by telephone or wrote for clarification if the studies were described as RCTs but there was poor reporting of the methodology. We excluded quasi-randomised trials and trials where the reports described them as randomised but which proved not to be randomised on further examination.

Types of participants

Participants of any age or either sex with any neuropathic pain were eligible.

Types of interventions

Oxcarbazepine versus placebo or any other intervention, regardless of administration route, dosage, or length of treatment. We allowed co-interventions if they were offered equally to both arms of the trial.

Types of outcome measures

We planned to measure outcomes as close to eight weeks (minimum six weeks) as possible. When outcomes were reported after different durations of treatment we extracted the data measured as close to the specified time as possible, but not less than the minimum. In fact we could only obtain 16-week follow-up data from the included trials, so we only performed analysis of results at the 16th week.

Primary outcomes

The primary outcome measure was reduction in patient-reported pain scores by 50% from the baseline, measured on commonly used pain scales such as the Visual Analogue Scale (VAS), the Verbal Rating Scale (VRS), the Numerical Rating Scale (NRS) (Williamson 2005) and the Faces Pain Scale (FPS) (Bieri 1990).

Secondary outcomes

1. Reduction in patient-reported pain scores by 30% from the baseline, measured on commonly used pain scales.

2. Patients' global impression of their change in pain at eight weeks.

3. Overall quality of life measures, as changes or levels at eight weeks using the Short Form-36 Health Survey (SF-36) (Ware 1992), including both the physical health summary, mental health summary and the pain subscale.

4. Adverse effects measures occurring in the eight weeks after start of treatment. Adverse events were classified as any adverse effect, adverse effects which led to withdrawal from treatment, and serious adverse effects which were life threatening, required hospitalisation or were fatal.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Neuromuscular Disease Group (CNMDG) Specialized Register (30 October 2012) for randomised trials using the following search terms: (oxcarbazepine or Trileptal or Trexapin) AND (neuropathic pain or cervical radiculopathy or lumbar radiculopathy or diabetic neuropathy or peripheral neuropathy, neuropathic pain or postherpetic neuralgia or HIV-related neuropathy or spinal cord injury or trigeminal neuralgia or complex regional pain syndrome type II AND pain). We adapted this strategy to search the following databases: CENTRAL (2012, Issue 10), MEDLINE (January 1966 to October 2012), EMBASE (January 1980 to October 2012) and the Chinese Biomedical Retrieval System (January 1978 to October 2012). We also searched the National Institutes of Health (NIH) databases and the World Health Organization (WHO) International Clinical Trials Registry Platform for current ongoing registered trials.

The detailed search strategies are in the appendices: MEDLINE (Appendix 1), EMBASE (Appendix 2), CENTRAL (Appendix 3) and Chinese Biomedical Retrieval System (Appendix 4).

Searching other resources

We wrote to the companies (for example Novartis Pharmaceuticals) who made oxcarbazepine and to pain experts asking for information about other or ongoing trials. We examined the Novartis clinical trials results database with the assistance of the CNMDG Managing Editor. We also searched reference lists of review articles and included studies.

Data collection and analysis

Two review authors (MZ and NC) independently selected the studies for inclusion, assessed their risk of bias and extracted relevant data. The CNMDG Managing Editor also assisted in the identification of trial reports by performing an independent review of English language search results. One author (NC) entered the data into the Cochrane statistical software Review Manager 5 (RevMan 5) and the other one (MZ) checked it. The review authors resolved disagreements through discussion.

Selection of studies

Two review authors scrutinised all the titles and abstracts identified by the searches to determine which might fulfil the selection criteria. We obtained full reports of all the potentially eligible studies (when available) to determine if they met the inclusion criteria for the review. We included randomised trials reporting the analgesic effects of oxcarbazepine with subjective assessment of pain of neuropathic origin. We excluded studies that included participants with chronic headache and migraine.

Data extraction and management

We extracted the data from included trials using a specially designed data extraction form. The following data items were extracted.

  • Participants: number, age range, gender, type of neuropathic disorder, setting.

  • Intervention: dosing regimen, duration, route of administration.

  • Control: placebo, other intervention.

  • Outcomes: analgesic outcome measures and results, withdrawals and adverse effects (minor and major).

  • Design: methods of randomisation, study design (parallel group, cross-over), treatment duration and duration of study follow-up, and whether specifically designed to measure pain.

We also included risk of bias criteria on the data extraction form: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other concerns about bias.

Assessment of risk of bias in included studies

Two authors (MZ and NC) independently assessed risk of bias according to the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008b; Higgins 2011). The authors resolved any disagreement by discussion.

The authors considered six specific domains (namely sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other issues). They assessed the adequacy of each included study in relation to the entry as at low, high or unclear risk of bias.

Measures of treatment effect

Only dichotomous variables regarding our outcome measures were available from the included trials, so we calculated the relative benefit (expressed as risk ratio (RR)) in RevMan with the 95% confidence interval (CI).

Unit of analysis issues

We would have analysed cross-over trials in two ways: firstly using only the data from the first treatment period, and secondly using data from both treatment periods provided that the washout period was adequate. We would have analysed the results with the generic inverse variance (GIV) method.

In addition, we recorded any data relating to patient preference.

Dealing with missing data

We dealt with missing data, such as missing standard deviations, by attempting to contact the authors via email or telephone. If participant dropout led to missing data we conducted an intention-to-treat (ITT) analysis whenever possible. For dichotomous outcomes, we regarded participants with missing outcome data as treatment failures and included these in the analysis. For continuous outcomes, we carried forward the last recorded value for participants with missing outcome data (Higgins 2009).

Assessment of heterogeneity

We performed formal statistical testing of heterogeneity between the trials using the RevMan software.

Data synthesis

We presented the pooled outcomes data from all similar studies using risk ratios (RRs) and 95% confidence intervals (CIs).

We also reported results as number needed to treat for an additional beneficial outcome (NNTB) for the specified percentage change in pain scores and number needed to treat for an additional harmful outcome (NNTH) for mild and serious adverse drug reactions.

We planned to perform analyses using a fixed-effect model unless significant heterogeneity was found, when we used a random-effects model. Where appropriate, we combined data from included studies using RevMan.

We also included a 'Summary of findings' (SoF) table, which presented the main findings of the review including information about the quality of the evidence, the magnitude of effects and the sum of the available data on the main outcomes (Schünemann 2008). We included the following outcomes.

  1. Reduction in patient-reported pain scores by 50% from baseline.

  2. Reduction in patient-reported pain scores by 30% from baseline.

  3. Patients with obvious or significant improvement after 16 weeks of treatment.

  4. Serious adverse events.

Subgroup analysis and investigation of heterogeneity

Where data were available, we planned to undertake subgroup analysis according to the types of neuropathic pain (peripheral neuropathic pain and central neuropathic pain).

Sensitivity analysis

We planned to conduct sensitivity analyses to examine the effects of excluding poor quality studies, defined as those with a moderate or high risk of bias as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Since all the included trials were rated as of moderate quality, we did not perform any sensitivity analyses in the present review.

This review has a published protocol (Zhou 2009). Deviations from the protocol are described in Differences between protocol and review.

Results

Description of studies

Results of the search

The electronic searches retrieved a number of references: 12 from the Cochrane Neuromuscular Disease Group Specialized Register, 71 from MEDLINE, 95 from EMBASE, 14 from CENTRAL, 3 from DARE and 18 from the Chinese Biomedical Retrieval System. From the searches in other resources, including replies from the companies, company databases and the reference lists of found articles, we retrieved five additional references, one of which is an ongoing trial (NCT01302275) and another is a study awaiting classification (Brainer-Lima 2003). From the total of 186 references (excluding duplicates) we identified 36 records reporting the efficacy or safety, or both, of oxcarbazepine for the treatment of different neuropathic pain conditions. Most of them were judged not to meet the entry criteria of the present review because the titles or abstracts indicated that they were open-label clinical trials comparing the efficacy and safety outcomes at the end of studies with the baseline conditions. Of the 21 remaining possibly appropriate records we excluded nine references (see Characteristics of excluded studies). We included four trials (described in nine references) (Beydoun 2006; Dogra 2005; Grosskopf 2006; Novartis 2004) which met the eligibility criteria (see Characteristics of included studies) and two studies are awaiting classification (Brainer-Lima 2003; Liebel 2001). An additional study is ongoing (NCT01302275). See Figure 1 for a flow chart illustrating study selection.

Figure 1.

Study flow diagram.

Included studies

Although we tried to identify studies pertaining to various kinds of neuropathic pain three of the included studies, which involved a total of 634 participants, investigated people with painful diabetic neuropathy (Beydoun 2006; Dogra 2005; Grosskopf 2006) and one trial involved 145 participants with neuropathic pain due to radiculopathy (Novartis 2004). We did not identify any trial eligible for inclusion that investigated other kinds of neuropathic pain.

