Predictive variables of prescription opioid misuse in patients with chronic noncancer pain. Development of a risk detection scale: A registered report protocol.

BACKGROUND: Opioid therapy is utilized for a broad range of chronic pain conditions. Several studies have highlighted the adverse effects of opioid medication due to the misuse of these drugs. The gradual increase in the use of opioids has become a global phenomenon and is generating social concern. Several treatment guidelines have strongly recommended assessing the risks and benefits of pharmacological treatment with opioids. These guidelines also recommend the psychological assessment of patients with chronic noncancer pain in order to make informed decisions on the advisability of intervention with opioids. Some authors have emphasized the relevance of assessing the risk of opioid misuse in patients with noncancer chronic pain before initiating treatment. METHODS AND ANALYSIS: Two studies will be conducted, each with a different primary objective. The primary objective of the first study (Study 1) will be to conduct a comprehensive investigation to identify the factors most closely associated with subsequent opioid misuse; and based on the results of Study 1, the primary objective of the second study (Study 2) will be to develop a brief, reliable, valid, and useful instrument that would enable health care providers to make decisions on opioid prescription and on the required level of monitoring and follow-up. These decisions would have positive consequences for patient wellbeing. Study 1 will include a logistic regression analysis to test the hypothetical model. Study 2 will have a longitudinal design and include three assessment sessions in order to develop a measure to assess the risk of prescribed opioid misuse and to analyse its reliability and validity. Participants will be individuals with chronic noncancer pain attending three Pain Units. These individuals will either be undergoing pharmacological treatment that includes opioid analgesics (Study 1, N = 400) or are going to commence such treatment (Study 2, N = 250).

Introduction

Current empirical evidence shows that chronic pain is a major health issue and one of the most common reasons for patients to seek medical help [1-3]. Chronic pain is pain that lasts or recurs for longer than 3 months [3]. Given the complex nature of chronic pain, its appropriate treatment often requires individualized assessments by multidisciplinary teams capable of addressing the physical and psychological aspects of pain [4, 5]. It also requires pharmacological treatment, which is a common component of chronic pain management regimens [6, 7]. Such treatment often includes the use of nonopioid and opioid analgesics, as well as adjuvant medications used to prevent or treat the adverse effects of analgesics or enhance the effect of opioid analgesics. Opioid therapy is now utilized for a broad range of chronic pain conditions [8]. Several studies have highlighted the adverse effects of opioid medication due to the misuse of these drugs [9-13], which has been defined as the use of opioids in a manner other than how they are prescribed [14]. Prescription opioid misuse may involve a wide range of behaviours, including overuse [14]. In our project, misuse is defined as the overuse of prescribed opioids (i.e., taking more opioids than prescribed). In Spain, there is growing concern about the use and misuse of opioid analgesics [15, 16]. In 2019, the Spanish Ministry of Health Care published a report on medication use. The report analysed opioid consumption based on prescribing data obtained by the Spanish National Health System from private and public health care sources, including hospitals. The results showed an increase in opioid consumption in Spain from 10.02 daily doses/1000 inhabitants/d in 2010 to 18.73 daily doses/1000 inhabitants/d in 2018. This gradual increase in the use of opioids has become a global phenomenon and is generating social concern. Ray et al., [17] found that the increased use of opioids for long-term treatment increases the risk of death due to both unintentional overdose and cardiorespiratory problems. Apart from their conventional use, an even more worrisome issue is prescription opioid misuse. Therefore, prior risk assessment has emerged as a crucial step in making informed decisions on the risks of starting treatment with opioid drugs.

Several factors have been identified as being associated with the increased risk of addictive substance misuse. One of the most widely studied risk factors is a previous history of addiction [12, 18–20]. However, this risk factor alone is unable to completely account for this phenomenon. Other studies have addressed predictors of misuse in relation to age [21, 22], smoking [23], obesity [9], psychological disorders such as depression, anxiety, and Posttraumatic Stress Disorder [24, 25], or a history of childhood abuse [18].

Regarding the misuse of prescribed medications, several studies have shown the predictive value of patients’ concerns about medication [26-28]. Higher levels of catastrophizing and the nonacceptance of pain make patients more vulnerable to prescription opioid misuse [29-31]. Empirical research has indicated that anxiety sensitivity is associated with catastrophizing in pain patients [32, 33] and that anxiety sensitivity is a risk factor for substance misuse [34-36]. There is also extensive empirical evidence in support of an association between impulsivity and addiction [37, 38]. Several studies have found a link between impulsivity and opioid misuse [39, 40]. Finally, several studies have analysed sex differences in the use and misuse of opioids [41, 42] and in the correlates of risk for opioid misuse among chronic pain patients prescribed opioids for chronic pain [43, 44].

