elif mutlu.

              1. Introduction

             Opioid dependence (OD) is a relapsing medical condition that imposes substantive costs on society. The most widely used pharmacotherapeutic agents in the treatment of OD are opioid receptor agonists that work to balance the neurobiological dysregulation of individuals who have become dependent on opioids, and prevent opioid withdrawal symptoms [11]. In the medical literature, drugs that act as agonists are widely accepted as the most effective treatment method [13]. The issue that remains to be solved is whether the effectiveness of pharmacotherapies varies across populations and cultures. Substance dependence is a complex condition with many dimensions, notably the biological, psychological, social and political ones. For this reason, it is crucial to examine treatment effectiveness in different settings and populations to see if differences are manifested in treatment outcomes.

 

             There are several studies that support the effectiveness of buprenorphine-naloxone in the treatment of opioid dependence [9, 10]. In terms of safety, this therapy has been compared with methadone and found to be superior [3].The effectiveness and safety profile of this combination have led to its widespread use globally in the outpatient treatment of opioid dependence. The scarcity of research on OD treatment effectiveness is partly a result of the relatively recent availability of buprenorphine-naloxone. The buprenorphine-naloxone combination is the only pharmacotherapeutic agent that has been approved in Turkey for OD treatment. It became available in 2010 and its prescription is restricted to psychiatrists working in specialized substance dependence treatment units, called AMATEMs (Alcohol and Drug Research, Treatment and Training Centres). The medication is used both for managing withdrawal and for maintenance treatment in individuals over the age of 16, with a maximum daily dose of 24 mg. To reduce the risk of diversion, standard urine analysis (to detect buprenorphine levels) is required for each prescription. Moreover, some centres demand pill count documentation via the medical insurance network. There are no standard national guidelines regulating the utilization of this medication to date. 

 

             So far there have been no large-scale studies investigating the prevalence of opioid use in Turkey. A few surveys have, however, been carried out on special populations, such as high-school students, or in pilot cities. Two consecutive multisite studies conducted three years apart on high-school students between the ages of 15-17 in 9 and 15 cities, respectively, found that 1.6 to 2.1% of those populations had used heroin at least once [4, 16]. In addition, there are estimates of the prevalence of problematic drug use, defined as 'injecting drug use or long duration or regular use of opioids, cocaine or amphetamines' by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), which, in the year 2011, was calculated to be 12,733, or less than 0.1% of the Turkish population [5]. When compared with European countries or the US, where problematic drug use as a percentage of the population is estimated to be between 0.1% and 0.7%, these values are relatively low. Nevertheless, we conclude that opioid – especially heroin – dependence is a growing problem in Turkey, especially in the younger population [22].

 

             As clinicians, we saw a dramatic increase in the number of patients applying for treatment as soon as the medication became available in Turkey [21]. Our aim in this study was to investigate the effectiveness of buprenorphine-naloxone outpatient treatment and the factors associated with it. We hope that this study can serve as a pilot study, and that its results can be incorporated in future treatment models that will be accepted nationally.

 

             2. Methods 

             2.1. Participants
             76 participants were recruited from patients who were admitted to the outpatient clinic between the dates of March 2010 and March 2011 to receive buprenorphine-naloxone maintenance treatment as therapy for opioid dependence. The inclusion criteria were a diagnosis of opioid dependence according to the DSM IV-TR (Diagnostic and Statistical Manual of Mental Disorders, fourth edition-Text Revision) and willingness to sign the informed consent form [1]. Additional consent was obtained for the urine scans. 

 

             All patients underwent the standard protocol in use at the AMATEM centre [6]. At intake, sociodemographic and clinical data were collected from all patients. Follow-up data were collected after 12 months.