We found that the four included trials were from a series of studies supported by the manufacturer, so they had similar design, inclusion and exclusion criteria, efficacy and safety assessments (Beydoun 2006; Dogra 2005; Grosskopf 2006; Novartis 2004).

The four studies were all placebo-controlled, double-blind, parallel-group trials and were conducted in multiple clinics and research centres. The reported study periods differed: a total of 72 weeks for the Dogra 2005 study, and 18 weeks for the Beydoun 2006, Grosskopf 2006 and Novartis 2004 studies. The Dogra 2005 trial consisted of a two-week pre-randomisation screening phase, an 18-week double-blind treatment phase and a 52-week open-label extension phase; while the latter three trials consisted of the screening phase (two weeks) and the double-blind treatment phase (16 weeks) (Beydoun 2006; Grosskopf 2006; Novartis 2004). The double-blind treatment phase was further divided into a titration period of four weeks and a maintenance period of 12 weeks in each study, and an additional follow-up period of two weeks for safety monitoring in the Dogra 2005 study.

Inclusion and exclusion criteria were explicitly stated. The three studies investigating treatment for painful diabetic neuropathy recruited men and non-pregnant, non-lactating women aged 18 years or older with an established clinical diagnosis of type 1 or 2 diabetes mellitus and with a history of neuropathic pain for six months to five years prior to study entry. Stable diabetic control and a certain pain severity and variability were also required. The other trial investigating participants with radiculopathy enrolled participants aged 18 years or older, of both genders, with a diagnosis of radiculopathy and evidence of motor deficit or reflex loss on examination, a history of neuropathic pain for six months or longer, and a VAS score of 50 or higher. Exclusion criteria were: patients with other types of pain, significant medical or psychiatric illnesses, a prior history of hyponatraemia, drug or alcohol abuse, amputations other than the toes, previous treatment with oxcarbazepine or a history of sensitivity to carbamazepine or its metabolites (see Characteristics of included studies). The baseline characteristics of participants were reported to be well matched between groups in each trial in terms of demography, duration of the primary disorders, and duration and severity of neuropathic pain. In total, the studies in this review included 421 males and 358 females, of whom 469 received oral oxcarbazepine and 310 received placebo. The mean duration of neuropathic pain (2.4 to 7.7 years) and average VAS score (100-point scale) of participants before treatment (70.7 to 76.9) in each group were also reported and no significant differences between any groups were found.

After the screening phase, eligible participants were randomised to placebo or to oxcarbazepine treatment with a given target dose. There was only one active group in the Dogra 2005 (oxcarbazepine 1800 mg/day), Grosskopf 2006 (oxcarbazepine 1200 mg/day) and Novartis 2004 (oxcarbazepine 1800 mg/day) studies, while in the Beydoun 2006 study one of the three doses of oxcarbazepine (300 mg, 600 mg, 900 mg) was given twice a day to participants in the different experimental groups. For the present analyses, 83 participants with painful diabetic neuropathy were analysed in the oxcarbazepine 600 mg/day group, 158 in the 1200 mg/day group and 157 in the 1800 mg/day group; and 71 participants with pain due to radiculopathy were analysed in the oxcarbazepine 1800 mg/day group. At the beginning of the treatment phase, participants took a small initial dose of study medication (300 mg/day) and then the oxcarbazepine was titrated over four weeks according to tolerability or the given maximum dose. During the subsequent maintenance period, treatment remained at the dose reached at the end of the titration period. Meanwhile participants in the control group received matching placebo tablets. The percentages of participants who achieved their target dose at the end of the Beydoun 2006 study were 82% (600 mg/day), 62% (1200 mg/day) and 56% (1800 mg/day); and 55% in the active group in the Dogra 2005 study. The mean oxcarbazepine dose during the maintenance period was 1455 ± 389 mg/day for the Dogra 2005 study and 1091 ± 222 mg/day for Grosskopf 2006. Acetaminophen was allowed in all trials as rescue medication, some other analgesics or drugs like benzodiazepines, non-steroidal anti-inflammatory drugs, opioids or stable doses of selective serotonin reuptake inhibitors were permitted during the study phase in one trial (Novartis 2004) but not allowed in the other three studies (Beydoun 2006; Dogra 2005; Grosskopf 2006).

Variables were evaluated after treatment for 16 consecutive weeks (Beydoun 2006; Grosskopf 2006) or 18 consecutive weeks (Dogra 2005) and withdrawals were recorded in detail. There were high percentages of dropouts, with the overall percentages of participants completing the studies being 67% (Beydoun 2006), 72% (Dogra 2005) and 67% (Grosskopf 2006). Common reasons for discontinuation included adverse effects, protocol violations and unsatisfactory responses to treatment. Most efficacy analyses were performed with an ITT analysis, which comprised all randomised participants regardless of completeness of treatment or follow-up, based on the last observation carried forward (LOCF) principle.

The outcome measures were also similar among the four trials. They all used a VAS for participants to report their pain severity. For the three trials investigating painful diabetic neuropathy (Beydoun 2006; Dogra 2005; Grosskopf 2006), the primary outcome was the change in average daily VAS scores between baseline and the end of double-blind treatment. The fourth trial compared the average VAS score between groups during the last week of double-blind treatment (Novartis 2004). Other efficacy variables used in the four trials included: the patient's global assessment of therapeutic effect (GATE), onset of therapeutic effect, durability of treatment effect, and sleep disturbances. Quality of life was also assessed by the SF-36 Health Survey and the Profile of Mood States (POMS) on up to five occasions throughout the double-blind phase. In addition, all included trials reported adverse events during the treatment phase and serious adverse events and those leading to discontinuation were clearly described (Beydoun 2006; Dogra 2005; Grosskopf 2006; Novartis 2004).

Excluded studies

We excluded nine studies (Beydoun 2002; Beydoun 2007; Gong 2010; Hu 2010; Li 2011; Lindström 1987; Rémillard 1994; Venancio-Ramirez 2004; Zhou 2010) on inspection of the text because they: did not refer to any of the outcome measures specified in our protocol and the sponsor company could not find the full text or any useful data (Beydoun 2002); were open-label studies only evaluating the changes between the pre- and post-treatment conditions, without control groups (Beydoun 2007; Rémillard 1994); did not use a blind design (Gong 2010; Hu 2010; Li 2011; Zhou 2010); or involved a short follow-up duration, less than the minimum we specified in our protocol (Lindström 1987; Venancio-Ramirez 2004). See Characteristics of excluded studies.

Another study was only available as an abstract (Liebel 2001), which did not refer to any of the outcome measures specified in our protocol. We identified an additional abstract from the reference list of a review (Brainer-Lima 2003). The study randomised 20 participants with cancer-related neuropathic pain to oxcarbazepine or amitriptyline. Opiates were then gradually discontinued. It was unclear from the abstract whether each group received the same opioid regime. We have not received any reply from the authors of the abstracts, the two trials are therefore awaiting classification.

We also found a trial which is still ongoing (NCT01302275). It is a phase 4 clinical trial with a randomised, double-blind, placebo-controlled design aiming to determine if the effect of oxcarbazepine on chronic peripheral nerve pain depends on the supposed mechanism of the pain. It includes participants with definite or probable neuropathic pain due to polyneuropathy, postherpetic neuralgia or peripheral nerve injury; the estimated number of participants to be enrolled is 120. Inclusion and exclusion criteria are explicitly stated in the online report. Participants in the experimental group receive oxcarbazepine capsules orally and the dose is gradually increased over a period of 21 days from 300 mg daily to 2400 mg/day and maintained at that dose for three weeks, while placebo capsules are increased from one per day to eight per day. The primary outcome measure is total pain rated on a numeric scale (zero to 10 points). Secondary outcomes are response rate, neuropathic pain symptom inventory, patients' global impression of change, rating of evoked pain, sleep disturbance, quality of life and use of escape medication. The trial started in February 2011, and is estimated to be completed in December 2013. See Characteristics of ongoing studies.

Risk of bias in included studies

The four included trials all had a large sample of participants and standardised protocols. The methodological quality of the trials was assessed according to the Cochrane 'Risk of bias' tool (Higgins 2008b; Higgins 2011). All four trials were rated as at a high risk of bias mainly because of a large and imbalanced proportion of missing outcome data across groups (Figure 2).

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

All included studies were multicentre, placebo-controlled, double-blind, parallel-group trials. Based on the published methods, we considered allocation sequence generation and concealment, blinding, and outcome reporting to be well performed to avoid bias for the three trials involving patients with diabetic neuropathy (Beydoun 2006; Dogra 2005; Grosskopf 2006). For the only trial involving patients with radiculopathy, we were unable to obtain detailed information about the methods of allocation (Characteristics of included studies).

