Gabapentin add-on therapy for patients with spinal cord injury associated neurogenic overactive detrusors that are unresponsive to combined anticholinergic and beta-3 adrenergic therapy.

INTRODUCTION: Spinal cord injury is a major cause of lifelong morbidity and functional micturition problems. Some patients are refractory to the available therapeutics, even when used in combination. In this paper we report our results of using gabapentin as an add-on treatment in refractory overactive detrusor cases secondary to spinal cord injury.
MATERIAL AND METHODS: A total of 27 patients who had a spinal cord injury between the levels of the second thoracic and fourth lumbar vertebrae and had an overactive detrusor in urodynamic studies were included in this retrospective study. The patients were selected due to the fact that they also had not responded to a combination of an anticholinergic and mirabegron and had neuropathic pain. Gabapentin treatment was added to the previous therapy. Demographics, previous treatments, chronic conditions, urodynamic findings, clinical and urodynamic responses are reported in this paper.
RESULTS: We observed a response to treatment in the urodynamic studies of 11 patients (40.17%), in terms of decreased detrusor contractions, maximal detrusor pressure, and the number of incontinence episodes. Sixteen patients did not respond to the gabapentin add-on therapy and were referred for Botulinum toxin injections to the bladder.
CONCLUSIONS: Gabapentin add-on therapy can be considered as a third or further option, before Botulinum toxin injection, for patients with neurogenic overactive detrusor who did not respond to the combination of anticholinergics and mirabegron. The approved usage of gabapentin for neurogenic pain justifies its usage in this area. In our selected patient group, who had not responded to the combination therapy, we observed a clinical benefit in one-third of the patients. Copyright by Polish Urological Association.

INTRODUCTION

Spinal cord injury (SCI) is a major cause of lifelong morbidity [1]. Current papers report an incidence rate of 54 cases per one million, according to US data [2]. Although there is a decline in the incidence in the young population, as well as some improvements in overall life quality, the management of a neurogenic bladder after an SCI is still a challenging and crucial issue [3-6]. After an SCI, neurogenic bladder dysfunction may be present as neurogenic detrusor overactivity (NDO) or sphincter detrusor dyssynergia (DSD), which are due to SCI in the suprasacral levels, or as detrusor hypoactivity or complete areflexia as a result of damage to the sacral spinal cord [7]. The management of an underactive detrusor has mainly relied on the active usage of clean intermittent catheterization, which is lifesaving [8]. On the other hand, the management of a neurogenic overactive detrusor is based on medical therapeutics that act on the receptors of the detrusor muscle cells [9]. Blockers of the acetylcholine receptors, namely anticholinergics, and an agonist of the beta-3 adrenergic receptors, mirabegron, are usually used as the first choice treatment, either in combination or as a single therapy [10]. In concordance to the contemporary clinical guidelines, unresponsive patients are recommended to be considered for Botulinum toxin-A injections into the bladder wall, which is more invasive than an oral treatment [11]. With the aim of providing an option to these patients, several molecules have been reported to be successful in an experimental fashion [12]. Among them, gabapentin, a sodium channel blocker, has also been found to be clinically beneficial in suppressing contractions of the detrusor with an acceptable side effect profile in both adults and children, as well as in neurogenic overactive bladder as in overactive bladder syndrome [13-18]. In this paper we report the results of a single neuro-urology working group that comprises 27 adult patients who did not respond to the combination of an anticholinergic and mirabegron and were treated with add-on gabapentin therapy.

MATERIAL AND METHODS

Between June 2016 and June 2020, a total of 27 patients who had a history of traumatic SCI were admitted to our working group that consisted of three urologists, a neurosurgeon, a neurologist, and a physical therapy and rehabilitation specialist. All interventions in the study were a matter of routine patient follow-up and compatible with the declaration by the World Medical Association on the Ethical Principles for Medical Research Involving Human Subjects.