Some authors have emphasized the relevance of assessing the risk of opioid misuse in patients with noncancer chronic pain before initiating treatment [9, 45]. In fact, several treatment guidelines have strongly recommended assessing the risks and benefits of pharmacological treatment with opioids [9]. These guidelines also recommend the psychological assessment of patients with chronic noncancer pain in order to make informed decisions on the advisability of intervention with opioids [9, 18, 46]. Current instruments used to assess such risk do not include many of the variables that previous research has found to be associated with opioid misuse and have also been shown to have very limited predictive capacity [10, 47]. In general, there is relatively limited evidence on the accuracy of these tools in predicting misuse [48]. The limitations of these current measures are among the main reasons that Kaye et al., [12] published a review of this area in 2017. They suggested that, at the time of writing, there was still no risk assessment procedure or any empirically determined set of predictive variables that were adequate for identifying patients with chronic noncancer pain at risk of opioid misuse.

In addition, Chou et al., [9] suggested that clinicians should take some basic steps to prevent opioid misuse before starting patients on opioid therapy and addressed the importance of having available a reliable method by which to determine whether patients could take opioids in a responsible and reliable manner. This fundamental issue can only be addressed by the prior identification of subject variables that could predict the risk of misuse.

In summary, there remains an urgent need for comprehensive scientific research using high-quality methodology to identify a set of variables that could reliably predict opioid misuse in chronic pain patients. The results could then be used to guide the development of a practical measure that could be administered to patients by health care providers before making therapeutic decisions.

Study overview

This project will be led by a research group from the Faculty of Psychology at the University of Málaga (Spain), supported by grants from the Spanish Ministry of Science and Innovation (PID2019-106086RB-I00) and the Regional Government of Andalusia (HUM-566).

Two studies will be conducted, each with a different primary objective. The primary objective of the first study (Study 1) will be to evaluate a theoretical model of opioid drug misuse that includes the key variables that have been identified in previous research as predictors of adherence to appropriate opioid treatment use in patients with chronic noncancer pain who are receiving opioids. The primary objective of Study 2 will be to develop and evaluate the validity of a brief instrument that will include the aspects demonstrated to be most relevant in predicting the misuse of prescription opioids in Study 1.

Hypothesis

Table 1 shows the hypotheses of the present project.

Table 1

Hypotheses.

Study 1: Testing the hypothetical model	There is a significant positive association between prescription opioid misuse and H1 to H17:	H1. Family history of substance abuse
		H2. Personal history of substance abuse
		H3. Being aged between 16 and 45 years
		H4. History of preadolescent sexual abuse
		H5. Psychological disease (ADD, OCD, bipolar, schizophrenia)
		H6. History or current diagnostic of depression
		H7. A history of smoking and being a current smoker
		H8. Body mass index greater than 30
		H9. Symptoms of depression
		H10. Symptoms of anxiety
		H11. Symptoms of Post-Traumatic Stress Disorder (PTSD)
		Concerns about medication and medication use: (H12) perceiving medication as needed (H13) concern about negative scrutiny, and (H14) concerns about tolerance
		H15. Pain catastrophizing
		H16. Impulsivity
		H17. Anxiety sensitivity
	There is a significant negative association between prescription opioid misuse and H18:
		H18. Pain acceptance
	There are gender differences in the correlates of risk for opioid misuse (H19 and H20):	H19. Opioid misuse in women will be more strongly associated with emotional issues and affective distress, with opioid medications being used to help stabilize their mood and relax. Therefore, symptoms of anxiety, depression, or PTSD are expected to have higher correlations with opioid misuse in women than in men.
		H20. Men may be more strongly affected by environmental factors involved with associating with others who are prone to using illicit substances. Thus, a history of or current addiction to opioids, alcohol, or other prescription or nonprescription drugs in family or friends are all expected to have higher correlations with prescribed opioid misuse in men than in women.
Study 2: Development of a measure to assess the risk of prescribed opioid misuse, and the analyses of its reliability, validity, sensitivity, specificity and accuracy.	The total score of the new scale will show (H21-H23):	H21. A moderate correlation with the Opioid Risk Tool (ORT-10; Webster and Webster, 2005) (construct validity). In the case that domains included in the ORT are also included in the new scale, the magnitude of the expected correlation will be higher.
		H22. Higher levels of sensitivity, specificity, and accuracy than the ORT.
		H23. High levels of accuracy (≥95% correct classification rate), sensitivity (≥95%), and specificity (≥95%) for classifying patients as being at risk of opioid misuse at 6 months and 12 months after the initial prescription of opioids for chronic pain management.

Methods

Participants

The participants will be individuals with chronic noncancer pain attending three Pain Units in the following centres: Hospital Clínico Universitario Virgen de la Victoria (Málaga), Hospital Regional Universitario (Málaga), and Hospital Costa del Sol (Marbella, Málaga). These individuals will either be undergoing pharmacological treatment that includes opioid analgesics (Study 1, N = 400) or are going to commence such treatment (Study 2, N = 250)

Inclusion criteria:

Chronic noncancer pain.

Being older than 18 years.

Ability to understand and sign the informed consent form.

Exclusion criteria:

Incapable of understanding the instructions.