All four trials clearly reported withdrawals after randomisation. The main reasons for discontinuation, in both the oxcarbazepine and placebo groups, included adverse events, lack of efficacy and protocol violations, but the numbers of participants with incomplete outcome data and the reasons for withdrawal were imbalanced across groups. To deal with missing outcome data, the trial authors performed analyses based on the ITT population using the LOCF approach, where all withdrawn participants had the average weekly VAS score from their last week of treatment carried forward for assessment. However, participants might have withdrawn before they found any obvious effect, so imputing outcomes in this way for missing participants (especially for early withdrawals) could lead an underestimation of the true effect. We attempted to contact the authors and company to obtain the missing data but failed. There were no detailed descriptions of the results for completers and dropouts in the reports, so we could not conduct an ITT analysis by regarding participants with missing outcome data as failures with no response. Since the dropout rates were high in all groups (19.1% to 56.3%), and they were significantly higher in the oxcarbazepine groups than the control groups (Beydoun 2006; Dogra 2005; Grosskopf 2006; Novartis 2004), a potential risk of bias against oxcarbazepine due to incomplete outcome data should be considered (Higgins 2008b). All outcomes specified in the protocols were reported in the published reports, so the three studies investigating participants with diabetic neuropathy were probably free of bias from selective reporting (Beydoun 2006; Dogra 2005; Grosskopf 2006). We also found a trial that was only published in abstract form (Novartis 2004) and which fulfilled the inclusion criteria of the present review.All expected outcomes in the protocol were reported online. To try to avoid publication bias we included the unpublished data from this trial.

Although sharing a similar design, the included trials reported some outcomes in different ways, which made it impossible for us to combine data from the three trials investigating the same condition, diabetic neuropathy (Beydoun 2006; Dogra 2005; Grosskopf 2006) in a meta-analysis. In fact, their results (for example reduction in pain intensity) were inconsistent. For the primary outcome, for example, we could only obtain relevant data from the single positive trial (Dogra 2005); the two negative trials did not provide data for inclusion in the primary outcome meta-analysis.

Effects of interventions

See: Summary of findings for the main comparison Oxcarbazepine versus placebo for painful diabetic neuropathy

We planned to evaluate the effects of treatment after eight weeks, but we could not extract the relevant data because the included trials all reported outcomes 16 weeks after starting the treatment and the rates of change in the measured outcomes per week were not constant (Beydoun 2006; Dogra 2005; Grosskopf 2006; Novartis 2004). We could therefore only extract and analyse data as close as possible to 16 weeks after the beginning of treatment. In this review, we analysed the effects of three daily doses (600 mg, 1200 mg and 1800 mg) of oral oxcarbazepine versus placebo for painful diabetic neuropathy or neuropathic pain due to radiculopathy. There were no eligible trials of oxcarbazepine in other dosages, by other administration routes, compared to any other intervention or for other kinds of neuropathic pain.

Primary outcome measure

Reduction in patient-reported pain scores by 50% from the baseline

The included trials measured pain severity on a VAS, a commonly used pain scale that is 100 units in length with anchors of 'no pain' at the left end and 'worst pain imaginable' at the right end. The primary efficacy variable of this series of studies was the average daily VAS score during the last week (the 16th week) of double-blind treatment compared with baseline, and the average changes were compared between groups to evaluate the analgesic efficacy of oxcarbazepine. Authors did not always report the proportion of participants whose pain scores were reduced by 50% from the baseline, which was the primary focus of our review. We extracted relevant data from only one included study for each condition (Dogra 2005; Novartis 2004).

For participants with painful diabetic neuropathy, the results showed that the proportion of the oxcarbazepine (1800 mg/day) group whose pain scores were reduced by 50% from the baseline was statistically higher than that of the placebo group (24/69 (34.8%) versus 14/77 (18.2%)), with a RR of 1.91 (95% CI 1.08 to 3.39; P = 0.03; Analysis 1.1) and a NNTB of 6.0 (95% CI 3.3 to 41.0). There were no data available regarding our primary outcome measure (50% reduction in pain intensity) or the first secondary outcome measure (30% reduction in pain intensity) from the two negative trials, so we were unable to resolve the discrepancies between the included trials. For neuropathic pain due to radiculopathy, oxcarbazepine showed insignificant efficacy in reducing pain intensity by 50% from baseline comparing to placebo (7/71 (9.9%) versus 14/77 (18.9%); RR 0.52, 95% CI 0.22 to 1.22; P = 0.13; Analysis 2.1).

To evaluate the efficacy of oxcarbazepine, investigators calculated the mean changes in VAS scores from baseline to the end of double-blind treatment, but the conclusions were inconsistent. Dogra and colleagues found that participants treated with oxcarbazepine (1800 mg/day) experienced a significantly larger decrease from baseline in mean VAS score compared with placebo (-24.3 versus -14.7 units; P = 0.0108) (Dogra 2005) but in the other three trials (Beydoun 2006; Grosskopf 2006; Novartis 2004) the three doses of oxcarbazepine (600 mg/day, 1200 mg/day, 1800 mg/day) all failed to produce statistically significant pain relief.

Secondary outcome measures

Reduction in patient-reported pain scores by 30% from the baseline

We were able to extract the proportion of participants with a 30% reduction in VAS score from baseline to the 16th treatment week only from the Dogra 2005 study. A statistically higher percentage of participants in the oxcarbazepine group experienced this level of pain relief compared with placebo (31/69 (44.9%) versus 22/77 (28.6%); RR 1.57, 95% CI 1.01 to 2.44; P = 0.04; Analysis 1.2). The NNTB value was 6.1 (95% CI 3.1 to 113.6).

Patients' global impression of their change in pain

Investigators of this series of studies used GATE to assess patients' global impression of their change in diabetic neuropathy; GATE was measured on a seven-point Likert scale with scores ranging from -3 (very much improved) to 3 (very much deteriorated). In the present review, we compared the proportions of participants who reported all degrees of improvement (-3 to -1 point for GATE) and significant or obvious improvement (-3 to -2 point for GATE) after 16 weeks of treatment in the oxcarbazepine and placebo groups (Analysis 1.3; Analysis 2.2; Figure 3). We could obtain relevant data from three included studies (Beydoun 2006; Dogra 2005; Novartis 2004). The other study (Grosskopf 2006) concluded only that no significant difference in this measure was found. From the meta-analysis for global impression of the change in pain of participants with painful diabetic neuropathy, 72.5% (50/69) of participants who received oxcarbazepine felt globally improved, significantly more than for those who received placebo (40.3% (31/77); RR 1.80, 95% CI 1.32 to 2.45). By combining relevant data from the Beydoun 2006 and Dogra 2005 studies, the meta-analysis (Analysis 1.3) also showed a statistically significant difference between the experimental and control groups in producing significant or obvious improvement in participants with painful neuropathy (150/327 (45.9%) versus 50/166 (30.1%), respectively; RR 1.46, 95% CI 1.13 to 1.88). The NNTB with all dosages of oxcarbazepine was 6.4 (95% CI 4.1 to 14.4) for significant or obvious global improvement. For participants with neuropathic pain due to radiculopathy, there was no significant difference between the oxcarbazepine and placebo groups in either all degrees of improvement (35/71 (49.3%) versus 27/74 (36.5%); RR 1.35, 95% CI 0.92 to 1.98) or significant or obvious improvement (17/71 (23.9%) versus 11/74 (14.9%); RR 1.61, 95% CI 0.81 to 3.20) (Analysis 2.2).

Figure 3.

Forest plot of comparison: 1 Oxcarbazepine versus placebo for painful diabetic neuropathy, outcome: 1.3 Patients' global impression of their change in pain.

Overall quality of life measures

The SF-36 Health Survey, consisting of both physical and mental health summaries, was used to assess the overall quality of life in the included studies. It was performed on different occasions during the double-blind phase including at the eighth week, which was the time we planned according to our protocol (Zhou 2009) to measure this outcome. However, scores were not recorded for each follow-up period and some information could only be obtained at week 16 or at the termination visit. At the end of double-blind treatment in the Dogra 2005 trial, a significant difference was seen in the aggregate mental health score (P = 0.03) between oxcarbazepine- and placebo-treated participants (in favour of oxcarbazepine), but not in any SF-36 scales or the aggregate physical health score. In reports of the other two included trials (Beydoun 2006; Grosskopf 2006), the authors stated only that there were no significant differences between the oxcarbazepine groups and placebo groups on the quality of life questionnaire, but we were unable to obtain data for meta-analysis. Nor were we able to obtain relevant data from the trial published only as an abstract (Novartis 2004).

Adverse effects

Adverse events often started during the titration period and resolved prior to study end. The frequently reported adverse events included dizziness, headache, nausea, somnolence, fatigue, vomiting, back pain, diarrhoea, tremor and blurred vision; most were mild to moderate in intensity and resulted in dosage adjustment. The number of participants with any adverse event could be extracted only from the Novartis 2004 study, but adverse events leading to withdrawal or serious outcomes were reported in detail in each trial.

