Day-to-day Hedonic and Calming Effects of Opioids, Opioid Craving, and Opioid Misuse Among Patients With Chronic Pain Prescribed Long-term Opioid Therapy

Leah Frimerman; Maria Verner; Amanda Sirois; Katherine Scott; Alice Bruneau; Jordi Perez; Yoram Shir; Marc O. Martel

Disclosures

Pain. 2021;162(8):2214-2224. 

In This Article

Methods

Study Design and Participants

This was a longitudinal, observational, cohort study conducted among patients with chronic non-cancer pain prescribed long-term opioid therapy. Patients (n = 103) were recruited from primary care settings as well as from the McGill University Health Centre Alan Edwards Pain Management Unit, a tertiary care pain management setting. All participants underwent a telephone screening to ensure they met eligibility criteria. Patients included in the study met the following inclusion criteria: (1) aged 18 or older, (2) chronic (≥6 months) non-cancer pain, (3) currently prescribed a stable (≥3 month) dose of opioids, (4) taken orally, and (5) on a daily basis. Patients were excluded from participation if they met any of the following criteria: (1) use of rectal, intrathecal, intravenous, intramuscular, or subcutaneous routes of opioid administration and (2) cognitive impairment (eg, intellectual disability or dementia) preventing completion of study procedures.

Procedures and Measures

All study procedures were approved by the Research Ethics Board of the Research Institute of the McGill University Health Centre. Eligible patients were scheduled for a baseline assessment laboratory visit at the Montreal General Hospital.

Baseline Visit. On arrival, patients were asked to read and sign a consent form. They were then asked to complete a demographic questionnaire, which included information about age, sex, ethnicity, employment status, education, and marital status. Patients then reported all the medications they were currently taking. Opioid types and doses were recorded through inspection of patients' prescription documentation (ie, pharmacy printout) or medication container. Patients were then asked to complete the following questionnaires:

Brief Pain Inventory: The Brief Pain Inventory (BPI[77]) was used to assess the number and location of patients' pain sites.

Drug Abuse Screening Test: The Drug Abuse Screening Test (DAST[70]) was used to assess past-year substance use problems involving illicit drugs. The DAST is a well-accepted 10-item screening tool that has been used in chronic pain populations.[62,65,71]

Prescription Drug use Questionnaire: The Prescription Drug Use Questionnaire (PDUQ)[17] was used to assess lifetime history of substance use treatment. Patients were asked to report any past history of substance use treatment involving either alcohol or illicit drugs. The Prescription Drug Use Questionnaire has been used in numerous studies conducted among patients with chronic pain prescribed opioids.[5,17]

Daily Diaries. Before beginning the diary period, patients were provided with instructions on how to use the software (ie, REDCap) through which diaries were completed. During the 14-day diary period, patients were asked to provide daily reports every evening based on the past 24 hours. Diary reports were date- and time-stamped to ensure validity, to record specific times when diary reports were made, and to monitor patients' compliance.

Daily Reports of Pain Intensity: Patients were asked to rate the average level of pain they experienced over the past 24 hours using a visual analogue scale (VAS) that ranged between 0 (no pain) to 100 (extreme pain). This measure is a diary adaptation of the standard VAS item used in the BPI[77] to assess pain intensity among patients with chronic pain. The BPI is one of the most commonly used measure to assess pain intensity among patients with chronic pain.[21,41,77]

Daily Reports of Positive and Negative Affect: Patients were asked to rate how much they have felt various positive and negative emotions in the past 24 hours on a scale that ranged from 0 (not at all) to 4 (extremely). This measure is a diary adaptation of the Positive and Negative Affect Scale (PANAS).[82] For PA, patients rated how enthusiastic, excited, alert, determined, and inspired they felt. For NA, patients rated how nervous, upset, distressed, scared, and afraid they felt. Consistent with previous research, scores on these items were averaged to create separate measures of PA and NA, respectively.[19,26,47] The reliability and validity of the Positive and Negative Affect Scale has been supported in numerous studies among patients with chronic pain.[19,26,60] In our study, the internal reliability of items assessing PA (Cronbach α = 0.88) and NA (Cronbach α = 0.89) was excellent.

Daily Reports of Catastrophizing: Daily catastrophizing was assessed using a diary version of the Pain Catastrophizing Scale (PQS).[18,75] Patients were asked to report on different thoughts and emotions associated with pain based on the past 24 hours using a scale ranging from 0 (very slightly or not at all) to 4 (extremely). Studies have supported the reliability and the validity of the daily Pain Catastrophizing Scale as a measure of daily pain catastrophizing.[18] In this study, the internal reliability of items used to assess catastrophic thinking (Cronbach α = 0.89) was excellent.

Daily Reports of Opioid Craving: Patients were asked to rate the level of opioid craving they experienced over the past 24 hours using 3 different items: (1) How often have you found yourself thinking about your opioid medication and your next opioid doses? (2) How often have you experienced a desire to use your opioid medication? (3) How often have you craved your opioid medication? Items were rated on a VAS that ranged from 0 (never) to 100 (very often). These items were adapted from the Opioid Craving Scale[56] and used in many studies among patients with chronic pain prescribed long-term opioid therapy.[53,54,81] These items have been found to have adequate psychometric properties and the internal reliability of craving items in this study was excellent (Cronbach α = 0.94).