Current (or history of) psychotic symptoms.

Lack of fluency in spoken and written Spanish.

Number of participants

Study 1. Testing the hypothetical model. According to Freeman [49], in logistic regression analysis, the sample size must be [n = 10 * (k + 1)] (where k = number of variables). This study will require at least 190 participants [10 * (18+1) = 190]. However, the total number of participants will be 200. Furthermore, to cross-validate the model in a new sample, a further 200 patients will be needed. Therefore, Study 1 will include a total of 400 patients.

Study 2: Development of a measure to assess the risk of prescribed opioid misuse and the analysis of its reliability and validity. The aforementioned formula [49] will be used to test the predictive model: however, the number of variables will depend on the results of Study 1. In any case, we will increase the resulting number of participants by 30% in order to safeguard against any dropout at the various assessment stages during the longitudinal study. The aforementioned criteria will be applied [50-52] to test the psychometric properties of the instrument and to determine sample size. However, research has shown that a minimum subject-to-variable ratio of 5-to-1 in linear regression analysis can produce stable and reasonably accurate estimates of the regression coefficients [53]. In summary, in the absence of knowing the number of domains that will be included in the new scale, it seems reasonable to plan for recruiting a sample of 250 patients to take part in the three assessment sessions.

Procedure

Study 1: Testing the hypothetical model

Phase 1. Identify the variables that predict opioid misuse. At the end of their visit to their pain specialist, the patients who fulfil the eligibility criteria will be informed of the study aims and their participation will be requested. Written informed consent will be obtained prior to data collection. Each participant will take part in a semi-structured interview with a psychologist from the research team to obtain demographic, social, or medical history data. A battery of questionnaires will also be completed by each participant in the assessment session. These questionnaires will measure the variables that we expect to be related to opioid misuse and the current misuse of prescription opioids. In order to recruit the necessary number of participants, 140 patients with chronic noncancer pain receiving pharmacological treatment that includes opioid analgesics will be interviewed in each Pain Unit. The patients will always be assessed in their usual health centre.

Phase 2. Cross-validation. Based on the results of the regression analysis conducted in Study 1, the variables that predict opioid misuse in a sample of 200 patients will be identified. The model will then be cross-validated with a different sample of 200 patients with the same characteristics.

Study 2: Development of a measure to assess the risk of prescribed opioid misuse and the analysis of its reliability and validity

Study 2 will include 3 phases: development of the initial item pool (Phase 1) and a prospective analysis with three measurement stages (Phases 1, 2 and 3).

Phase 1. Development of the initial item pool. Once the variables that predict opioid misuse have been identified, we will develop a scale to assess these domains Firstly, the research team will choose an initial pool of 6 items per domain and a panel of experts in methodology will rate the items in relation to the appropriateness of their formulation, with changes being made following their suggestions. Secondly, a brief and precise definition of each construct will be developed. Thirdly, an expert panel will be carefully chosen to ensure their knowledge of the content domain. The experts will be asked to rate the representativeness and relevance of each item in relation to the definition of the constructs. Inter-rater agreement will be calculated, discrepancies will be discussed, and the process will be repeated until acceptable levels of agreement are achieved (.70 to .80) [54, 55]. The three items most representative of each domain will be chosen to be part of the initial instrument. A pilot study with a group of at least 10 patients will be conducted to test the readability and comprehensibility of the items and changes will be made if necessary.

At the end of their visit to their pain specialist, the patients who fulfil the eligibility criteria (i.e., those who are going to begin treatment with opioid analgesics) will be informed of the study aims and their participation will be requested. Written informed consent will be obtained prior to data collection. Each participant will take part in a semi-structured interview with a psychologist from the research team to obtain demographic, social, or medical history data. The first 10 patients will be asked to participate in the pilot study of the instrument.

Subsequent patients (a total of 250) will then complete the revised scale (EDRAO) and the Opioid Risk Tool (ORT-10) in the first assessment session. Patients will be informed of the longitudinal design of the study.

Phases 2 and 3. Prospective analysis. Second and third assessment sessions. After the initial session, the patients will be contacted twice at 6-month intervals (for each of two check-up visits to the pain specialist) to make an appointment for further evaluation.

In the second assessment session (6 months after the initial visit) and the third (12 months after the initial visit), patients will again complete the EDRAO for test-retest purposes and the COMM to measure current misuse of opioids. In addition, patients will be monitored for indexes of misuse. A pain specialist (i.e., member of the working team) will provide us with information about indexes 1–2 and the psychologist will ask patients about indexes 3–11 in a semi-structured interview (see list of misuse indexes below, in Variables and Instruments). Table 2 shows the procedure.

Table 2

Procedure.