 

             The mean age of the participants was 32.71 years (standard deviation [SD]=8.10). Female patients accounted for only 6.27% of the group. A clear majority (92.1%) of the patients had health insurance, and most of them (64.5%) were employed. 18.4% did not have regular employment. Most of the patients (94.4%) had a monthly income of less than 1,130 US dollars (2,000 Turkish Lira). 7.9% of the participants had a history of immigration. 14.5% of the participants reported that at least one member in their family regularly used a substance other than alcohol. Daily doses of buprenorphine-naloxone varied between 2 mg and 24 mg. A majority of the patients (68.4%) took buprenorphine-naloxone doses of 8 mg or less. The mean dose was 8.50 mg/day (SD=2.74). 59.2% of the patients attended the OTP. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

             2.2.  Measures
             Sociodemographic and clinical data were collected from patients using a standard written form. The sociodemographic form comprised questions on age, gender, education, type of insurance, employment status, history of immigration, and current, ongoing legal problems related to drug abuse. The clinical form included questions on history of previous treatments (including methadone, Levacetylmethadol (LAAM) or other medications) without a time criterion, intravenous (IV) drug use and family history of drug abuse. A single psychiatrist was responsible for all the interviews.

 

             To determine the factors that predicted remission we performed logistic regression analysis on two separate models: sociodemographic characteristics and history of drug abuse and treatment. The sociodemographic variables consisted of age, gender, employment status, history of immigration, monthly income, history of substance abuse among family members, and presence of hepatitis C. History of substance abuse and treatment comprised the items concerning IV drug use, current buprenorphine-naloxone dose, additional substance abuse, number of hospitalizations, the longest previous remission period under treatment, and history of substitution treatment in the past.

 

             The urine screenings were conducted by trained technicians using the cloned enzyme donor immunoassay (CEDIA) method at the hospital's toxicology unit. Other laboratory data (hepatitis markers and urinalyses) were collected from the patients' medical records. Hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (AntiHCV) were used to screen for hepatitis B and hepatitis C. The markers were detected by the enzyme immunoassay method as well.

 

             2.3. Design
             This single-site longitudinal study was designed to evaluate the outcomes of the OD treatment programme of AMATEM. All patients underwent the standard protocol of the AMATEM centre. Treatment outcomes were evaluated in terms of treatment retention and opioid or other substance use (i.e. relapse). Data were recorded each month from the beginning 
of outpatient treatment. 

 

             2.4.  Procedure
             For this study, we utilized the standard outpatient OD treatment procedure implemented at AMATEM. Patients were taken into hospital and remained as inpatients throughout the induction and stabilization phases, which took approximately three weeks. Once stabilization was attained and outpatient treatment began, the sociodemographic and clincal data such as patients’ history of substance use, psychiatric comorbidities, social support network and family situations were recorded. Based on these, each patient was placed in one of two risk categories, high and low risk, according to which the frequency of their visits to the clinic were determined. Patients with a low level of social support, comorbidities such as depression and anxiety, current social conflicts, and polydrug use (with special attention to alcohol and/ or benzodiazepine use) were considered to be at high risk of relapse, and such patients were scheduled for check-up visits at 1-week intervals. Urinalysis was performed at each visit. Patients attending the psychotherapeutic group therapies regularly with high motivation for treatment and change were considered to be in the low-risk category and were scheduled for check-up visits once or twice monthly.

 

             The check-up visits were performed by a psychiatrist on the research team and took approximately 15 minutes. Drug cravings, side-effects of the medication, illicit drug use and the general psychiatric condition of the patient were evaluated. Brief interventions to favour relapse prevention were conducted as necessary.

 

             At each visit, urinalysis was performed. Patients were accompanied by an observer while giving urine samples. The standard toxicology data collected comprised parameters on buprenorphine, opiates, ethyl glucuronide and benzodiazepine, and the analysis was performed using the cloned enzyme donor immunoassay (CEDIA) method. Metabolites of other substances were tested for on demand when necessary.

 

             Opioid-positive urine samples were interpreted either as relapses or ‘slips’, depending on their frequency and the amount of substance used, together with the surrounding behavioural patterns of use.

 

             If a participant committed a ‘slip’, the frequency of his/her check-up visits was increased and they stayed in the programme. In the case of a relapse, however, the patient’s treatment was halted and the patient was either referred to an inpatient programme or other treatment options were considered. Our OD treatment can be considered a high-threshold programme that aims to reduce the use of opioids, as well as other substances of abuse. Patients were dismissed from the programme if their use of substances other than opioids did not cease.