In total, 25.6% (102/398) of participants with painful diabetic neuropathy in the oxcarbazepine group and 6.8% (16/236) in the placebo group discontinued treatment prematurely due to adverse effects, resulting in an RR of 3.83 (95% CI 2.29 to 6.40) with a significant difference between groups (P < 0.00001) (Analysis 1.4; Figure 4). Serious adverse events occurred in a small number of participants. Some were considered related to treatment, such as erythema multiforme, severe fatigue, weakness, lightheadedness, headache leading to hospitalisations. Meta-analysis of these results revealed a statistically significant difference: the RR for serious adverse events comparing the experimental group (33/398, 8.3%) with the control group (6/236, 2.5%) was 3.65 (95% CI 1.45 to 9.20) with a P value of 0.006 (Analysis 1.4; Figure 4). Thus we calculated the NNTH as 17.4 (95% CI 11.0 to 42.0) for serious adverse drug reactions. In the single trial investigating patients with neuropathic pain due to radiculopathy, the proportions of participants who experienced any kind of adverse events (68/71 (95.8%) versus 58/74 (78.4%); RR 1.22, 95% CI 1.07 to 1.39; P = 0.002) and who withdrew due to adverse events (30/71 (42.3%) versus 11/74 (14.9%); RR 2.84, 95% CI 1.55 to 5.23; P = 0.0008) were significantly higher in the oxcarbazepine group than in the placebo group. Additionally, six serious adverse events (8.5%) occurred in the oxcarbazepine group and two (2.7%, including one death) in the control group, showing a non-significant difference (RR 3.13, 95% CI 0.65 to 14.98; P = 0.15) (Analysis 2.3).

Figure 4.

Forest plot of comparison: 1 Oxcarbazepine versus placebo for painful diabetic neuropathy, outcome: 1.4 Adverse effects.

Subgroup analysis

Lower and higher daily dose (600 mg/day, 1200 mg/day, 1800 mg/day)

Experimental participants with painful diabetic neuropathy could be divided into groups according to the target dosage of oxcarbazepine (600, 1200 or 1800 mg/day) used in each trial, and a dose-effect relationship was suggested in a dose-ranging study (Beydoun 2006). We conducted subgroup analyses of these three daily doses for outcomes where relevant data were available.

The percentage of participants who reported a significant or obvious improvement (-3 to -2 point for GATE) in pain was statistically greater in the 1800 mg/day oxcarbazepine group versus placebo (76/157 (48.4%) versus 50/166 (30.1%); RR 1.60, 95% CI 1.21 to 2.11). There was no statistically significant difference from placebo with oxcarbazepine at 600 mg/day (30/83 (36.1%) versus 33/89 (37.1%); RR 0.97, 95% CI 0.66 to 1.45) or 1200 mg/day (44/87 (50.6%) versus 33/89 (37.1%); RR 1.36, 95% CI 0.97 to 1.92) (Analysis 3.1; Figure 5). The NNTB could not be calculated for the 600 mg/day oxcarbazepine group because the event rate was lower than that of the placebo group, while it was 7.4 (95% CI 3.6 to 97.1) in the 1200 mg and 5.5 (95% CI 3.5 to12.8) in the 1800 mg daily oxcarbazepine groups.

Figure 5.

Forest plot of comparison: 2 Subgroup analysis: different daily doses of oxcarbazepine versus placebo for painful diabetic neuropathy, outcome: 2.1 Patients with obvious or significant improvement after 16-week treatment.

As for adverse effects, events leading to discontinuation occurred more frequently with the higher daily doses of oxcarbazepine (38/158 on 1200 mg; and 55/157 on 1800 mg) compared to the placebo group (10/159, RR 3.83, 95% CI 1.97 to 7.41; 12/166, RR 4.83, 95% CI 2.68 to 8.70, respectively). The difference between 600 mg/day oxcarbazepine and placebo was non-significant (RR 1.61, 95% CI 0.60 to 4.32) (Analysis 3.2). Although the rates of adverse effects were increasing and dose-dependent, the confidence intervals were wide and overlapping. The comparisons of serious side effects between the experimental and control groups showed a similar trend toward a dose-dependent relationship: the highest daily dose (1800 mg/day) of oxcarbazepine treatment led to the highest percentage of serious adverse events (17/157, 10.8%) while the corresponding values were 14/158 (8.9%) for 1200 mg/day and 2/83 (2.4%) for 600 mg/day oxcarbazepine. Compared to the placebo group, the two higher doses of oxcarbazepine caused significantly more serious side effects (Analysis 3.3; Figure 6). For serious adverse events, the NNTH was 77.5 (95% CI 19.0 to 37.5) for 600 mg/day, 14.3 (95% CI 8.4 to 48.5) for 1200 mg/day and 11.9 (95% CI 7.2 to 33.0) for 1800 mg/day oxcarbazepine.

Figure 6.

Forest plot of comparison: 2 Subgroup analysis: different daily doses of oxcarbazepine versus placebo for painful diabetic neuropathy, outcome: 2.3 Serious adverse effects.

Discussion

Despite attempts to develop more rational therapeutic approaches, treatment for some patients with neuropathic pain is still unsatisfactory. As a second-generation antiepileptic drug, oxcarbazepine was found to have some effect in treating several types of neuropathic pain in some open-label studies (Magenta 2005) and controlled trials, but the evidence was not convincing. We collected and extracted data from relevant RCTs for a more complete systematic analysis of the efficacy and safety of oxcarbazepine for neuropathic pain.

Summary of main results

We included four RCTs, all of which compared oral oxcarbazepine with placebo for the systematic treatment of neuropathic pain; three trials investigated people with painful diabetic neuropathy and the other involved participants with neuropathic pain due to radiculopathy. Since the trials were from the same series of studies, similar designs, methods, treatment and follow-up periods, and efficacy and safety variables allowed the combination of some but not all relevant data. The results of meta-analyses indicated a slight effect in relieving the pain (both with VAS reduction by 50% and 30% from baseline) due to diabetic neuropathy and good improvement of patients' global impression of their change (especially with significant or obvious improvement) (Summary of findings for the main comparison). However, such results were mainly based on data from the single positive trial since the two negative trials did not provide enough data that could be included in the meta analyses. So the efficacy of oxcarbazepine for painful diabetic neuropathy is still uncertain. Results from the subgroup analyses, according to different target daily dose, suggested trends toward dose-effect relationships both for global recovery and adverse events. The highest daily dose (1800 mg/day) of oxcarbazepine had the greatest effect on pain relief but also led to the most adverse events, especially serious ones. For participants with radiculopathy, data from the only trial showed that oxcarbazepine could neither significantly relieve the pain nor improve patients' global impression of change compared to placebo.

The benefits of oxcarbazepine were largely owing to the positive results of one study (Dogra 2005), which investigated a higher dose (1800 mg/day) of oxcarbazepine. The other two included trials (Beydoun 2006; Grosskopf 2006) both failed to produce statistically significant differences between each dose of experimental drug and placebo, although there was a statistically significant trend favouring the two higher dose (1200 and 1800 mg/day) groups (Beydoun 2006). Neither of these studies was included in the meta-analysis, which is thus enormously biased towards the positive report. The investigators themselves put forward a number of factors to explain the differences in outcome among the trials. Besides the higher dose that was used in the positive trial, its lower placebo response might at least partially contribute to the statistically significant findings. In the placebo group of the Dogra 2005 study, the mean change of VAS scores from the baseline to the treatment end was -14.7 units, and about 22% of participants experienced an obvious or significant improvement; whereas the corresponding values were -19.1 units and 37.3% for the Beydoun 2006 study and -22.0 units for the Grosskopf 2006 study (percentage of improved participants was not reported). This phenomenon can be explained by the different experimental populations and the established conclusion that the placebo effect varies substantially among people with painful diabetic neuropathy (Backonja 2003; Beydoun 2006; Eisenberg 2007). Further, the effect of early discontinuations due to adverse events should also be considered. In the positive study (Dogra 2005) 7.8% (6/77) of participants withdrew from the placebo group because of adverse events, compared to 27.5% (19/69) from the oxcarbazepine group (1800 mg/day); a comparable percentage of participants withdrew in the placebo group of the Beydoun 2006 study (6.7% (6/89)) but the percentage of withdrawals in the 1800 mg oxcarbazepine group was much higher (40.9% (36/88)). Although analyses were based on ITT populations, the impact of different withdrawal rates on the treatment-effect estimation cannot be overlooked for reasons mentioned in the Risk of bias in included studies section.