Study: Objective	Phases: Objective	Sample	Variables
Study 1: Testing the hypothetical model (N = 400)	Phase 1: Identify the variables that predict opioid misuse	Individuals who undergo pharmacological treatment that includes opioid analgesics (N = 200)	• Demographic, social, and medical history data
			• Pain intensity
			• Family and personal history of substance abuse
			• History of preadolescent sexual abuse
			• Specific psychological disorders (attention deficit disorder, obsessive-compulsive disorder, bipolar disorder, schizophrenia or depression)
			• Anxiety and depression symptoms
			• Post-Traumatic Stress Disorder
			• Concerns about medication and medication use
			• Pain catastrophizing
			• Impulsiveness
			• Anxiety sensitivity
			• Pain acceptance
			• Index of opioid misuse
	Phase 2: Cross-validation of model	The same as phase 1 (N = 200)	Based on the results of the regression analysis conducted in phase 1, the variables that predict opioid misuse
Study 2. Development of a new measure to assess the risk of prescribed opioid misuse and the analyses of its reliability and validity (N = 250)	Phase 1: Development of the initial item pool	An expert panel	Selection of three items most representative of each domain will be chosen to be part of the initial instrument
		Pilot group to test the readability and comprehensibility of the items (N = 10)	• The new instrument (EDRAO)
		Patients who are going to start pharmacological treatment that includes opioids (N = 250)	• EDRAO
			• A standardized instrument to measure the risk of opioid misuse (ORT-10)
	Phase 2: Prospective analysis (2nd assessment)	The sample in phase 2, 6 months later (N = 250)	Indexes of misuse
			Indexes of misuse (COMM)
	Phase 3: Prospective analysis (3rd assessment)	The sample in phase 3, 6 months later (N = 250)	Indexes of misuse
			Indexes of misuse (COMM)

Predictors of opioid misuse. Each participant will take part in a semi-structured interview with a psychologist to measure the following variables:

Demographic, social, and medical history data. We will record the medication that patients are currently taking and the medication prescribed by the specialist (including doses) in their first visit in Pain Unit.

Pain intensity. Patients will be asked to rate their mildest, average, and worst pain during the past 2 weeks, as well as their current pain, on a scale ranging from 0 to 10, with a “0” indicating “no pain” and “10” indicating pain as “intense as you could imagine”. A composite pain intensity score will be calculated for each subject by calculating the average of the mildest, average, worst, and current pain. Composites of 0-to-10 ratings are highly reliable measures of pain intensity in chronic pain patients [56].

Variables and instruments

In order to measure the variables included in Hypothesis H1-H6, the Spanish version of the -10). [22] will be used. The Spanish version is currently being validated as part of a PhD dissertation by our research team. The ORT-10 is a 10-item scale that assesses five domains or risk factors for prescription opioid misuse derived from clinical experience and a literature review conducted by the developers of the measuring instrument. The domains include a family and personal history of substance abuse, age, a history of preadolescent sexual abuse, and specific psychological disorders (i.e., having a diagnosis of attention deficit disorder, obsessive-compulsive disorder, bipolar disorder, schizophrenia, or depression). Each risk factor is weighted and attributed a point value believed to reflect its risk relative to the other risk factors. Items are scored and the total score can range from 0 to 26. A score of 3 or less indicates a low risk of future opioid misuse, a score of 4 to 7 indicates a moderate risk of opioid misuse, and a score of 8 or higher indicates a high risk of opioid misuse.

All the other predictor variables will be measured (also during the interview) with the following instruments:

Symptoms of Depression and/or Anxiety. Hospital Anxiety and Depression Scale (HADS) [57]. This is a self-report scale that contains two 7-item scales, one for anxiety and one for depression, each of which are scored on a 4-point scale. A score from 8 to 10 indicates possible cases and a score of 10 or more indicates probable cases. The Spanish version of the scale shows appropriate reliability and validity [58].

The presence of symptoms of Post-Traumatic Stress Disorder (PTSD). The Spanish version of the Posttraumatic Stress Disorder Checklist-Civilian Version (PCL-5) [59] will be used to assess PTSD as described in DSM-5. This instrument comprises a 20-item self-report checklist which is rated on a 5-point Likert-scale (ranging from 1 = never to 5 = very often) to indicate the degree to which each particular symptom had been experienced by the participant over the past month.

Concerns about medication and medication use. Participants’ concerns about pain medication will be measured using the short form of the Pain Medication Attitude Questionnaire- 14 (PMAQ-14) [26]. The Spanish version of this scale is currently being adapted by our research group as part of a PhD dissertation. It comprises 14 items grouped into 7 domains (addiction, need, scrutiny, side effects, tolerance, mistrust, and withdrawal). Each item is scored on a 6-point Likert-scale ranging from 0 (“never true”) to 5 (“always true”). The scale shows good reliability and validity [26].

Pain catastrophizing. Pain Catastrophizing Scale (PCS). This scale is a 13-item measure in which respondents indicate on a 5-point scale the degree to which they experience various thoughts and feelings while in pain [60]. It consists of three subscales assessing rumination, magnification, and helplessness and also provides a total score on catastrophizing. The total score alone will be used in this study. The Spanish version of the scale shows good reliability and validity and its internal consistency is high [61].