 

             The outpatient therapeutic programme (OTP) was the psychotherapeutic component of the programme, and took the form of standardized group sessions held twice a week. These groups focused on relapse prevention, utilized the cognitive behavioural approach and were delivered by psychologists working at the AMATEM unit [15]. Participation was encouraged, but was not mandatory. Based on the primary evaluations given by a psychiatrist and a psychologist, motivated participants were recommended to attend an OTP.  

 

             2.5. Definitions 
             For the sake of clarity, we find it worth giving an operational definition of three concepts as they are used in this study: remission, relapse and nonremission. Remission is defined here as successfully remaining in the treatment programme without any urine scans that show positive for opioids for the duration of 12 months. Relapse is defined as having urine scans that are positive for opioids for two consecutive months. The non-remission group consisted of all patients in the relapse group, along with the patients who dropped out at any time during the course of the study without there being any known reason. While a certain percentage of the patients who dropped out did so due to relapses, we did not have corroborating data on this. 

             2.6. Statistical Analysis
             The chi-square and the t-test (Fisher’s exact test) were performed using SPSS 18.0 (Statistical Package for the Social Sciences 18.0) to take account of sociodemographic and clinical data. A p-value equal to or less than 0.05 was considered significant. To identify the factors predicting remission, logistic regression was used. The possible factors identified using univariate analyses were further entered into the Cox regression analysis to determine independent predictors of remission. The effect of treatment on the duration of remission was investigated using the logrank test. Kaplan-Meier survival estimates were calculated, too. 

 

             3. Results

             3.1. Subject Characteristics 
             Sociodemographic and clinical data collected from the medical records of the 76 patients are shown in Table 1.

 

             30.6% of these patients were using heroin only, whereas 40% reported polydrug use. The most commonly used extra-opioid substance was cannabis (18.1%). The percentage of IV drug use was 45.3%. Approximately one-third of the patients reported that they shared needles and syringes with others. Prevalence rates of Hepatitis C and Hepatitis B were found to be 18.4% and 2.6%, respectively. 38.7% of the participants had undergone substitution treatment in the past; methadone was reported as the most commonly used substitution medication (18.7%).

 

             3.2.  Treatment Outcomes
             As mentioned above, remission was assessed operationally as the absence of opioid-positive urine screenings throughout treatment. 43 of 76 patients (45.6%) were in remission and remained in treatment during the 12-month follow-up period. 

 

             The non-remission group consisted of a total of 33 participants; 7 patients (22%) relapsed and dropped out, 3 relapsed patients (9%) were redirected to inpatient treatment, and 23 patients (69%) dropped out of the programme without there being any known reason.

 

             Comparisons of the sociodemographic and clinical charactersitics of the remission group and the non-remission group at the end of the 12-month period showed that patients with a history of drugrelated legal problems (p=0.01), with polydrug use (p=0.02), without a family member with drug abuse (p=0.01), those who attended the OTP (p =0.01) and those who had a high monthly income (p=0.04) were more likely to be in remission (Table 2).

 

             Comparing those in remission and in non-remission, no significant differences were found in terms of age, gender, employment status, history of immigration, IV drug use or substitution drug use in the past. 

 

             3.3 Predictors of remission
             In assessing the sociodemographic variables under review, income level, history of substance abuse among family members, and the presence of drugrelated legal problems were found to be significant in predicting remission (Table 3). In evaluating the history of drug abuse and treatment variables, nonopioid substance abuse and history of substitution in the past were found to be significant in their effects on staying in remission.

 

             Lastly, the cumulative remission rates of the whole sample were determined using the KaplanMeier method. The results showed that the cumulative remission rate was 70% at the end of the 6th month and 56.6% at the end of the 12th month (Figure 2).