Although the reports of trials included in this review state that most side effects related to the study drugs were mild to moderate in severity, both the proportions of any events and those leading to withdrawals were statistically higher in the oxcarbazepine group than the placebo group. The frequency of such adverse events was evidently dose related. So the speed and period of titration, and the observation and management of intolerance, should be rescheduled in further studies, and the most appropriate target dose might be further investigated for patients with neuropathic pain. Furthermore, it has been suggested that some human leukocyte antigen (HLA) alleles (for example HLA-B*1502 and HLA-A*3101) are associated with carbamazepine-induced skin-related adverse drug reactions that are sometimes serious and potentially life-threatening in certain populations. This association was not investigated in the included trials of the present review. Reports about the association of HLA alleles with oxcarbazepine are limited. Because of the close structural relationship with carbamazepine, if suggestive signs and symptoms appear then treatment should be withdrawn immediately (Drug Safety Update 2012).

Overall completeness, applicability and quality of the evidence

The four included trials were well designed and conducted in multiple centres. However, there are still unacceptable problems mainly due to imbalances in the completeness of outcome data. The considerable inconsistencies in placebo responses could also undermine the reliability of the combined results. Although the placebo response in neuropathic pain varies considerably among trials, and is difficult to regulate and control, RCTs are still the most powerful evidence on which to base conclusions (GRADE). The mean pain severity at randomisation differs from trial to trial but has not been further analysed in this review because of limited data. These differences could also impact the results to some extent. All of the included trials reported relevant outcomes for pain relief, patients' quality of life and safety, but data were not always available for meta-analysis for each outcome. Most of our results came from one or two eligible trials, or from descriptive analyses. So the evidence from this review is incomplete and may not be widely applicable.

The efficacy of oxcarbazepine has also been investigated for types of neuropathic pain other than diabetic neuropathy and radiculopathy (for example trigeminal neuralgia and postherpetic neuralgia). Several studies (Beydoun 2002a; Beydoun 2002b; Carrazana 2003; Nasreddine 2007), which were RCTs, compared oxcarbazepine with carbamazepine in participants with trigeminal neuralgia; all the results consistently showed that both drugs had comparable effectiveness in relieving pain and improving the quality of life. These studies have only been published as a meta-analysis in abstract form (Beydoun 2002a; Beydoun 2002b) or in reviews (Carrazana 2003; Nasreddine 2007), where detailed descriptions and data are unavailable. Thus they could not be included in the current review. A postherpetic neuralgia study showed a significant decrease in VAS score and improvements in participants' quality of life (Criscuolo 2005) but had an open-label design. As a result, we cannot draw any firm conclusions about oxcarbazepine for the treatment of non-diabetic neuropathic pain.

Agreements and disagreements with other studies or reviews

In agreement with the conclusions of our systematic review, to date the European Federation of Neurological Societies (EFNS) guidelines (Attal 2006; Attal 2010) have not recommended oxcarbazepine for people with diabetic neuropathic pain because of insufficient and conflicting evidence. The guidelines confirmed oxcarbazepine as one of the first-line drugs for classical trigeminal neuralgia, whereas with no eligible trials we are unable to draw any conclusion in this review about the use of oxcarbazepine for this type of neuropathic pain.

Authors' conclusions

Implications for practice

On the basis of moderate quality evidence from one trial in diabetic peripheral neuropathy, oxcarbazepine is effective in reducing pain for this condition. However, this conclusion does not take into account negative results from other trials of oxcarbazepine in diabetic peripheral neuropathy that could not be included in our analysis. We did not find any evidence from randomised controlled trials to determine the efficacy or safety of oxcarbazepine for other kinds of neuropathic pain other than one low quality trial in people with radiculopathy. Most adverse effects related to oxcarbazepine are rated as mild to moderate in severity, but adverse events leading to discontinuation of drug administration or serious adverse events are not uncommon.

Implications for research

More well designed, large, multicentre, randomised placebo- or active-controlled trials investigating oxcarbazepine are needed. The response in neuropathic pain of other causes should be investigated. A dose-ranging design should be considered to determine whether a dose-response relationship is present, and the most appropriate target dose might be studied further.

Acknowledgements

We are grateful for the assistance of the Cochrane Neuromuscular Disease Group.

The editorial base of the Cochrane Neuromuscular Disease Group is supported by the MRC Centre for Neuromuscular Diseases.

The Trials Search Co-ordinator of the Cochrane Neuromuscular Disease Group, Angela Gunn, provided literature searches.

Data and analyses

Download statistical data

Comparison 1. Oxcarbazepine versus placebo for painful diabetic neuropathy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Reduction in patient-reported pain scores by 50% from the baseline1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 16 weeks after starting the treatment1146Risk Ratio (M-H, Fixed, 95% CI)1.91 [1.08, 3.39]
2 Reduction in patient-reported pain scores by 30% from the baseline1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 16 weeks after starting the treatment1146Risk Ratio (M-H, Fixed, 95% CI)1.57 [1.01, 2.44]
3 Patients' global impression of their change in pain2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 All improved patients after 16-week treatment1146Risk Ratio (M-H, Fixed, 95% CI)1.80 [1.32, 2.45]
3.2 Patients with obvious or significant improvement after 16-week treatment2493Risk Ratio (M-H, Fixed, 95% CI)1.46 [1.13, 1.88]
4 Adverse effects3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Adverse events leading to withdrawals3634Risk Ratio (M-H, Fixed, 95% CI)3.83 [2.29, 6.40]
4.2 Serious adverse events3634Risk Ratio (M-H, Fixed, 95% CI)3.65 [1.45, 9.20]
Analysis 1.1.

Comparison 1 Oxcarbazepine versus placebo for painful diabetic neuropathy, Outcome 1 Reduction in patient-reported pain scores by 50% from the baseline.

Analysis 1.2.

Comparison 1 Oxcarbazepine versus placebo for painful diabetic neuropathy, Outcome 2 Reduction in patient-reported pain scores by 30% from the baseline.

Analysis 1.3.

Comparison 1 Oxcarbazepine versus placebo for painful diabetic neuropathy, Outcome 3 Patients' global impression of their change in pain.

Analysis 1.4.

Comparison 1 Oxcarbazepine versus placebo for painful diabetic neuropathy, Outcome 4 Adverse effects.

Comparison 2. Oxcarbazepine versus placebo for neuropathic pain due to radiculopathy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Reduction in patient-reported pain scores by 50% from baseline1145Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.22, 1.22]
2 Patients' global impression of therapeutic effect1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 All improved patients after 16-week treatment1145Risk Ratio (M-H, Fixed, 95% CI)1.35 [0.92, 1.98]
2.2 Patients with obvious or significant improvement after 16-week treatment1145Risk Ratio (M-H, Fixed, 95% CI)1.61 [0.81, 3.20]
3 Adverse events1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 All kinds of adverse events1145Risk Ratio (M-H, Fixed, 95% CI)1.22 [1.07, 1.39]
3.2 Adverse events leading to withdrawals1145Risk Ratio (M-H, Fixed, 95% CI)2.84 [1.55, 5.23]
3.3 Serious adverse events1145Risk Ratio (M-H, Fixed, 95% CI)3.13 [0.65, 14.98]
Analysis 2.1.

Comparison 2 Oxcarbazepine versus placebo for neuropathic pain due to radiculopathy, Outcome 1 Reduction in patient-reported pain scores by 50% from baseline.

Analysis 2.2.

Comparison 2 Oxcarbazepine versus placebo for neuropathic pain due to radiculopathy, Outcome 2 Patients' global impression of therapeutic effect.

Analysis 2.3.

Comparison 2 Oxcarbazepine versus placebo for neuropathic pain due to radiculopathy, Outcome 3 Adverse events.

Comparison 3. Subgroup analysis: different daily doses of oxcarbazepine versus placebo for painful diabetic neuropathy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Patients with obvious or significant improvement after 16-week treatment2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 600 mg oxcarbazepine daily1172Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.66, 1.45]
1.2 1200 mg oxcarbazepine daily1176Risk Ratio (M-H, Fixed, 95% CI)1.36 [0.97, 1.92]
1.3 1800 mg oxcarbazepine daily2323Risk Ratio (M-H, Fixed, 95% CI)1.60 [1.21, 2.11]
2 Adverse effects leading to withdrawals3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 600 mg oxcarbazepine daily1172Risk Ratio (M-H, Fixed, 95% CI)1.61 [0.60, 4.32]
2.2 1200 mg oxcarbazepine daily2317Risk Ratio (M-H, Fixed, 95% CI)3.83 [1.97, 7.41]
2.3 1800 mg oxcarbazepine daily2323Risk Ratio (M-H, Fixed, 95% CI)4.83 [2.68, 8.70]
3 Serious adverse effects3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 600 mg oxcarbazepine daily1172Risk Ratio (M-H, Fixed, 95% CI)2.14 [0.20, 23.21]
3.2 1200 mg oxcarbazepine daily2317Risk Ratio (M-H, Fixed, 95% CI)4.68 [1.38, 15.95]
3.3 1800 mg oxcarbazepine daily2323Risk Ratio (M-H, Fixed, 95% CI)4.55 [1.55, 13.37]
Analysis 3.1.