Impulsiveness. The Spanish version of the Barratt Impulsiveness Scale for adults (BIS-11) [62-64] will be used to measure impulsiveness. It is composed of 30 items that are answered on a 4-point scale (from 1 = rarely or never to 4 = always) where 4 indicates the most impulsive response. The higher total score, the higher level of impulsiveness. The Spanish Version of the scale shows good reliability and validity [64].

Anxiety sensitivity. Anxiety Sensitivity Index-3 (ASI-3). This instrument is an 18-item questionnaire where respondents indicate the degree to which they fear the negative consequences of anxiety symptoms on a 5-point Likert-type scale [65]. The results of validation studies provide cross-cultural evidence for construct validity and the concurrent validity of the Spanish ASI-3 [66].

Pain acceptance. Chronic Pain Acceptance Questionnaire (CPAQ). We will apply the Spanish version of the questionnaire (CPAQ-SV) [67, 68]. This instrument consists of 20 items. Similar to the original questionnaire, the CPAQ-SV yields a total score and two subscale scores for Pain Willingness and Activity Engagement. The subscales of the CPAQ-SV show good internal consistency [68]. Two studies on the CPAQ-SV [68, 69] have supported the validity of a 20-item version with two subscales corresponding to two independent factors. In addition, the CPAQ-SV demonstrates good criterion validity.

Indexes of opioid misuse. Current misuse of prescribed opioids. The Spanish translation of the Current Opioid Misuse Measure (COMM) [70] will be used. The Spanish version of this scale is currently being adapted by our research group as part of a PhD dissertation. It is a brief self-assessment instrument to monitor chronic pain patients on opioid therapy. The COMM contains 17 items rated from 0 = "never" to 4 = "very often" (see Table 1). The COMM was developed to track patient status over time, and so the items included in the COMM can be used repeatedly and provide an estimate of the patients’ “current” status. Thus, the items cover a 30-day period (i.e., “In the past 30 days…”) and only behaviour that could change from time to time are included (i.e., historical items are excluded). The 17 items are summed to create a total score. A total score of 9 or more is considered a positive indication of opioid misuse. Meltzer et al., [71] found higher COMM scores in patients with chronic pain who had a prescription drug use disorder than in those who did not have the disorder, thus supporting the construct validity of the instrument.

We will measure opioid misuse from two perspectives; self-reports via structured interviews and physician reports. Thus, the following behaviours are some indexes of misuse that will be measured:

Requesting more opioid medication before the next appointment with the physician

Going to primary care or emergency services in order to obtain more opioid medication before the next appointment

Requesting more opioids than prescribed by the doctor in the pharmacy

Requesting more opioids via a third person or by Internet

Admitting to seeking euphoria from opioids

Admitting to wanting opioids for anxiety

Requesting opioids from other providers

Unauthorized dose escalation

Reporting lost or stolen prescriptions

Requesting refills instead of a visit to the clinic

Behaviours 1 to 2 will be identified through the patients’ DIRAYA cards, which are their electronic health records (Historia Digital de Salud del Ciudadano) held in the Andalusian Public Health System. They can be readily accessed by the pain physicians (i.e., the four components of the working team). Behaviours 3 to 10 could be detected through interviews with the patients. Patients with more than 2 indexes of misuse will be considered positive for prescribed opioid misuse. Therefore, a total score of 9 or higher on COMM and/or more than 2 indexes of misuse will be considered positive for prescribed opioid misuse. This will be a cheap, easy, and objective method to evaluate the patients’ misuse of prescribed opioid medicines. It is worth mentioning that this study excludes urine toxicology screens as an appropriate measure of misuse. Since the sample will be composed of patients undergoing an opioid treatment regimen, the presence of these substances would be expected. This screen tests for the presence of an additional non-prescribed drug in urine [12], which is not our aim. In any case, urine and blood opioid tests are not currently used in the Andalusian Public Health System. In fact, Fentanyl misuse is currently detected through the DIRAYA card in three of the participant pain units. Moreover, urine or blood analysis would be of little value for detecting quick-release transdermal Fentanyl treatment, and therefore such tests would not be appropriate given the aims of this project.

Study 2: Develop a measure to assess the risk of prescribed opioid misuse and examine its reliability and validity

The new scale (EDRAO) will be applied. In order to test its validity, the Opioid Risk Tool (ORT-10 [22]; see above) and all of the indexes of misuse measured in Study 1 (explained above) will be used at the two assessment points of Study 2.

Statistical analyses

Data analyses will be conducted using the Statistical Package for the Social Sciences version 26.0 (SPSS; Chicago, IL, USA).

