To date there is no evidence-based data for efficacious treatment of neuropathic pain in dogs with Chiari-like malformation (CM) and syringomyelia (SM). The objective of this prospective cross-over study was to compare the effect of gabapentin versus topiramate, as an add-on treatment to carprofen, on quality of life (QoL) of dogs experiencing signs of neuropathic pain due to CM/SM. A visual analogue scale (VAS) was used to assess the QoL: (1) on day 0; (2) after 1 week of carprofen only; (3) after 2 weeks on carprofen and gabapentin; and (4) after 2 weeks on carprofen and topiramate. No significant difference was observed between VAS after gabapentin or topiramate (P=0.91). However, an improvement in QoL was observed when gabapentin was compared with baseline (P=0.009), but not for topiramate. In conclusion, the addition of gabapentin was more effective in improving QoL than carprofen alone, but the study failed to identify that gabapentin was more efficacious than topiramate. Perhaps the more favourable side effect profile of the former makes it more suitable for the treatment of neuropathic pain associated with CM/SM but further placebo-controlled trials are required to assess the efficacy of these drugs.
- Cavalier King Charles Spaniel
- Neuropathic pain
- Quality of life
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Chiari-like malformation (CM) and syringomyelia (SM) constitute a painful disease complex described in dogs, especially in Cavalier King Charles spaniels (CKCS), that is characterised by overcrowding of the caudal cranial fossa, caudal cerebellar herniation and the development of syringes (fluid-filled spaces) within the spinal cord (Rusbridge and MacSweeny 2000, Rusbridge and Knowler 2003). It is not clear how these syringes are formed, but suspected reduced craniospinal compliance and lack of synchronicity between the cerebrospinal fluid (CSF) and systolic pulse waves may play a role (Driver and others 2013a). This lack of synchronicity can create pressure gradients in perivascular spaces that could act as a one-way valve drawing in CSF (Bilston and others 2010). Consequently, fluid accumulates within the spinal cord central canal which expands and eventually leads to intraparenchymal cavities within the spinal cord (Driver and others 2010, 2013a, b).
CM/SM in people and dogs has been associated with clinical signs suggestive of neuropathic pain (NeP) (Rusbridge and Jeffery 2008, Hatem and others 2010, Plessas and others 2012). NeP is defined as pain caused by disordered neural processing, which can have a variety of causes (Woolf and Mannion 1999). Asymmetrical syringes, particularly those involving the dorsal horn, have been especially associated with pain in dogs (Rusbridge and others 2007, Schmidt and others 2013). Additionally, recent reports suggest that a decrease in expression of the pain-related neuropeptides substance P and calcitonin gene-related peptide in the spinal cord, as well as increased concentrations of substance P and interleukin-6 in the CSF may play a role in the development of NeP in dogs with CM/SM (Hu and others 2011, Schmidt and others 2013). Both substance P and calcitonin gene-related peptide are neuropeptides produced by nociceptive afferents with target receptors in the dorsal horn. Interleukin 6 is a proinflammatory cytokine produced by glial cells in spinal dorsal horn, which can contribute to hyperalgesia (Todd 2009, Wei and others 2013).
NeP usually manifests by behavioural signs suggesting allodynia (pain arising from a non-noxious stimulus, e.g. avoidance behaviour, vocalisation or other excessive reaction to gentle touch) (Rusbridge and Jeffery 2008, Plessas and others 2012). Dogs with a wide asymmetrical syrinx may show ‘phantom’ scratching behaviour (rhythmic scratch without making purposeful skin contact induced by touch, clothing, walking and excitement), which is thought to be due to damage to inhibitory neurons influencing spinal cord central pattern generators for scratching (Rusbridge 2013).
In people there is increasing evidence that antiepileptic drugs such as gabapentin, pregabalin, topiramate and other drugs can have a beneficial effect on treating NeP through various modes of action (Attal and others 1998, Tai and others 2001, Serpell and others 2002, Levendoğlu and others 2004, Finnerup and others 2005, Khoromi and others 2005, Siddall and others 2006, Dworkin and others 2007, Finnerup and others 2010). Based on this information, gabapentin is used widely in veterinary patients with suspected NeP, but there are no data on its effect (Rusbridge and Greitz 2006, Rusbridge and Jeffery 2008, Wolfe and Poma 2010). On the other hand, topiramate's use in veterinary patients for the management of NeP has been very limited, and only two case reports have shown a beneficial effect (Plessas and others 2013, Grant and Rusbridge 2014).