 

             Cox regression analysis revealed that employment status (p=0.03) and history of immigration (p=0.02) were significant in predicting the duration of remission for the whole sample (Table 4).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

             4. Discussion

             This study was designed to examine the effectiveness and identify the predictors of buprenorphinenaloxone treatment in a sample of opioid-dependent individuals in Turkey. We found that 56.6% of patients had not used opioids at the end of the 12-month treatment period. This finding is consistent with those of previous studies [12, 19, 20]. At the end of the 5th month of treatment, 70% of participants were still in treatment. At the end of the 12th month of treatment 56.6% of patients were in The treatment. This finding indicates that a considerable percentage of patients drop out of treatment after the 6th month, and draws attention to the need for longterm treatment programmes that have so far been lacking in Turkey.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

             Patients that attended OTP stayed in remission at a higher rate. This finding is consistent with previous reports showing that psychotherapeutic interventions and social support increase the effectiveness of OD treatment [2]. We believe that a comprehensive, biopsychosocial approach to the treatment of OD is a crucial factor in maximizing treatment effectiveness, based on previous empirical studies as well as our clinical observations. The main focus of the OTP administered to the participants was relapse prevention. Additionally, topics such as strategies for coping with high-risk situations such as interpersonal conflicts and managing cravings were covered. The role of OTP in preventing relapse in alcohol-dependent individuals has been previously demonstrated [7]. In addition to its direct effects on drug-related behaviour, our clinical observations suggest that any type of psychosocial programmes, such as OTP, possess secondary functions within treatment, because they allow closer and more frequent contact with treatment providers and the therapeutic environment.

 

             Having drug-related legal problems at the time of assessment emerged as a strong predictor of positive treatment outcomes. According to the Turkish legal system, both substance use and possession are penalized either with mandatory substance dependence treatment or by jail, depending on the verdict. In the case of mandatory treatment, the individual must remain substance-free for 12-months after the termination of treatment, if that status was validated by regular urine tests. This incentive to remain opioidfree in order to avoid further legal problems might explain the higher remission rates observed in the group that had legal issues. It should be added that there is some evidence to the contrary, stating that having a legal responsibility to undergo treatment might lower its effectiveness [24]. However, our finding that being involved in legal problems had a positive effect on treatment effectiveness in the particular population assessed in the present study might be due to the lack of availability of treatment. In other words, some individuals who might not otherwise obtain treatment due to the inadequacy of the treatment system might get the chance to do so when mandated by a law court.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

             Higher incomes significantly predicted better treatment outcomes. This finding underlined the importance of the financial situation of the patient. In Turkey, buprenorphine-naloxone maintenance therapy is relatively expensive when the average socioeconomic status of opioid dependent individuals is taken into consideration [21]. This is because public insurance covers all medical examinations and urine and/ or blood analyses, but only about 80% of the cost of the medication. Moreover, the low number of treatment centres, and their distribution concentrated in larger cities, poses significant problems in treatment availability. Taken together, the high cost and low availability might make seeking and continuing treatment even more difficult for patients who have a low or rather low socioeconomic status.

 

             Having a family member who had experienced problems with substance abuse/dependence was a significant predictor of poorer treatment outcome. This finding is consistent with earlier studies supporting the importance of addressing the environmental and social factors of individuals as part of OD treatment [14, 17]. Considering the absence of networking therapies that specifically target families in Turkey, the importance of family networking programmes emerges.

 

             One striking finding is that the individuals who had a record of polydrug abuse benefited most from the treatment. Although it seems to be a rare condition, there are data on this subject [20]. Ours is is a high-threshold maintenance programme; its aim is both to reduce extra-opiate substance abuse and to change addictive behaviours. According to this programme, ‘polydrug use’ is considered as a high-risk category, and such patients are requested to attend control visits at more frequent intervals; in cases where patients fail to control extra-opiate substance abuse, the programme is discontinued. This finding shows that extra-opiate substance abuse is reduced among polydrug users in the programme. Greater contact in the clinic due to the risk category can be considered as a factor that enhances remission.

 

             There were no significant differences in the daily dose of buprenorphine-naloxone between the remission and the non-remission group. Previous studies have, however, shown buprenorphine-naloxone doses to be correlated positively with better treatment outcomes [8]. That finding of a lack of effect might be attributable to the relatively small sample size. Although daily doses in our sample varied between 2 mg and 24 mg, the low standard deviation (SD = 2.74) points to the aggregation of the doses at the mean, 13 mg. Thus, before reaching a conclusion on the relationship between daily buprenorphinenaloxone dose and treatment outcomes, studies with better sample distribution regarding daily doses have to be conducted.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

             

             Having had OD treatment in the past predicted better treatment retention. Some of the participants had had previous experience in comprehensive OD treatment programmes with psychosocial support components. Since factors such as time spent in psychotherapy have been shown to exert positive effects on therapeutic outcome, it can be hypothesized that these patients' previous experience had a positive effect on their treatment analysed in the present study [18].