Firstly, socio-demographic data will be expressed as frequencies and percentages and continuous data will be expressed as means and standard deviations. Since opioid misuse is a dichotomous variable, logistic regression analysis will be used to identify significant associations between the set of variables included in the hypothetical model and opioid misuse. The patients’ time in pharmacological treatment with opioids, pain intensity, intake of benzodiazepines, type of chronic pain, and sex will be included as covariates in the regression analyses. The following steps will be taken to fit a parsimonious model with strong predictive covariates only. The potential risk factors that have been identified in the literature will be evaluated for potential univariate associations with opioid misuse. The independent-sample t-test will be used to analyse continuous variables and χ2 or Fisher’s exact tests will be used to analyse categorical or discrete variables. Multivariable conditional logistic regression will be used to identify the combined effect of several risk factors. Those with a univariate p value ≤.10 will be considered for inclusion in the model. Using a forward stepwise procedure, the variables that achieved a p value ≤.05 will remain in the final model. The results will be expressed as odds ratios (ORs) with 95% confidence intervals (CIs) and p values. A two-tailed P value of < .05 will be used as a cutoff for statistical significance.

Study 2: Developing a measure to assess the risk of prescribed opioid misuse and to examine its reliability and validity

As mentioned, an instrument will be developed to measure the constructs that, according to the results of Study 1, were significantly associated with opioid misuse. Since our aim is to develop a brief instrument, 3 items per construct will be selected by experts to assess each variable.

Item analyses

Firstly, in order to construct the shortest instrument possible, reduce the number of items, and retain only those with the highest discriminative power, t-tests will be run to determine which of the selected items identified patient status at the follow-ups (opioid misuse vs opioid non-misuse). Effect sizes (Cohen’s D) will be calculated and an effect size of 0.40 will be used as a cutoff to select items.

Sensitivity, specificity, and accuracy

Secondly, we will test the sensitivity, specificity, and accuracy of the final set of items. Receiver operating characteristic (ROC) curve analysis will be used to test the predictive validity of the final items of the EDRAO at follow-ups 1 and 2 as well as to determine the cut-off scores of the newly developed instrument. To determine the extent to which the values are influenced by outliers, the sample will be repeatedly randomly divided in half and the ROC curve will be calculated for each half separately.

Scale analyses

The stability of the instrument will be tested in a subsample of the participants and factor analysis will be used to study its dimensionality. In order to test the construct validity of EDRAO, we will analyse correlations between the scale and ORT-10.

National and local approvals

The project will be conducted in accordance with the Declaration of Helsinki and has received ethical clearance by the Institutional Ethics Review Board (ERC UMA) and the Regional Hospital Ethics Committee. This study is supported by grants from the Spanish Ministry of Science and Innovation (PID2019-106086RB-I00) and the Regional Government of Andalusia (HUM-566, P07-SEJ-3067).

Discussion

Several studies have highlighted the adverse effects of opioid medication due to their misuse [9, 11, 12, 22, 23]. In this regard, the increased use of opioids for long-term treatment increases the risk of death due to both unintentional overdose and cardiorespiratory problems. Therefore, prior risk assessment has emerged as a crucial step in making informed decisions on the risks of starting treatment with opioid drugs. Several treatment guidelines have strongly recommended assessing the risks and benefits of pharmacological treatment with opioids [9]. They have also recommended the psychological assessment of patients with chronic noncancer pain in order to make informed decisions on the advisability of interventions with opioids [18, 46]. The most commonly used measures for predicting the potential for opioid misuse do not include many of the variables shown to be associated with opioid use in previous research and have been shown to have very limited predictive capacity. Furthermore, these measurement instruments have not been adapted to the Spanish population and are therefore not being used in Spanish health centres. It is therefore essential to have a reliable method that can determine which patients could take opioids in a responsible and reliable manner. This fundamental issue can only be addressed by the prior identification of subject variables that could predict the risk of misuse. In summary, there remains an urgent need for comprehensive scientific research using high-quality methodology to identify a set of variables that would reliably predict opioid misuse in chronic pain patients. The results could then be used to develop a practical measure that could be administered to patients by health care providers before making therapeutic decisions. This project will fill this gap by providing a comprehensive model to identify the factors most closely associated with subsequent opioid misuse and a reliable, valid, and useful instrument that would enable health care providers to make decisions on opioid prescription and on the required level of monitoring and follow-up.

In addition, our group is currently adapting the Spanish versions of three valuable measurement instruments as part of a PhD dissertation, and we intend to make use of these in this project. Increasing the visibility of these instruments, alongside the development of a reliable and valid scale for assessing the risk of opioid misuse, will have a very positive impact on Pain Units and provide new tools to be used in clinical settings. The collaboration of three pain units and three pain specialist physicians will ensure the impact of the results in such health centres. Furthermore, the dissemination of our findings at the Andalusian Pain Society and Spanish Pain Society conferences will maximize the national impact of the project.

Finally, the results of the project will help to alleviate the serious consequences of the increasing use of opioid medications through the prior identification of subject variables that could predict the risk of prescription opioid misuse in patients with chronic noncancer pain. This will lead to very relevant changes in Pain Units by having a positive impact on the wellbeing of these patients.

This project fulfils the objectives of the Spanish Strategy of Science and Technology and Innovation (2017–2020) and, more specifically, those of Challenge 1 “Health, demographic change, and well-being”.