These antiepileptic drugs are mainly used to control chronic clinical signs and subsequently improve the quality of life (QoL). A recent study on CKCS with CM/SM experiencing NeP revealed that these dogs have compromised QoL and welfare (Rutherford and others 2012). These findings are similar to reports from human literature, which show that NeP in people has a serious negative impact on their QoL (Jensen and others 2007). This impact on the patient's welfare renders effective treatment of paramount importance, but relieving only the signs of pain does not necessarily improve the QoL (Ward and others 1998). Adverse effects associated with drug administration for the treatment of NeP can also compromise the QoL of these dogs. Thus, QoL may be a better parameter to assess, than a pain score alone, when assessing the effect of a drug on neuropathic pain.
The aim of this study was to compare prospectively, in a cross-over trial, the effect of gabapentin versus topiramate, as an adjunctive treatment to carprofen, on QoL of clinically affected CKCS with CM/SM, as assessed by the owners using a visual analogue scale (VAS), and record any adverse effects.
Materials and methods
Forty Cavalier King Charles spaniel dogs were included in the trial from three different referral hospitals in the UK; Royal Veterinary College Small Animal Referrals Hospital (n=25), Stone Lion Veterinary Hospital (n=12) and Queen's Veterinary School Hospital of University of Cambridge (n=3). Ethical approval was issued by the Ethical Committees of the Royal Veterinary College, University of London (URN 2010–1072; date of approval 09 May 2011), and from the University of Cambridge (CR3; date of approval 14 April 2011). An Animal Test Certificate (ATC-S-025) was issued by the Veterinary Medicines Directorate for the use of non-licensed drugs.
Inclusion criteria included: diagnosis of CM/SM confirmed by MRI and a board-certified neurologist, evidence of at least one sign of NeP (i.e. vocalisation, facial rubbing, painful on gentle touch) or phantom scratching. Dogs were excluded if they were receiving any other treatment, or had epilepsy, renal, gastrointestinal or dermatological disease. If dogs were on chronic analgesic treatment, it was discontinued for at least 48 hour before entering in the trial.
Study design, drugs, evaluation
A six-week prospective, randomised, cross-over trial was performed assessing the effect of gabapentin (Neurontin, Pfizer) at 11.5±2.5 mg/kg, orally, eight-hourly and topiramate (Topamax, Janssen-Cilag) at 11.3±2.3 mg/kg, orally, eight-hourly as an adjunctive treatment to carprofen (Rimadyl, Pfizer Animal Health) at 2.2±0.5 mg/kg, orally, once a day, which was used as a baseline drug. All other medication was discontinued at the beginning of the trial. Carprofen was introduced after assessing QoL on day 0 (Fig 1). One week later QoL was reassessed and topiramate or gabapentin was randomly allocated as the first drug (drug A) to be added to carprofen for two weeks, by opening a sealed envelope from a pool containing equal numbers of allocations to each drug. At the end of the drug A period the QoL was assessed, and during week 4 the dogs received carprofen only (wash-out period). On weeks 5 and 6 gabapentin (drug B) was added, if topiramate was the first drug, or topiramate, if gabapentin was the first drug. At the end of the drug B period QoL was assessed and the trial period ended.
The dogs’ global QoL in relation to the clinical signs was assessed only by their owners four times over the six-week trial using a VAS (De Boer and others 2004, Plessas and others 2012). Four 100 mm lines ranging from 0 mm (clinically normal dogs) to 100 mm (dogs with severe clinical signs that would necessitate euthanasia) were used on the same sheet of paper. The owner recorded the VAS assessment based on their subjective evaluation of QoL by intersecting the printed 100 mm line with a second perpendicular line.
The clinicians of one institution (Royal Veterinary College) dealing with the trial were blinded to the order of the tested drugs at the time of the consultation with the owners of the dogs, but this was not feasible in the other two institutions. Subsequently, the drugs were labelled as drug 0 (for carprofen) and after randomisation drug A (for the first adjunctive drug) and drug B (for the second adjunctive drug). The owners of the dogs were not blinded about carprofen, but they were blinded to the use of topiramate and gabapentin by adding the tablets or the capsules in brown pill containers labelled A or B. However, because of safety regulations, it was not possible to change the capsules of gabapentin, which had the trade name written on them.
Statistical analysis was performed with a commercial software package (Prism V.6 for Mac Os X, Graphpad Software 2012). All quantitative data were assessed for normality with the D'Agostino and Pearson omnibus normality test and graphically. Means and SDs were calculated for normally distributed data. A one-way analysis of variance for paired values was used to compare the VAS between groups and if P was <0.05 then post hoc analysis using Tukey's test was performed. All tests were performed two-sided. A P value of less than 0.05 was considered statistically significant. Data are presented as mean±SD. A combination of intention-to-treat and per protocol analysis was performed.
Ad hoc sample size was estimated to be 32 dogs using an online sample size formula for a cross-over study (MGH Biostatistics Center 2011). The mean and sd for the sample size calculation was derived from data accumulated in a confidential drug trial by one of the authors (HAV).