Comparison 3 Subgroup analysis: different daily doses of oxcarbazepine versus placebo for painful diabetic neuropathy, Outcome 1 Patients with obvious or significant improvement after 16-week treatment.

Analysis 3.2.

Comparison 3 Subgroup analysis: different daily doses of oxcarbazepine versus placebo for painful diabetic neuropathy, Outcome 2 Adverse effects leading to withdrawals.

Analysis 3.3.

Comparison 3 Subgroup analysis: different daily doses of oxcarbazepine versus placebo for painful diabetic neuropathy, Outcome 3 Serious adverse effects.

Appendices

Appendix 1. MEDLINE (OvidSP) search strategy

Database: Ovid MEDLINE(R) <1946 to October Week 3 2012>
Search Strategy:
--------------------------------------------------------------------------------
1 randomized controlled trial.pt. (339605)
2 controlled clinical trial.pt. (85425)
3 randomized.ab. (242346)
4 placebo.ab. (135629)
5 drug therapy.fs. (1578525)
6 randomly.ab. (173863)
7 trial.ab. (251056)
8 groups.ab. (1136962)
9 or/1-8 (2939707)
10 exp animals/ not humans.sh. (3797751)
11 9 not 10 (2497281)
12 (oxcarbazepine or trileptal$ or trexapin).mp. (1224)
13 Radiculopathy/ (3272)
14 Diabetic Neuropathies/ (11395)
15 Neuralgia, Postherpetic/ (513)
16 Spinal Cord Injuries/ (26088)
17 Trigeminal Neuralgia/ (5363)
18 exp Complex Regional Pain Syndromes/ (4142)
19 (neuropath$ pain or cervical radiculopathy or lumber radiculopathy or diabetic neuropath$).mp. (21012)
20 (peripheral neuropath$ or postherpetic neuralgia or HIV neuropath$ or spinal cord injur$ or trigeminal neuralgia or complex regional pain syndrome).mp. (50650)
21 or/13-20 (74261)
22 11 and 12 and 21 (71)
23 22 and 20111101:20121030.(ed). (1)

Appendix 2. EMBASE (OvidSP) search strategy

Database: Embase <1980 to 2012 Week 43>
Search Strategy:
--------------------------------------------------------------------------------
1 crossover-procedure.sh. (35377)
2 double-blind procedure.sh. (111601)
3 single-blind procedure.sh. (16569)
4 randomized controlled trial.sh. (331618)
5 (random$ or crossover$ or cross over$ or placebo$ or (doubl$ adj blind$) or allocat$).tw,ot. (908624)
6 trial.ti. (136873)
7 or/1-6 (1037646)
8 (animal/ or nonhuman/ or animal experiment/) and human/ (1217670)
9 animal/ or nonanimal/ or animal experiment/ (3327400)
10 9 not 8 (2754501)
11 7 not 10 (951313)
12 limit 11 to embase (739107)
13 (oxcarbazepine or trileptal$ or trexapin).mp. (6675)
14 radiculopathy/ (6452)
15 radicular pain/ (1836)
16 diabetic neuropathy/ (16378)
17 postherpetic neuralgia/ (3462)
18 spinal cord injury/ (33492)
19 trigeminus neuralgia/ (7885)
20 exp complex regional pain syndrome/ (6871)
21 (neuropath$ pain or cervical radiculopathy or lumbar radiculopathy or diabetic neuropath$ or peripheral neuropath$).mp. (68480)
22 (postherpetic neuralgia or HIV neuropath$ or spinal cord injur$ or trigeminal neuralgia or complex regional pain syndrome).mp. (52944)
23 or/14-22 (129539)
24 12 and 13 and 23 (95)
25 24 and 20111101:20121030.(dd). (11)

Appendix 3. CENTRAL search strategy

#1 oxcarbazepine OR trileptal* OR trexapin
#2 "neuropathic pain" OR "neuropathy pain"
#3 "cervical radiculopathy"
#4 MeSH descriptor Radiculopathy, this term only
#5 "lumber radiculopathy"
#6 "diabetic neuropathy" OR "diabetic neuropathies"
#7 MeSH descriptor Diabetic Neuropathies explode all trees
#8 "peripheral neuropathy" OR "peripheral neuropathies"
#9 "postherpetic neuralgia"
#10 MeSH descriptor Neuralgia, Postherpetic, this term only
#11 "HIV neuropathy" OR "HIV neuropathies"
#12 MeSH descriptor Spinal Cord Injuries explode all trees
#13 "spinal cord injury" OR "spinal cord injuries"
#14 "trigeminal neuralgia" OR "trigeminus neuralgia"
#15 MeSH descriptor Trigeminal Neuralgia explode all trees
#16 "complex regional pain syndrome"
#17 MeSH descriptor Complex Regional Pain Syndromes explode all trees
#18 (#2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17)
#19 (#1 AND #18)

Appendix 4. Chinese Biomedical Retrieval System Database search strategy

(NB. all of the search terms were translated to Chinese terms when we conducted the searches)
1. neuropathic pain
2. radiculopathy
3. cervical radiculopathy
4. lumber radiculopathy
5. diabetic neuropathy
6. peripheral neuropathy
7. postherpetic neuralgia or PHN
8. HIV neuropathy
9. Spinal Cord Injuries
10.trigeminal neuralgia
11.complex regional pain syndrome or CRPS
12.1-11/or
13.oxcarbazepine
14.trileptal
15.qulai or renao or wanyi (trade names of oxcarbazepine in Chinese)
16.13-15/or
17.random
18.control
19.clinical trial
20.blind procedure
21.placebo
22.17-21/or
23.12 and 16 and 22

What's new

DateEventDescription
29 October 2013Amended

Corrected RR in abstract for adverse events leading to withdrawals (radiculopathy).

Editorial revisions to abstract and conclusions: no change to findings.

Contributions of authors

Mi Yang and Ning Chen searched for studies and extracted data and Cairong Zhu carried out analyses. All authors were involved with writing of the protocol and the full review.

Declarations of interest

None

Differences between protocol and review

We searched the Chinese Biomedical Retrieval System in addition to other databases. We did not search the Trials Register of the Cochrane Pain, Palliative and Supportive Care Group. We added a 'Summary of findings' table to the review, which was not mentioned in the protocol.

For the 'Risk of bias' assessments we used 'High', 'Low' or 'Unclear' risk of bias, according to Higgins 2011.

In our protocol we stated that for continuous data we would calculate the weighted mean difference (WMD) or standardised difference (SMD). Only dichotomous data were available from the included trials. There were no cross-over trials for analysis.

We planned sensitivity analyses on the basis of trial quality and subgroup analyses on the basis of type of neuropathic pain. We did not perform them because all trials were of moderate quality; and subgroup analysis on the basis of type of neuropathic pain was not possible.

Changes in authorship have taken place since publication of the protocol: Guo J, Li Q, Yang X, Yang J withdrew and Wu F became an author.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Beydoun 2006

MethodsA multicentre, double-blind, placebo-controlled, randomised, parallel-group, dose-ranging study to evaluate the efficacy and safety of three daily doses of oral oxcarbazepine (600, 1200, and 1800 mg) as monotherapy for painful diabetic neuropathy. It consisted of a 2-week pre-randomisation screening phase and a 16-week double-blind phase (including a 4-week titration period and a 12-week maintenance period).
Participants

A total of 347 participants with painful diabetic neuropathy were included and randomised in a 1:1:1:1 ratio to oxcarbazepine 600 mg/day (300 mg bid; n = 83), 1200 mg/day (600 mg bid; n = 87), 1800 mg/day (900 mg bid; n = 88), or placebo (n = 89).

Gender (% male) 600 mg, 900 mg, 1200 mg oxcarbazepine and placebo: 60%; 52%; 53%; 56%. Mean age, years (SD) 600 mg, 900 mg, 1200 mg oxcarbazepine and placebo: 61.1 (10.7); 60.3 (10.3); 59.3 (9.3); 62.1 (10.3).

Inclusion criteria: men and non-pregnant women; 18 years of age or older; with a diagnosis of diabetes mellitus (type 1 or 2) and pain attributed to diabetic neuropathy for 6 months to 5 years; with a pain rating score of at least 50 units on a 100-unit VAS at the screening visit, stable glycaemic control (as evidenced by a HbA1c level of ≤11% at baseline), and baseline serum sodium levels of 35 mmol/L or higher; the VAS must have averaged at least 40 units during the pre-randomisation phase, with < 25% variability in the last 7 days prior to randomisation.