Conclusions

The results of this project will provide medical professionals with an instrument to detect the risk of opioid misuse in patients with chronic noncancer pain. The accurate and early detection and classification of patients who are at the greatest risk of opioid misuse will allow alternative medications to be considered. Should physicians decide that treatment with opioids is indicated, it will also help to determine the level of monitoring that will be needed based on the risk group to which the patient has been classified.

5 Mar 2021

PONE-D-21-02639

Predictive variables of prescription opioid misuse in patients with chronic non-oncologic pain. Development of a risk detection scale : A registered report protocol

PLOS ONE

Dear Dr. Ramírez-Maestre,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Apr 12 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Vijayaprakash Suppiah, PhD

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We recognize that, as this is a Registered Report Protocol, you do not yet have data available to share. However, as per PLOS' guidelines, we do expect authors to provide a Data Availability Statement and outline your data management plan and/or state how you expect their data to be made available (https://journals.plos.org/plosone/s/criteria-for-publication#loc-7). To this effect, please confirm that you will be able to make your data available when your study is completed and if it is accepted for publication.

3. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

4. Please ensure that you include a title page within your main document. You should list all authors and all affiliations as per our author instructions and clearly indicate the corresponding author.

5. Please include your tables as part of your main manuscript and remove the individual files. Please note that supplementary tables (should remain/ be uploaded) as separate "supporting information" files

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Reviewer #1: Yes

Reviewer #2: No

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Major comments

The authors are planning to conduct two studies, each with a different primary objective: (1) conducting a comprehensive study to identify the factors most closely associated with subsequent opioid misuse and, (2) developing a brief, reliable, valid, and useful instrument informed by this research that would enable healthcare providers to make decisions regarding opioid prescription and the needed level of monitoring and follow-up.

In study 1, A battery of questionnaires will also be completed by each participant in the assessment session. These questionnaires will measure the variables that we expect to be related to opioid misuse, and the current misuse of prescription opioids. And then, on the basis of the results of the regression analysis conducted in Study 1, those variables that predict opioid misuse in a sample of 200 patients will be identified. A cross validation of the model will then be conducted with a different sample of 200 patients with the same characteristics.

Subsequently, in study 2, to develop a measure to assess risk of prescribed opioid misuse, and to analyze its reliability and validity, a longitudinal design with three assessment sessions will be applied.

This referee think that this study protocol is well designed and the manuscript is well written, but there are several grammatical errors on the manuscript.

Reviewer #2: The authors have presented a nice presentation of two protocols that will be conducted in order to identify some predictors of opioid misuse and then to develop a scale to be used in clinical practice

The topic is surely important and highly debated and the protocols try to add some important informations to scientific debate

Unfortunately I think that there are some major concerns that should be addressed in order to improve the quality of the manuscript, of the protocols and in order to have a better reproducible dataset.

The first major concern that should be addressed is about the concept of "misuse" defined in the title. Opioids in chronic pain patients can lead not only to misuse but also to abuse. Please discuss better this two problems and define better how authors' protocols can help clinicians to identify the two different problems

The second major concern is about the definition of chronic pain. How do the authors define "chronic pain"?Please provide a definition : temporal definition or pathophysiological definition? It is strange that authors have considered several psychological and demographic factors to be correlated to misuse/abuse but they have not considered if different chronic pain syndromes could be related to different risk for misuse/abuse. Please discuss it and provide explanations (better if you can consider them)

The third concern is about the sample size explanation: the authors stated "the sample size must be: [n = 10 * (k + 1)] (being k= number of variables). In this study we will need at least 180 participants [10 * (16+1) = 160]." How do you decide that K is 16?Please discuss it more in detail

Finally minor concerns

You have stated that there will be limitations to the available data: please provide an explanation

It should be better to revise all the text with a native English speaker

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Young-Chang Arai

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

3 Apr 2021

Dear Dr. Vijayaprakash Suppiah,

We very much appreciate your new suggestions regarding our paper (PONE-D-21-02639

Predictive variables of prescription opioid misuse in patients with chronic noncancer pain. Development of a risk detection scale: A registered report protocol). We have revised the paper accordingly and hope the new version is now acceptable for publication.

This is a Registered Report Protocol and so we do not yet have data available to share (not even a minimal data set). However, I confirm that we will be able to make our data available when our study is completed and if it is accepted for publication.

In the following, we explain how the reviewers' suggestions have been taken into account in the new version. Changes in the text can be found in red.

Journal’s requirements:

Please ensure that you include a title page within your main document. You should list all authors and all affiliations as per our author instructions and clearly indicate the corresponding author

Answer. The title page has been included within our main document

Please include your tables as part of your main manuscript and remove the individual files. Please note that supplementary tables (should remain/ be uploaded) as separate "supporting information" files.

Answer. Following the Journal´s requirements, the tables have been included as part of our main manuscript.

Reviewer comments:

Reviewer #1 (R#1)

This referee think that this study protocol is well designed and the manuscript is well written, but there are several grammatical errors on the manuscript.