Daily Reports of Hedonic and Calming Effects: The hedonic and calming effects of opioids were assessed by asking patients to rate the degree of pleasantness and calmness they experienced over the past 24 hours related to the use of opioids. Feelings of pleasantness ("How pleasant was the feeling associated with your opioid medication?") and feelings of calmness ("To what extent did your opioid medication calm you down?") were assessed separately and rated on a VAS scale that ranged from 0 (not at all) to 100 (extremely). These items were adapted from scales designed to assess hedonic and calming effects associated with other substances in the context of daily diary studies.[13,67,68]

Opioid Misuse: Opioid misuse was assessed using items from the Current Opioid Misuse Measure (COMM[11]). The Current Opioid Misuse Measure items were used to assess the frequency of 3 distinct types of opioid misuse behaviors (ie, using more opioids than prescribed, using opioids for non-pain symptoms, and borrowing opioids) using the following COMM items: "In the past 14 days, how often have you had to take more opioid medication than prescribed? How often have you used your pain medicine for symptoms other than pain? How often have you borrowed medication from someone else?" COMM items were completed at the end of the diary period (ie, day 14) using a scale that ranged from 0 (never) to 4 (very often). For the purposes of this study, COMM items assessing emotional or psychiatric issues were removed because of the potential overlap between these items and psychological variables included in this study. Removing these items allowed us to ensure that associations between study measures and opioid misuse were not artificially inflated because of overlapping item content. Items assessing more general aberrant behaviors (eg, "showing up at the clinic without an appointment") were also excluded given that these items are not directly indicative of opioid misuse. After removing COMM items related to emotional/psychiatric issues and aberrant behaviors, the Cronbach's alpha (α = 0.67) remained acceptable, supporting the internal reliability of this subset of COMM items. Several studies have supported the reliability and validity of COMM items for the identification of patients who are misusing opioids over the course of long-term opioid therapy.[10,11,40]

Data Reduction and Analysis

Data analysis was performed using IBM-SPSS v.24 (SPSS Inc, Chicago, IL). The normality of distributions and other statistical assumptions for each of the study analyses was examined. Unless otherwise noted, all statistical assumptions were met. Descriptive statistics were presented as means and SDs for continuous variables and percentages for categorical variables.

Main study analyses were conducted using multilevel modeling given the hierarchical data structure of this study in which repeated daily measures (level 1 units) were nested within participants (level 2 units). With the ability of multilevel modeling to account for randomly missing level 1 data,[63,69] all 103 study participants were included in multilevel analyses without the need for any data imputation procedures. Across all assessment time points, compliance with the diary protocol was very high, with an overall completion rate of 96.4%. When combining the 7 main level 1 variables that were assessed in this study (ie, pain intensity, catastrophizing, NA, PA, feelings of pleasure, feelings of calmness, and opioid craving), there was a total of 10,094 possible data points (103 participants × 7 variables × 14 time points), and a total of 9732 data points were observed (96.4%). Analyses indicated that patients with and without missing data did not differ significantly on any of the main study variables (all P's > 0.05).

Before conducting primary study analyses, a series of analyses were conducted to examine the influence of patient demographics (ie, age, sex, ethnicity, education, marital status, and employment status), opioid regimen characteristics (ie, opioid types, opioid doses, and dosing frequency), pain characteristics (ie, number of pain locations and pain duration), and psychological or psychiatric variables (ie, past history of substance use disorders) on main study outcomes (ie, opioid craving or opioid misuse). As recommended,[72,83] variables significantly associated with main study outcomes were included as covariates or effect modifiers in main study analyses.

To examine whether the hedonic and calming effects of opioids contributed to opioid misuse, within-person averages of pleasure and calmness were first computed by aggregating reports across the 14 diary days. Spearman correlation analyses were then computed between these variables and prescription opioid misuse (ie, total COMM scores). Correlation analyses were conducted separately for the hedonic and calming effects of opioids as well as separately for the 3 distinct types of opioid misuse behaviors (ie, overusing opioids, using opioids for non-pain symptoms, and borrowing or shopping opioids).

Multilevel linear regression analyses were then conducted to examine the within-person associations between opioid effects (ie, hedonic and calming effects) and opioid craving. In these analyses, level 1 opioid craving was used as the outcome variable and level 1 pleasure and calmness reports were used as independent variables (IVs) in 2 distinct multilevel models. These analyses were followed by a series of multilevel moderation analyses examining the potential moderators of these associations. More specifically, multilevel moderation models were built using opioid craving as the dependent variable, and analyses examined whether the association between opioid effects (ie, hedonic and calming effects) and opioid craving was moderated by patients' daily levels of pain intensity (level 1), catastrophizing (level 1), NA (level 1), or PA (level 1). In these models, 2-way interaction terms between opioid effects and each of the potential moderators (ie, pain intensity, catastrophizing, NA, or PA) were specified. These interaction terms were included in separate multilevel models after the inclusion of appropriate main effects. Any significant 2-way interaction effect would suggest that the association between opioid effects (ie, hedonic and calming effects) and opioid craving is moderated by pain intensity, catastrophizing, NA, or PA.

All multilevel models were performed using maximum-likelihood estimation and included a first-order autoregressive variance covariance matrix (AR1) to account for autocorrelations between repeated assessments. All multilevel models included a random intercept and fixed effects for IVs of interest. As recommended,[24,59] all IVs were within-person centered before being entered in multilevel models.[24,59] Effect sizes were estimated for main multilevel analyses by calculating the percentage reduction in unexplained variance at the within-person level, relative to the unexplained variance of the null model. This measure of explained variance is analogous to the R2 value traditionally reported when conducting ordinary least squares regression.[37,38,63]

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