A survey for ketamine abuse and its relation to the lower urinary tract symptoms in Taiwan

We aimed to explore the correlation between ketamine abuse and lower urinary tract symptoms (LUTS) and epidemiology of ketamine cystitis. Questionnaire records of ketamine abusers, such as sex, age, and details of using ketamine, including consumption method, amount, duration of ketamine use, and LUTS, were obtained from two private rehabilitation centers. We analyzed these factors and established a severity forecasting module. One hundred and six ketamine abusers completed the questionnaires. LUTS showed an onset time of 24.67 ± 26.36 months among ketamine abusers. Overactive bladder symptom score, international prostate symptom score-storage, interstitial cystitis symptom index, interstitial cystitis problem index, and visual analogue scale score were 5.25 ± 4.43, 5.95 ± 5.72, 10.96 ± 6.66, 9.73 ± 5.82, and 2.55 ± 3.18, respectively. All symptom scores were positively correlated with the duration of ketamine abuse. Ketamine snorting was significantly correlated with all symptom scores compared to smoking. Hydrodistention, intravesical hyaluronic acid instillation, intravesical injection with botulinum toxin, and hyperbaric-oxygen therapy showed better effect than oral treatment. Ketamine can induce severe storage symptoms, such as frequency or nocturia depending on the duration of abuse. Ketamine snorting may cause worse LUTS than smoking. Combining ketamine and other substances may exacerbate LUTS. Intravesical therapy may lead to better outcomes than oral treatment.


Discussion
Long-term ketamine abuse may cause severe LUTS and bladder dysfunction. However, epidemiological data of ketamine-associated LUTS in Taiwan remain unknown. Our results show that ketamine abuse can induce severe storage symptoms, such as frequency or nocturia, depending on the duration of ketamine use. The combined use of ketamine and other substances (i.e., marijuana and MDMA) may exacerbate LUTS. Half of the ketamine abusers with LUTS did not seek medical advice.
Ketamine use was found to be predominant in men. This finding is in line with a USA-based report from 2007 11 and drug misuse declaration from 2009 to 2010 in England. Previous literature has shown that the age of first-time ketamine use was approximately 16 years, which is compatible with our data 12 . Many abusers during this period are easily influenced by their peers.
www.nature.com/scientificreports www.nature.com/scientificreports/ More than 50% of ketamine abusers had LUTS such as increased urinary frequency and urgency, nocturia, urethral pain, and incomplete emptying, while increased frequency, incomplete emptying, and nocturia were the most bothersome problems of ketamine abusers.
Snorting and smoking are the most frequent ways to use ketamine. Ketamine abusers may chop up ketamine crystals into powder by X-ACTO knife or razor blade, and the powder is then inhaled directly. Once inside the nose and sinuses, the drug is absorbed from the nasal mucosa quickly. The onset time for euphoria is about 3-5 minutes. Our data showed that the frequency of smoking and snorting was nearly equal; however, ketamine snorting caused more severe LUTS (Fig. 2). This is likely due to a higher amount of ketamine entering the circulation via direct snorting. In addition, the duration of ketamine use via snorting was longer than that via smoking, which might be another reason why ketamine snorting induced more severe LUTS than smoking.
All the symptom scores were positively correlated with the duration of ketamine abuse, implying that more the contact time with ketamine, the more obvious LUTS and bladder pain become. It generally takes about 2 years to develop LUTS in ketamine abusers. In our study, OABSS significantly increased with the combined use of ketamine and marijuana (P = 0.016). Cannabinoids are the active components of marijuana, and select cannabinoid receptors, CB1 and CB2, have been identified in the human detrusor and urothelium 13 . Activation of these receptors could modulate bladder afferent activity and the micturition reflex 14 . In patients with painful bladder syndrome and idiopathic detrusor overactivity, the density of CB1 expression is enhanced in line with afferent sprouting 15 . This might explain the worse storage symptoms in the abusers who combined the use of ketamine and marijuana.
Combined use of ketamine and MDMA significantly increased the ICPI score (P = 0.034). The major mechanism of MDMA is central stimulation and a rapid liberation of noradrenaline from peripheral adrenergic terminals. Ketamine may exacerbate MDMA-induced central dopamine toxicity. Whether MDMA worsens LUTS via central stimulation is to be clarified by further research.
Ketamine-associated LUTS was found to be under-treated. About 50% of ketamine abusers with LUTS in this survey did not seek medical advice. All of the symptom scores in the non-treated group were lower than those in the treated group. These data suggested that half of ketamine abusers with LUTS experienced mild symptoms, which did not affect their daily life. For those who received treatment, oral medication was the most common therapy, but the response rate was only 53%. Intravesical therapy, such as hydrodistention, hyaluronic acid instillation, and Botulinum toxin injection, seemed to have a better effect. This result is compatible with the treatment www.nature.com/scientificreports www.nature.com/scientificreports/ outcome of interstitial cystitis 16 . Since there are only a few reported case series, a standard treatment plan for ketamine cystitis has not been established. In the current study, intravesical botulinum injection had the highest response rate among different kinds of intravesical therapy; however, the patient number was small. This result is compatible with that of a previous study 17 . Nonetheless, whether this should be considered as a primary therapy for ketamine cystitis needs further investigation.
On March 5, 2019, the US Food and Drug Administration has approved esketamine (SpravatoTM) for treatment-resistant depression 18 . Esketamine is a nasal solution available as a nasal spray. Although its recommended daily dosage is low, there are concerns whether its long-term usage may cause lower urinary tract problems, such as urgency, painful sensation, and irregular frequency. The amount of published data on the long-term safety of ketamine treatment in mood disorders is extremely limited and are mostly case series. Therefore, a long-term, cohort study is warranted.
The main limitation of this study is that there was only subjective assessment and a lack of objective assessment. There was also lack of control and objective assessment in the study. The results may have sex bias as the study had few female participants. Details of oral medication could not be verified; thus, we were not able to determine which medicine was effective to relieve LUTS caused by ketamine abuse.