Thank you very much for your positive comments. A professional translator (native English speaker) has reviewed again the text.

Reviewer #2 (R#2)

1. The first major concern that should be addressed is about the concept of "misuse" defined in the title. Opioids in chronic pain patients can lead not only to misuse but also to abuse. Please discuss better this two problems and define better how authors' protocols can help clinicians to identify the two different problems

Answer. We agree with reviewer. In fact, we just wanted to assess the overuse of opioids prescribed. New text has been included in the introduction section (new text shown in red), explaining that the misuse of opioids "... has been defined as the use of opioids in a manner other than how they are prescribed (Martel, Edwards, & Jamison, 2020). Prescription opioid misuse may involve a wide range of behaviours, including overuse (Martel et al., 2020). In our project, misuse is defined as the overuse of prescribed opioids (i.e., taking more opioids than prescribed)” (lines 79-82)

New reference:

14- Martel MO, Edwards RR, Jamison RN. The relative contribution of pain and psychological factors to opioid misuse: A 6-month observational study. American Psychologist. 2020; 75(6): 772. https://psycnet.apa.org/doi/10.1037/amp0000632

2. The second major concern is about the definition of chronic pain. How do the authors define "chronic pain"? Please provide a definition : temporal definition or pathophysiological definition? It is strange that authors have considered several psychological and demographic factors to be correlated to misuse/abuse but they have not considered if different chronic pain syndromes could be related to different risk for misuse/abuse. Please discuss it and provide explanations (better if you can consider them)

Answer. Thank you for your comment. We have used a temporal definition, according to the proposal of Treede et al., (2019). Following R#2 suggestion, the following sentence has been included in the introduction section:

“Chronic pain is pain that lasts or recurs for longer than 3 months (Treede et al., 2019)”. (line 70-71)

We found your point about considering if different chronic pain syndromes could be related to different risk for misuse/abuse to be very interesting. However, including more variables in this project would increase the difficulty of recruiting the sample because of having to increase the required number of participants. It is relevant to bear in mind that this project has received funding for only 4 years, and this period might not be enough if the complexity of the study is increased.

In any case, according to R#2´s suggestion, the type of chronic pain (following the IASP new classification 2019) will be included in the analysis as covariables:

“The patients’ time in pharmacological treatment with opioids, pain intensity, intake of benzodiazepines, type of chronic pain, and sex will be included as covariates in the regression analyses”. (line 377)

3. The third concern is about the sample size explanation: the authors stated "the sample size must be: [n = 10 * (k + 1)] (being k= number of variables). In this study we will need at least 180 participants [10 * (16+1) = 160]." How do you decide that K is 16? Please discuss it more in detail

Answer: We absolutely agree with the reviewer. This is a mistake. Eighteen variables will be included in the regression model (Study 1) (see Table 2):

• Demographic, social, and medical history data:

o Sex, age, time in pharmacological treatment with opioids, intake of benzodiazepines, and type of chronic pain (5 co-variables).

• Pain intensity

• Family and personal history of substance abuse

• History of preadolescent sexual abuse

• Specific psychological disorders (attention deficit disorder, obsessive-compulsive disorder, bipolar disorder, schizophrenia or depression).

• Anxiety and depression symptoms (2 variables)

• Post-Traumatic Stress Disorder

• Concerns about medication and medication use

• Pain catastrophizing

• Impulsiveness

• Anxiety sensitivity

• Pain acceptance

• Index of opioid misuse

Therefore, that text has changed:

“According to Freeman (49), in logistic regression analysis, the sample size must be [n = 10 * (k + 1)] (where k = number of variables). This study will require at least 190 participants [10 * (18+1) = 190]."

4. You have stated that there will be limitations to the available data: please provide an explanation.

Answer: I apologise. What we wanted to say is that as a Registered Report Protocol, we do not yet have data available to share (not even a minimal data set).

5. It should be better to revise all the text with a native English speaker

Answer: Following R#2’s suggestion, a professional translator (native English speaker) has reviewed the text again.

Submitted filename: RESPONSE TO REVIEWERS_V3.docx

Click here for additional data file.

29 Apr 2021

Predictive variables of prescription opioid misuse in patients with chronic noncancer pain. Development of a risk detection scale : A registered report protocol

PONE-D-21-02639R1

Dear Dr. Ramírez-Maestre,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Vijayaprakash Suppiah, PhD

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: After this referee read this version and found out that the authors amended the manuscript well, the referee is satisfied with the content.

Reviewer #2: The authors have deeply revised the text accordingly reviewers' suggestions improving the quality of the data presented

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Young-Chang Arai

Reviewer #2: No

3 May 2021

PONE-D-21-02639R1

Predictive variables of prescription opioid misuse in patients with chronic noncancer pain. Development of a risk detection scale: A registered report protocol

Dear Dr. Ramírez-Maestre:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Vijayaprakash Suppiah

Academic Editor

PLOS ONE