 

             Being employed and having a history of immigration both emerged as predictors of a better treatment outcome. The effects of employment status on treatment retention have been demonstrated in the literature, and being employed has been shown to be correlated with higher psychosocial functioning and better social integration [17, 23]. Considering that the majority of immigrant individuals in this study were Turkish citizens returning from certain European countries (such as Germany, Austria, and the Netherlands), the reason that immigrants were more likely to be in remission might be due to their higher level of information on, or experiences with, opiate substitution programmes.

 

             

 

 

 

 

 

 

 

 

 

 

 

 

 

             The strength of the present study is the 1-year follow-up for patients who had been receiving treatment under a standard protocol. Buprenorphinenaloxone is the first and the only opiate substitution therapy in Turkey. The present study is the first one to be carried out in Turkey on the efficacy of opiate maintenance therapy. Since it aimed to determine the efficacy of a buprenorphine-naloxone programme and the factors that predict remission, it can be used a guide for future therapeutic models.

 

             The outcome data were collected at the end of treatment and at a 12-month follow-up interview. Follow-up studies are invaluable in implementing substance dependence research, due to the risk of relapses and the importance of determining timing in estimating when individuals are most likely to experience them. In addition, determining the predictors for positive treatment outcomes in a Turkish sample is crucial, as buprenorphine-naloxone therapy is relatively young in Turkey and there might be culturally specific factors that influence outcomes.

 

             One limitation of the current study was its small sample size. A total of 30 of the 76 participants dropped out of treatment; 7 reported having relapsed, but there is no information available on the reasons why the remaining 24 participants dropped out. The small sample size also indirectly resulted in a skewed distribution of the average daily dose of buprenorphine. Thus, a relationship between dose and treatment effectiveness could not be observed. Future studies controlled to ensure an even daily dose distribution now need to be carried out to further assess the relationship between daily buprenorphine dose and treatment outcomes.

 

             All these findings demonstrate that buprenorphine-naloxone maintenance therapy is an effective treatment option in OD in Turkey. The success of this treatment is not determined by the medication alone. Findings underline the importance of therapy programmes, family networking therapies, collaboration with the legal system, and population-based implementations, especially those that target the socioeconomic characteristics of patients. They also indicate the necessity of implementing buprenorphinenaloxone maintenance therapy together with other therapeutic approaches, particularly in such countries as Turkey, in which drug dependency treatments are neither widespread nor sufficiently structured.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

REFERENCES

1. A.P.A. (2000): Desk Reference to the Diagnostic Criteria from DSM-IV-TR. American Psychiatric Association, Washington, DC.

2. Amato L., Minozzi S., Davoli M., Vecchi S. (2011): Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Cochrane Database Syst Rev. 9: CD005031.

3. Auriacombe M., Franques P., Tignol J. (2001): Deaths attributable to methadone vs buprenorphine in France [research letter]. JAMA. 285(1).

4. Corapcioglu A., Ogel K. (2004): Factors associated with Ecstasy use in Turkish students. Addiction. 99(1): 67-76.

5. Emcdda (2011): Annual Report: The state of the drugs problem in Europe EMCCDA, Lisbon.

6. Evren C., Can Y., Mutlu E., Karabulut V., Demirci A. Ç., Umut G., Çetin T. (2012): Suboxone (buprenorfinnalokson) uygulama kılavuzu. BRSHH Kitaplığı., İstanbul.

7. Evren C., Durkaya M., Dalbudak E., Çelik S., Çetin R., Çakmak D. (2010): Factors related with relapse in male alcohol dependents: 12 months. J Psychiatry and Neurol Sci. 23: 92-99.