All patients had a referral urodynamic study which was compatible with detrusor overactivity despite regular use of an anticholinergic and mirabegron. A Visual Analogue Score (VAS) was obtained to evaluate concurrent neuropathic pain. The primary aim of gabapentin usage was the treatment of neuropathic pain (not off-label usage). A bladder diary comprising three consecutive days was obtained from each patient during their initial admission. After obtaining the diary, gabapentin therapy was initiated with a dosage of 100 mg a day, and the dose was increased to 200 (2*100) mg on the second day, 300 (3*100) mg on the third day, and 900 (3*300) mg at the first week, respectively. The dose of the gabapentin was increased to a maximum of 3600 mg per day according to the requirements of the patients. The patients were scheduled with outpatient appointments every 15 days, and the patients, or their caregivers, were instructed to complete a new bladder diary for the three consecutive days after each visit. Gabapentin dosage was further tailored, based on the response of the patient, up to 800 mg a day. Patients who responded to the gabapentin treatment were scheduled in regular yearly urodynamic studies while unresponsive patients were evaluated with a new urodynamic study and considered for Botulinum toxin injections to the bladder. Clinical data obtained from the urodynamic studies, the bladder diaries, and the symptom scores before and after the gabapentin treatment were collected and compared.

Kolmogorov-Smirnov tests were performed to evaluate whether the interval data showed a parametric distribution. Therefore, interval data is presented as mean (standard deviation (SD) and nominal data are expressed as total numbers (n). Pre- and post-treatment findings were compared using a two-tailed t-test, p values smaller than 0.05 were deemed as significant.

RESULTS

The mean age was 32.03 (SD: 6.7) years, the mean time duration between the SCI and referral to our group was 8.8 (SD: 2.3) months. The SCI area was cervical, thoracic, and thoracolumbar in 13, 5, and 9 patients, respectively. Neuropathic pain was prevalent in lower extremities in 15 patients while in both upper and lower extremities in 12 patients. The cause of the SCI was motor vehicle accident in 12 patients, falls in 9 patients, recreational injuries in 3 patients, sport injuries in 2 patients, and a gunshot injury in one patient.

We observed significant amelioration in terms of patient-reported numbers of daily incontinence episodes as well as increased maximal bladder volumes and decreased maximal detrusor pressures in urodynamic studies in a total of 11 (40.17%) patients in our cohort. A significant decrease in the VAS scores for the neuropathic pain was also observed in this group.

The unresponsive patient group comprised of 16 patients who were also found to benefit from the gabapentin add-on treatment in terms of the amelioration of the neuropathic pain, which was apparent in the comparison between the pre- and post-treatment VAS scores. However, the urodynamic results and the number of incontinence episodes did not show a significant difference in these patients. These patients were referred for Botulinum toxin injection into the bladder wall.

The clinical data of the study group is summarized in Table 1.

Table 1

Clinical data of the cohort

Parameter	Responsive Group	Unresponsive Group
Visual Analogue Score Pre-treatment Post-treatment p value	5.45 (1.55)2.54 (0.98)<0.001*	6.18 (1.73)3.62 (1.11)<0.001*
Daily Incontinence Episodes Pre-treatment Post-treatment p value	6.54 (2.7)2.27 (1.54)<0.001*	8.37 (2.82)7.56 (2.12)0.09
Maximal Detrusor Pressure Pre-treatment Post-treatment p value	38.81 (15.17)21.72 (8.62)0.01*	29.62 (10.7)30.18 (10.51)0.79
Maximal Bladder Volume Pre-treatment Post-treatment p value	239.63 (58.19)262.81 (48.01)0.01*	219.62 (57.25)221.81 (54.73)0.57

Interval data is expressed as the mean. (SD)

– statistically significant comparison between the pre- and post-treatment results

DISCUSSION

SCI is a major disabling condition which has an incidence of between 14 to 54 cases per million of the population in different areas around the globe, with a significant dominance of males [2, 19, 20, 21]. The most common etiological factors are traffic accidents and falls, according to previous reports [20, 21, 22]. In our study, all patients were male, and our age group was respectively young with a mean age of 32.03 (SD: 6.7) years. The most common etiologies in our cohort were also those of accidents and falls that comprised 12 and 9 patients, respectively. Unfortunately, we cannot provide any incidence rate or demographic distribution data because of the selective nature of the patient group in our study. On the other hand, we can report that as a multidisciplinary neuro-urology working group, we are faced with 2 to 5 refractory NDO cases per year, which makes one case per physician per year for our group. To the best of the authors’ knowledge, a comprehensive nationwide mapping of SCI cases in our country is not available in the literature and consider that a thorough report is warranted. Fortunately, individuals who have suffered from SCI are usually managed in specialized institutions, thus, such a comprehensive study or prospective trials in selected patients seems possible in these institutions.