Exclusion criteria included: people with other types of pain; clinically significant medical or psychiatric illnesses; a prior history of hyponatraemia or non-compliance; drug or alcohol abuse in the preceding year; amputations other than the toes; treatment with lithium or monoamine oxidase inhibitors; previous treatment with oxcarbazepine; a history of sensitivity to carbamazepine or its metabolites.

InterventionsParticipants received the initiated dose of 300 mg oxcarbazepine (one tablet) or matching placebo daily for three days, then one tablet bid from the fourth day. Thereafter, the dose was increased by one tablet every 5 days until the target dose of 600 mg/day, 1200 mg/day or 1800 mg/day for each group was reached. Dose reductions due to tolerability problems were allowed at any time during the study.
Outcomes

The primary outcome was change in mean VAS score from baseline to the end of the study (16 weeks).

Secondary outcomes included participants' Global Assessment of the Therapeutic Effect, onset of therapeutic effect, durability of treatment effect, sleep disturbances, and quality of life.

Safety was also assessed during the screening and double-blind treatment phases, consisting of monitoring vital signs, neurological and physical examinations, laboratory parameters, spontaneous reports of adverse events, and serious adverse events.

NotesTrial conducted between November 2001 and September 2003 at 37 centres across the United States. This study was funded by Novartis Pharmaceuticals Inc.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe study is similar to the Dogra study so it is likely that randomisation was adequate.
Allocation concealment (selection bias)Low riskThe study is similar to the Dogra study so it is likely allocation concealment have been performed.
Blinding (performance bias and detection bias)
All outcomes
Low riskIt was stated that there was a double-blind phase, and matching placebos were used.
Incomplete outcome data (attrition bias)
All outcomes
High riskMissing data of both groups were clearly described and an ITT analysis was performed. The number of withdrawals was not balanced across different doses of oxcarbazepine and placebo groups (respectively 16/83 at 600 mg/day oxcarbazepine, 34/87 at 1200 mg/day, 48/88 at 1800 mg/day, and 17/89 of participants on placebo), especially those due to adverse events (respectively 9/83, 20/87, 36/88, and 6/89 in each group).
Selective reporting (reporting bias)Low riskOutcomes listed in the methods section were all reported.
Other biasLow riskNo other potential bias was found.

Dogra 2005

MethodsA multicentre, placebo-controlled, double-blind, parallel-group study. It consisted of three phases: a 2-week pre-randomisation screening phase, a 18-week double-blind treatment phase (including a 4-week titration period, a 12-week maintenance period and a 2-week follow-up period), and a 52-week open-label extension phase. The primary efficacy analysis was performed on the ITT population.
Participants

A total of 289 patients were screened for the study, and 146 participants were included to be randomised to either oxcarbazepine (69 participants) or placebo (77 participants).

Gender (% male): oxcarbazepine 54%; placebo 62%.

Mean age (SD), years: oxcarbazepine 59.7 (10.4); placebo 60.5 (8.1).

The inclusion criteria were: male or female outpatients; 18 years of age or older; an established clinical diagnosis of diabetes mellitus (type 1 or 2); stable diabetic control as evidenced by (a) HbA1c level 11% or less at baseline, (b) average HbA1c over the 6 months prior to study entry within 1 unit (%) of baseline; a history of neuropathic pain between 6 months and 5 years in duration; pain rating of ≥ 50 units on the VAS at the first screening visit; average pain score of 50 units over 4 of the last 7 days prior to randomisation; 25% or less variation in the severity of the pain in the 7 days prior to randomisation, as assessed from the electronic diary information recorded daily during the screening phase.

The exclusion criteria were: presence of other pain that could confound assessment of neuropathic pain of diabetic origin; currently or had previously taken oxcarbazepine; presence of skin lesions that could affect the ability to assess their neuropathic pain, or if they had undergone amputations (other than toes); history of renal insufficiency (creatinine clearance < 30 mL/min); hyponatraemia (serum sodium levels < 135 mmol/L); chronic infectious disease; known hypersensitivity to oxcarbazepine or carbamazepine.

A total of 40 participants were withdrawn during the double-blind phase, for the following reasons: adverse effects, protocol violation, unsatisfactory effect, patient withdrew consent, lost to follow-up or administrative reasons. However, all of them were included in the ITT analyses.

InterventionsOral oxcarbazepine was initiated at 300 mg/day, increased 3 days later to 300 mg twice a day, and then titrated in 300 mg increments every 5 days as tolerated up to a maximum dose of 900 mg twice a day (1800 mg/day) over the 4-week titration period. There followed a 12-week maintenance period. The mean oxcarbazepine dose during the maintenance period was 1445 mg/day. In the control group, matched placebos were administered in the same way.
Outcomes

The primary outcome was the average daily VAS score for pain severity during the last week of double-blind treatment compared with baseline.

The secondary outcomes were the patient's global assessment of therapeutic effect, onset of therapeutic effect, durability of treatment effect, sleep disturbances and quality of life.

Safety assessments during the screening and double-blind treatment phases were also performed, including monitoring vital signs, neurological and physical status, laboratory parameters, spontaneous reports of adverse events and serious adverse events.

NotesConducted in 22 diabetes and neurology pain clinics and research centres in the USA and Canada. This study was funded by Novartis Pharmaceuticals Inc.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskParticipants were randomised in a 1:1 ratio to each group; "the randomisation scheme was created by Novartis Drug Supply Management using a validated system that automates the random assignment of treatment groups to randomisation numbers".
Allocation concealment (selection bias)Low riskIt was stated in the article that "the randomization scheme was created by Novartis Drug Supply Management using a validated system that automates the random assignment of treatment groups to randomization numbers. The randomization numbers were assigned to centres in blocks", so allocation concealment was likely to have been performed.
Blinding (performance bias and detection bias)
All outcomes
Low riskIn the double-blind phase, matched placebos were used and administered in the same way with the same initiated doses and increments.
Incomplete outcome data (attrition bias)
All outcomes
High riskThe numbers of withdrawals were not balanced across groups (25/69 of oxcarbazepine participants versus 15/77 of placebo participants), especially those due to adverse events (19/69 versus 6/77).
Selective reporting (reporting bias)Low riskOutcomes listed in the methods section were all reported.
Other biasLow riskNo other potential bias was found.

Grosskopf 2006

MethodsMulticentre, double-blind, placebo-controlled study, with a 2-week pre-randomisation screening phase and a 16-week double-blind treatment phase (including a 4-week titration period and a 12-week maintenance period).
Participants

A total of 141 participants were randomised to oxcarbazepine (n = 71) or placebo (n = 70).

Gender (% male): oxcarbazepine 40 (56); placebo 38 (54); all 78 (55). Mean age, years (SD): oxcarbazepine 60.8 (10.6); placebo 61.4 (10.6); all 61.1 (10.5).

The inclusion criteria included: males and non-pregnant, non-lactating females aged 18 years or older with established clinical diagnosis of diabetes mellitus type 1 or 2; with a history of neuropathic pain for 6 months to 5 years prior to study entry; stable diabetic control defined as HbA1c ≤ 11% at baseline and an average HbA1c within 1% of baseline over the 6 months prior to study entry; with a pain rating of 50 units or more on the 100-unit VAS at the first screening visit, and a mean VAS score of 40 units or more over 4 of the last 7 days prior to randomisation and with < 25% variability during the last 7 days prior to randomisation.
Exclusion criteria included: patients with pain that could confound assessment of neuropathic pain of diabetic origin; previous or current oxcarbazepine treatment; skin conditions that could affect assessment of pain; amputations (other than toes); renal insufficiency; serum sodium levels < 135 mmol/L; chronic infectious disease and known hypersensitivity to oxcarbazepine or carbamazepine.

InterventionsIn the treatment group, oral oxcarbazepine was initiated at 300 mg daily and titrated over 4 weeks to tolerability or maximum dose of 600 mg twice per day (1200 mg/day), and the dose remained unchanged throughout the maintenance period, except for dose reductions in the event of poor tolerability. Mean oxcarbazepine dose during the maintenance period was 1091 mg/day. In the control group, matched placebos were administered in the same way with the same initiated doses and increments.
OutcomesThe primary outcome was the average VAS score for pain severity for the final week of double-blind treatment compared with baseline. Secondary efficacy variables were participants' global assessment of therapeutic effect, onset of therapeutic effect, durability of therapeutic effect, sleep disturbances and quality of life.
NotesConducted in 22 centres in the USA, Germany and the UK. This study was funded by Novartis Pharmaceuticals Inc.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskIt was stated that participants were randomly assigned in a 1:1 ratio to each group; the detailed method of sequence generation was not specified in this article, but it was said that design of this study was similar to the Dogra study (Dogra 2005), so randomisation numbers were likely to have been used as well.
Allocation concealment (selection bias)Unclear riskThe method of allocation concealment was not described, but it was said that design of this study was similar to the Dogra study (Dogra 2005), so allocation concealment was likely to have been performed.
Blinding (performance bias and detection bias)
All outcomes
Low riskIt was stated to be a double-blind study, and matched placebos were used.
Incomplete outcome data (attrition bias)
All outcomes
High riskMissing data in both groups were clearly described and an ITT analysis was performed. But the numbers of withdrawals were not balanced across groups (29/71 of oxcarbazepine participants versus 17/70 of placebo participants), especially those due to adverse events (18/71 versus 4/70).
Selective reporting (reporting bias)Low riskOutcomes listed in the methods section were all reported.
Other biasLow riskNo other potential bias was found.