Forty dogs fulfilled the criteria and were included, of which 33 successfully completed the trial. Three dogs were lost to follow-up after enrolment, two dogs had incomplete VAS assessments and one dog dropped out of the trial after three days on topiramate, because of adverse effects perceived unacceptable to the owner (sedation, inappetence and ataxia). One dog (35 months old) died suddenly while being treated with carprofen and gabapentin, during the second part of the trial. No previous adverse effects were noted, and the dog was apparently healthy apart from the CM/SM. The owners declined postmortem examination, so the exact cause of death was not determined.
Of the 33 dogs, 17 were female (11 neutered) and 16 male (11 neutered) with a mean age of 73.3±27 months. Mean body weight was 9±1.9 kg. The mean VAS of QoL on day 0 was 41.3±21.3 mm, and after one week of carprofen administration 40±23.3 mm. At the end of a two-week course with adjunctive gabapentin VAS was 30.6±21.4 mm, and after topiramate VAS was 33.2±23.4 mm. No statistically significant difference (2.6 mm) was observed between gabapentin and topiramate (P=0.91). However, in a further exploratory analysis significant improvement in QoL was observed after gabapentin compared with baselines (P=0.002 compared with day 0 and P=0.009 compared with day 7), but not for topiramate (P=0.2 compared with day 0 and P=0.45 compared with day 7) (Fig 2). Topiramate VAS had one outlier, which scored 100 mm, mainly because of adverse effects. To explore the effect of this outlier further, a repeat analysis in which it was excluded revealed a significant improvement over baseline when using topiramate (P=0.009 compared with day 0 and P=0.02 compared with day 7). Interestingly, the addition of carprofen did not have an effect on QoL (P=0.88), despite the owners knowing that this was given as baseline pain relief. There was no period (order) effect between drug A and drug B.
Mild to moderate adverse effects were recorded during the trial (Table 1). From the 40 dogs initially included in the trial, nine developed adverse effects (22.5 per cent), for which one dropped out. One dog developed adverse effects while on carprofen only, four dogs while treated with carprofen/gabapentin, three dogs while treated with carprofen/topiramate and finally one dog while treated with carprofen/gabapentin as well as carprofen/topiramate. For topiramate, sedation and inappetence were the most common adverse effects. Aggression, ataxia, chewing of digits and facial rubbing were also noted. Sedation, polyphagia, vomiting, diarrhoea and inappetence were reported during carprofen/gabapentin treatment, which were mild and self-limiting. However, one apparently healthy dog died suddenly, when treated with carprofen/ gabapentin, but unfortunately postmortem examination was declined so the exact cause of the death could not be determined.
This randomised cross-over clinical trial is the first study, to the authors’ knowledge, to examine the effect of gabapentin versus topiramate on dog's QoL with CM/SM and clinical signs suggestive of NeP. No statistically significant difference was observed in assessed QoL between gabapentin and topiramate, however exploratory analysis comparing QoL to baselines suggest that gabapentin may be more beneficial than carprofen alone.
The effect of these drugs is comparable with that in people experiencing NeP. Gabapentin has shown to be effective in people, when compared with placebo treatment (Attal and others 1998, Tai and others 2001, Serpell 2002, Levendoğlu and others 2004). On the other hand, the effect of topiramate is less clear, and conflicting results have been reported from the limited trials in people (Khoromi and others 2005, Wiffen and others 2013).
Previous reports on the effect of gabapentin in the treatment of acute postoperative /perioperative pain in dogs did not show an effect, and this may not be a surprise when gabapentin's mechanism of action is studied (Wagner and others 2010, Aghighi and others 2012). It is believed that gabapentin's main analgesic effect is via binding to the α2δ-subunit of the voltage-gated Ca2+ channels, which are upregulated after nerve injury. This binding inhibits high-threshold neuronal Ca2+ currents that are necessary for excitatory neurotransmitter (glutamate and aspartate) release (Luo and others 2002, Li and others 2004, Coderre and others 2005, Baillie and Power 2006, Sills 2006). Glutamate is the main excitatory neurotransmitter for the nociceptive afferent pathways, and reduction of its release could reduce patients’ perception of pain (Todd 2009). Based on this mechanism of action, gabapentin might not be an effective drug in cases of acute or postoperative pain in which the α2δ- subunit of voltage-gated Ca2+ channels is not upregulated (Luo and others 2001, 2002, Boroujerdi and others 2011).