Conclusions
Ketamine abuse can cause voiding dysfunction. The severity of storage symptoms is correlated with the duration of ketamine use. Ketamine snorting may cause worse LUTS than smoking. The combined use of ketamine and other substances, such as marijuana and MDMA, may exacerbate LUTS. Intravesical therapy may produce better outcomes than oral medical treatment. With this model as a platform, further prospective studies are warranted to investigate the appropriate choice of treatment for this new clinical entity.

Materials and Methods
The self-administered questionnaires were employed in a cross-sectional design and ethical approval by the Institutional Review Board of Tri-Service General Hospital was obtained for data collection and analysis. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
Before answering the questionnaires, all participants were provided a verbal explanation about the contents of questionnaires and they provided informed consent. The scales included overactive bladder symptom score (OABSS), International Prostate Symptom Score-storage (IPSS-S), interstitial cystitis symptom index (ICSI), interstitial cystitis problem index (ICPI), and visual analogue scale (VAS). We gathered these data from two private rehabilitation centers in Taiwan between January 2015 and December 2015. Ninety-five men and 11 women were enrolled in the study. The survey contained information on sex, age, age when ketamine use started, and how they used ketamine (i.e., the amount and frequency of ketamine use). Details of their LUTS and treatment were also recorded. Ketamine users were also asked whether they were using a combination of ketamine and other common substances, such as amphetamine, marijuana, morphine, heroin, codeine, flunitrazepam, or ecstasy. The treatments that the subjects had received, such as oral medication, hydrodistention via cystoscopy, intravesical therapy, or hyperbaric-oxygen therapy, were verified. The symptom that improved first and the most bothersome symptom were also recorded. Data processing and statistical analysis were performed using SPSS Version 17.0. (SPSS Inc. Chicago) and STATISTICA 7.

Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.