The clinical picture of a SCI patient depends on the extent, whether it is complete or partial, and the level of the injury. A complete cervical disruption presents with tetraplegia while a partial lower lumbar injury may only affect a single extremity. Urinary functions are also in the same vein with the overall motor and sensory functions. Injuries of the cervical, thoracic, or lumbar spinal cord usually present with an NDO and DSD, while sacral injuries virtually always result in an underactive detrusor with a functional or flask external sphincter [11, 23]. Our study comprised only of complete suprasacral SCI lesions with refractory NDO and neuropathic pain, which represented our selected subgroup. Medical management options for these patients are comparatively few, thus, several studies were undertaken to increase the therapeutic choices. In experimental fashion, inosine, resiniferatoxin, an E-series prostaglandin 1 receptor antagonist, kynurenine gene transfer via viruses, gamma-aminobutyric acid A and B receptor agonists muscimol and baclofen, a transient receptor potential 1 and a transient receptor potential vanilloid 1 receptor antagonists, an arginase inhibitor, a prostacyclin receptor antagonist, an endothelin-A receptor antagonist, and memantine have been shown to be beneficial [24-33]. Clinical studies have indicated that mirabegron, tetrahydrocannabinol-cannabidiol oral spray, anticholinergic preparations, and gabapentin are effective in the management of a neurogenic overactive detrusor [13–18, 34, 35–39]. However, there is still a group of patients who are unresponsive to the combination of an anticholinergic with the β-adrenergic therapeutic. These patients are considered for Botulinum toxin injections or surgical options if the injections fail [11, 40]. Additionally, neuropathic pain is also a common component in the treatment for an individual who has suffered an SCI [41]. The management of neuropathic pain justifies the usage of gabapentin in these patients, akin to our study group. In our study, we aimed to utilize gabapentin’s role for the management of both neuropathic pain and the neurogenic overactive detrusor, and our results showed that it has a beneficial effect. Our results are compatible with previous studies, but with better urodynamic findings, decreased VAS scores, as well as continence status. As a result, we believe that add-on gabapentin therapy can be considered as a salvage option between the combinations of an anticholinergic with β-adrenergic and Botulinum toxin injection, and it is also beneficial in the management of the neuropathic pain of these patients.

As an important caution, physicians should be aware of the addictive and abuse potential of gabapentin [42]. Interestingly, to the best of the authors’ knowledge, previous papers that reported the success of gabapentin in the management of overactive bladder did not indicate any cases of addiction or abuse. Considering the follow-up periods of the available papers, future follow-ups must give importance to this point. A total of 11 patients benefited from gabapentin and continued the treatment. Among them, we have also not observed any signs of addiction or abuse. We believe that the abusive potential may also be related to the individual’s personality or behavior. This is an area of future research, and we consider that future follow-ups of the available studies that have used gabapentin may be a matter of interest.

Our study brings encouraging results in the management of an unresponsive NDO due to SCI; however, the study has some limitations. The weakest point is the small number of patients. The patients in the study have concurrent ''overactive bladder with unresponsive to anticholinergics and mirabegron'' and neuropathic pain. The small number of patients in the study may be explained by this situation. The cohort is a selected patient group. Therefore, we cannot indicate any demographic information or endorse a common clinical strategy based on our selected patients. The patient follow-up data is also limited after the initial treatment. A review of the patient charts revealed that among a total of 11 patients, only four of them are still being followed-up by our working group. We cannot report any long-term compliance data for the 7 patients who dropped out of our follow-up. Furthermore, we cannot report the success of Botulinum toxin injections in the unresponsive group in our cohort. Further follow-ups would show the compliance rates and long-term success of gabapentin add-on therapy. The condition of the unresponsive patients is also a matter of interest. Finally, we did not evaluate the concomitant medications that may affect outcomes in subgroups of responders and non-responders.

CONCLUSIONS

Gabapentin is an option for the treatment of NDO after SCI. The approved usage of this therapy for neuropathic pain may justify its usage for such patients outside of clinical trials. We believe that it can also be considered as a salvage option in refractory NDO cases as well as a primary option in patients who have NDO concurrent with neuropathic pain. Our experience with these patients adds to what is little known about gabapentin add-on therapy. Also, it may encourage other authors to work on this topic. However, prospective-randomized clinical trials with larger samples are needed to achieve a better understanding of gabapentin add-on therapy.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.