Novartis 2004

  1. a

    bid, twice daily; VAS, visual analogue scale; HbA1c, haemoglobin A1c; ITT, intention-to-treat.

MethodsMulticentre, double-blind, randomised, placebo-control study, with a 2-week pre-randomisation screening phase and a 16-week double-blind treatment phase (including a 4-week titration period and a 12-week maintenance period).
Participants

A total of 145 participants were randomised to oxcarbazepine (n = 71) or placebo (n = 74).

Gender (F:M): oxcarbazepine 43:28; placebo 36:38.
Mean age, years (SD): oxcarbazepine 53.8 (13.67); placebo 55.1 (12.33).

The inclusion criteria included: males or females aged 18 years or more with a diagnosis of radiculopathy and evidence of motor deficit or reflex loss on examination, a history of neuropathic pain for at least 6 months and a VAS score of 50 or more.

Exclusion criteria included: patients with prior oxcarbazepine experience, history of hyponatraemia or renal insufficiency (creatinine clearance < 30 mL/min), a known sensitivity to carbamazepine, or were being treated with lithium or monoamine oxidase inhibitors.

Interventions

In the treatment group, oral oxcarbazepine was initiated at 300 mg daily and titrated over 4 weeks to a maximum target dose of 1800 mg daily, and the final dose remained unchanged throughout the maintenance period.

In the control group, matching placebo tablets were administered in the same way.

OutcomesThe primary outcome was the average VAS score for pain severity during the last week of double-blind treatment. Secondary efficacy variables were participants' global assessment of therapeutic effect, durability of treatment effect, onset of therapeutic effect, proportion of days rescue medication administered during the double-blind phase, average daily dose of rescue medication administered during the double-blind phase.
NotesConducted in 40 centres: 3 in Great Britain and 37 in the US. This study was funded by Novartis Pharmaceuticals Inc. Study number CTRI476G2304.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRelevant information could not be obtained.
Allocation concealment (selection bias)Unclear riskRelevant information could not be obtained.
Blinding (performance bias and detection bias)
All outcomes
Low riskStated to be a double-blind study, and matched placebos were used.
Incomplete outcome data (attrition bias)
All outcomes
High riskMissing data in both groups were clearly described and an ITT analysis was performed, but data of one participant in the oxcarbazepine group was not included in the ITT analysis and the reason for this was not clarified. Additionally, the numbers of withdrawals were not balanced across groups (40/71 of oxcarbazepine participants versus 33/74 of placebo participants), especially those due to adverse events (30/71 versus 11/74) or lack of efficacy (4/71 versus 15/74).
Selective reporting (reporting bias)Low riskNo data from this trial were published, but all outcomes listed in the methods section were reported on the Novartis website (Novartis database).
Other biasLow riskNo other potential bias was found.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Beydoun 2002Available only as an abstract of a double-blind RCT, comparing efficacy and safety of oxcarbazepine versus carbamazepine for the treatment of 46 participants with new-onset trigeminal neuralgia. However, we were unable to obtain data for our prespecified outcomes from the published abstract. We could not find the full text of this article or retrieve any useful data from the authors and pharmaceutical company although we have attempted to.
Beydoun 2007A report of two open-label studies (involving 497 and 97 participants, respectively) to evaluate the long-term safety and tolerability of oxcarbazepine for diabetic neuropathy, without a control group.
Gong 2010A non-blind trial investigating 99 participants with trigeminal neuralgia, aiming to compare the efficacy and safety of oxcarbazepine with carbamazepine and topiramate.
Hu 2010A non-blind trial investigating 369 participants with trigeminal neuralgia, aiming to compare the efficacy and safety of oxcarbazepine to carbamazepine.
Li 2011A non-blind trial investigating 78 participants with trigeminal neuralgia, aiming to compare the efficacy and safety of oxcarbazepine to carbamazepine.
Lindström 1987Double-blind cross-over trial in which 15 participants with trigeminal neuralgia received oxcarbazepine or carbamazepine for only 3 weeks. The trial had a short follow-up duration, less than the minimum (six weeks) we specified in the protocol.
Rémillard 1994An open-label study with 20 participants investigating efficacy of oxcarbazepine for intractable trigeminal neuralgia, without a control group.
Venancio-Ramirez 2004Randomised trial of gabapentin and oxcarbazepine in 60 participants with postherpetic neuropathy. Four-week observation period too short to meet our inclusion criteria.
Zhou 2010A non-blind trial investigating 64 participants with trigeminal neuralgia, aiming to compare the efficacy of oxcarbazepine to carbamazepine.

Characteristics of studies awaiting assessment [ordered by study ID]

Brainer-Lima 2003

MethodsRandomised assignment to either oxcarbazepine or amitriptyline.
ParticipantsTwenty participants (12 women, 8 men, aged 28 to 85 years) with cancer-related neuropathic pain (neoplastic compression or infiltration of the nerves) treated with opiates.
InterventionsParticipants were randomly assigned to either oxcarbazepine (10) or amitriptyline (10) and opioids were discontinued gradually. The opiate reduction was initiated at the end of radiotherapy/chemotherapy protocols. Opiate reduction was a rate of 10% less total opiate dose each other day or as tolerability allowed.
Outcomes

Pain relief measured using a 100 mm Visual Analogue Scale (VAS)

Presence and severity of opioid withdrawal symptoms

NotesFurther information required. Unclear from the abstract whether opiate dosage was the same in each group.

Liebel 2001

MethodsDouble-blind multicentre randomised trial.
ParticipantsForty-eight participants aged 40 years or older with newly diagnosed untreated trigeminal neuralgia.
InterventionsParticipants were randomly allocated to either oxcarbazepine or carbamazepine group. The starting dose was 300 mg twice daily for oxcarbazepine and 200 mg twice daily for carbamazepine. Dosage was increased gradually up to achieve the best therapeutic effect combined with satisfactory tolerability.
Outcomes

Number of days with pain since the last visit

Change in nature of pain

Mean number of attacks of pain per day

Mean number of attacks of pain per week

Severity of pain

Global assessment of therapeutic efficacy

NotesOnly available as an abstract, which is not sufficiently detailed for assessment. Further information required.

Characteristics of ongoing studies [ordered by study ID]

NCT01302275

Trial name or titleOxcarbazepine for the treatment of chronic peripheral neuropathic pain (IMIOXC)
MethodsA randomised, double-blind, placebo-controlled trial.
Participants

The estimated number enrolled participants is 120.

Inclusion criteria: aged 18 years or older; both genders; definite or probable neuropathic pain; diagnosis of polyneuropathy, postherpetic neuralgia or peripheral nerve injury; pain duration > 3 months; pain rating at baseline ≥ 4 point NRS; informed consent obtained.

Exclusion criteria: other non-neuropathic pain condition; allergy to oxcarbazepine; renal or hepatic impairment; epilepsy; depression and other serious psychiatric disorders; serious medical condition; previous treatment for neuropathic that cannot be stopped; pregnancy; patients expected not to be able to comply with study protocol; treatment with anticonvulsants, antidepressants or opioids.

InterventionsIn the experimental group, oxcarbazepine capsules (300 mg) are gradually increased during 21 days from 300 mg daily to 2400 mg, and kept on that dose (2400 mg) for three weeks. In the control group, identical placebo capsules are increased gradually from 1 daily to 8 daily.
Outcomes

Primary outcome measures: total pain rated on numeric rating scale.

Secondary outcome measures: response defined as at least 50% reduction in pain score; Neuropathic Pain Symptom Inventory; Patient Global Impression of Change; rating of evoked pain; sleep disturbance; quality of life; use of escape medication

Starting dateFebruary 2011
Contact information

Danish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark, 8000. Contact person: Nanna B Finnerup, MD. +45 89493455 finnerup@ki.au.dk; Troels S Jensen, MD. +45 89494137 tsjensen@ki.au.dk.

Department of Neurology, Odense University Hospital. Odense, Denmark, DK-5000. Contact person: Søren H Sindrup, MD. +45 65412471 soeren.sindrup@ouh.regionsyddanmark.dk; Dyveke T Demant, MD. +45 65412485 dyveke.demant@gmail.com

NotesSponsored by Odense University Hospital.

Ancillary