8. Fareed A., Vayalapalli S., Casarella J., Drexler K. (2012): Effect of buprenorphine dose on treatment outcome. J Addict Dis. 31(1): 8-18.

9. Johnson R. D. (1995): Opioid involvement in feeding behaviour and the pathogenesis of certain eating disorders. Med Hypotheses. 45(5): 491-497.

10. Kosten T. R., Schottenfeld R., Ziedonis D., Falcioni J. (1993): Buprenorphine versus Methadone Maintenance for Opioid Dependence. J Nerv Ment Dis. 181(6): 358364. 11. Leshner A. I. (1998): Drug addiction research: moving toward the 21st century. Drug Alcohol Depend. 51(1-2): 5-7.

12. Ling W., Wesson D. R., Charuvastra C., Klett C. J. (1996): A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence. Arch Gen Psychiatry. 53(5): 401-407.

13. Mattick R. P., Breen C., Kimber J., Davoli M. (2003): Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev(2): CD002209.

14. Mclellan A. T., Alterman A. I., Metzger D. S., Grissom G. R., Woody G. E., Luborsky L., O’brien C. P. (1994): Similarity of outcome predictors across opiate, cocaine, and alcohol treatments: role of treatment services. J Consult Clin Psychol. 62(6): 1141-1158.

15. Ögel K., Ertekin G., Tamar D., Çakmak D. (1999): ATP Alkol Bağımlılığı Tedavi Programı. AMATEM, Istanbul.

16. Ögel K., Tamar D., Evren C. (2001): Prevalence of drug use among high school students in 15 cities Turk J Psychiatry. 12(1): 47-52.

17. Rounsaville B. J., Tierney T., Crits-Christoph K., Weissman M. M., Kleber H. D. (1982): Predictors of outcome in treatment of opiate addicts: evidence for the multidimensional nature of addicts’ problems. Compr Psychiatry. 23(5): 462-478.

18. Schwartz R. P., Kelly S. M., O’grady K. E., Mitchell S. G., Brown B. S. (2011): Antecedents and correlates of methadone treatment entry: a comparison of outof-treatment and in-treatment cohorts. Drug Alcohol Depend. 115(1-2): 23-29.

19. Soeffing J. M., Martin L. D., Fingerhood M. I., Jasinski D. R., Rastegar D. A. (2009): Buprenorphine maintenance treatment in a primary care setting: outcomes at 1 year. J Subst Abuse Treat. 37(4): 426-430.

20. Soyka M., Apelt S. M., Lieb M., Wittchen H. U. (2006): One-year mortality rates of patients receiving methadone and buprenorphine maintenance therapy: a nationally representative cohort study in 2694 patients. J Clin Psychopharmacol. 26(6): 657-660.

21. Tubim (2011): Turkish drug report: New developments, trends and in-depth information on selected issues. TUBIM, Ankara.

22. Unodc (2013): World Drug Report. UNODC, New York, NY.

23. West S. L., O’neal K. K., Graham C. W. (2000): A metaanalysis comparing the effectiveness of buprenorphine and methadone. J Subst Abuse. 12(4): 405-414.

24. Ziedonis D. M., Amass L., Steinberg M., Woody G., Krejci J., Annon J. J., Cohen A. J., Waite-O’brien N., Stine S. M., Mccarty D., Reid M. S., Brown L. S., Jr., Maslansky R., Winhusen T., Babcock D., Brigham G., Muir J., Orr D., Buchan B. J., Horton T., Ling W. (2009): Predictors of outcome for short-term medically supervised opioid withdrawal during a randomized, multicenter trial of buprenorphine-naloxone and clonidine in the NIDA clinical trials network drug and alcohol dependence. Drug Alcohol Depend. 99(1-3): 28-36.

 

Acknowledges

We would like to thank Mr Cüneyt Evren for support and advice.

 

Role of the funding source

Authors states that this study was financed with internal funds. No sponsor played a role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

 

Contributors

Elif Mutlu made the study design, the data collection, the statistical analysis, and prepared the draft Rabia Bilici made the statistical analysis. Authors revised and approved the final form of the manuscript.

 

Conflict of interest

Authors declared no conflict of interest.