Although the mechanism of action of topiramate is less well understood, its effect is believed to be due to modulation of voltage-gated sodium and calcium ion channels, potentiation of γ-aminobutyric acid inhibition, block of excitatory glutamate neurotransmission and inhibition of carbonic anhydrase (Chong and Libretto 2003). It is not clear which of these mechanisms of action contributes more to its antinociceptive properties but, as with gabapentin, inhibition of glutamate release may play an important role. Topiramate is not widely used in veterinary patients, and is mainly used as an antiepileptic drug, however two recent reports state its efficacy as an antinociceptive drug in a cat and a dog (Kiviranta and others 2013, Plessas and others 2013, Grant and Rusbridge 2014). Evidence though from patients suffering peripheral neuropathic pain show that topiramate was not superior to placebo treatment, but there is no adequate information for central neuropathic conditions (Wiffen and others 2013).
As aforementioned, topiramate can inhibit carbonic anhydrase, which can reduce CSF production (Celebisoy and others 2007). Given that CKCS can have altered CSF dynamics, a reduction in CSF could reduce the size of the syringes (Driver and others 2013a). As the latter has been correlated with signs of pain, reduction in syrinx size could potentially improve signs of pain (Rusbridge and others 2007). This was the main reason for selecting topiramate for comparison with gabapentin.
Mild to moderate adverse effects were noted during treatment with gabapentin and topiramate in 22.5 per cent of the dogs. For topiramate, sedation and inappetence were the most common adverse effects. Sedation with topiramate has been reported previously in dogs (Kiviranta and others 2013). Aggression, ataxia, chewing of digits and facial rubbing were also noted. The latter two adverse effects may relate to perioral and digital paraesthesias reported in people, presumably due to metabolic acidosis caused by carbonic anhydrase inhibition (Chong and Libretto 2003, Mirza and others 2009). Loss of appetite and weight loss have also been reported in people treated with topiramate, but the exact mechanism of these adverse effects is unclear (Raskin and others 2004). Sedation, polyphagia, vomiting, diarrhoea and inappetence were reported during carprofen/gabapentin treatment, which were mild and self-limiting.
This study highlights some difficulties in carrying out drug therapy trials in pet dogs, notably problems in enrolling sufficiently large numbers of cases to enable detection of small treatment effects and difficulties in maintaining blinding. For instance, there was no blinding of owners to carprofen treatment, and owners were able to identify the gabapentin capsules because the drug name was printed on them. However, reformulation of the capsules was not possible without compromising the safety regulations required for an Animal Test Certificate. Also, blinding of the clinicians was not possible in all the institutions involved in the trial.
Despite the observation in the present study that carprofen did not improve the QoL the authors cannot eliminate the possibility that the positive effect observed by the trialled drugs may be due to placebo effect. Currently the placebo effect for assessment of neuropathic pain in dogs is not known, but for other clinical trials in dogs an effect up to 46 per cent from baseline has been reported (Luo and others 2002, Li 2004, Coderre and others 2005, Baillie and Power 2006, Sills 2006, Munana and others 2010, Conzemius and Evans 2012). Unfortunately, placebo treatment could not be used in this trial for ethical reasons, so caution should be taken when interpreting the effect of gabapentin or topiramate compared with baselines, considering that their effect on QoL was less than 10 per cent. Further placebo-controlled trials will be required to better assess the effect of these drugs on clinically affected dogs, although this can be practically challenging for ethical reasons (Jeffery 2014).
A further difficulty was the extreme variability in the QoL assessments attributed to the owners. This exacerbates the loss of discrimination between small treatment effects, inherent in drug trials with small numbers of participants. However, evaluation of QoL is a useful outcome measure, because it intrinsically assesses a global measure of benefit, which may not be captured by more specific outcome measures. Despite all the limitations of this trial, which reflect the practical difficulties associated with client-owned animals and multicentre settings, it provides a scientific basis for further clinical trials on gabapentin and topiramate, and more evidence-based information for their clinical use.
In this prospective, randomised, cross-over study in clinically affected CKCS with CM/SM no significant difference was observed on their QoL when gabapentin was compared with topiramate. Data also suggests that the addition of either of these two drugs may be more effective than carprofen alone. Sedation was the most common adverse effect of both drugs with the addition of inappetence for topiramate; however the adverse effects associated with the latter drug were more severe. In conclusion, gabapentin's more favourable adverse effect profile may be more suitable than topiramate in dogs experiencing NeP, but further placebo-controlled prospective studies will be needed to better establish the comparative effect of these drugs.
The authors thank the owners of the patients who participated in this study and the veterinarians who referred them to us. Special thanks are due to Sandy Griffiths VN and the Stone Lion Veterinary Hospital, Goddard Veterinary Group. The authors also thank the various CKCS clubs, in particular the Companion Cavalier Club, for their continuous support for the investigation of these conditions. Finally, the authors thank the Research Office of the Royal Veterinary College for assessing the manuscript according to the Royal Veterinary College's code of good research practice (Authorisation number: CSS_00930).
*Present address:Davies Veterinary Specialists, Manor Farm Business Park, Higham Gobion, Hertfordshire SG5 3HR, UK
Provenance: not commissioned; externally peer reviewed
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