Addressing the Risks of Long-Term Opioid Therapy in Chronic Noncancer Pain

Study Overview
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Brief Summary
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PURPOSE: Assess the risks of long-term opioid therapy, especially opioid use disorders such as opioid-related chemical coping in chronic noncancer pain patients. Pain, particularly chronic pain, is a major threat to the quality of life worldwide and will become more so as the average age increases. Currently, over 30% of the world's population is known to have chronic pain. Among a plethora of treatment options, opioid agonists is one of treatment options for moderate to severe chronic pain. Although its consumption has increased during the last two decades,3 it remains below the requirements in most regions, including the Asian countries. In South Korea (S. Korea), opioid consumption for medical purposes in 2015 was still below average, ranked 43rd globally and 30th among 35 Organisation for Economic Co-operation and Development (OECD) countries (55 mg/capita in S. Korea vs. 258 mg/capita in an average of OECD countries). Conversely, in countries with high opioid consumption such as the United States of America (US), drug overdose deaths (the majority involving an opioid) have nearly quadrupled since 1999. The up to date literature on opioid use disorder (OUD) is characterized by great variability of definitions, measurements, demographics, and opioid use duration. Moreover, an overwhelming majority of the studies took place in the US, the country with the highest opioid consumption and a current opioid crisis. Additionally, stringent restrictions and regulations to prevent OUD may result in inadequate pain control and insufficient opioid therapy, especially in countries with relatively low-moderate opioid consumption rates. Therefore, in compliance with growth in medical opioid use and the lack of studies in countries with low-moderate opioid consumption, it is necessary to determine the occurrence of OUD in chronic noncancer pain (CNCP) patients receiving long-term opioid therapy (LtOT). In this study, we will perform a national, multicenter, observational cross-sectional study to address the current status of opioid treatment for CNCP in S. Korea, a country with moderate opioid consumption. The ultimate aims of this study are to estimate the frequency of OUD such as OrCC, to evaluate the functional and psychiatric characteristics of patients, and to determine the risk factors associated with OUD in CNCP patients receiving LtOT.

Detailed Description
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Chronic pain is a devastating disease often treated inadequately. More than 30 percent of the world population suffers from chronic pain. Among a plethora of treatment options, opioid agonists is one of treatment options for moderate to severe chronic pain. Although its consumption has increased during the last two decades, it remains below the requirements in most regions, including the Asian countries. In South Korea (S. Korea), opioid consumption for medical purposes in 2015 was still below average, ranked 43rd globally and 30th among 35 Organisation for Economic Co-operation and Development (OECD) countries (55 mg/capita in S. Korea vs. 258 mg/capita in an average of OECD countries). However, it is remarkable that the opioid consumption in S. Korea has increased 5-6 times since 2005 (10 mg/capita), ranking 3rd among Asian countries, preceded only by Vietnam (62 mg/capita) and Malaysia (60 mg/capita). One of the reluctant factors to prescribe opioids is induced reward responses, resulting in opioid use disorders (OUD). Particularly, in chronic noncancer pain (CNCP), concerns regarding drug dependence in the long-term opioid therapy (LtOT) remain its use controversial. The spectrum of OUD in CNCP patients is wide and varies from misuse without a compliant intake to addiction with a severe aberrant consumption. Between the extremes, opioid-related chemical coping (OrCC) may lie in a middle ground group, characterized by an inappropriate use of opioids to cope with emotional distress. Although, OrCC is a terminology first used in cancer patients, a recent study found a high correlation between the reports of aberrant medication-taking behavior by experienced providers and chemical coping by CNCP patients. OrCC should be distinguished from psychologic addiction, a neurobiological disease that corresponds with the most severe substance-use disorder referring to neuroplasticity and a substantial loss of self-control. All addicts are eventually chemical copers, but not all chemical copers are addicts. A better understanding of this intermediate status may be crucial to prompt to identify the risk of severe OUD and re-direct their management to avoid unnecessary opioid toxicity and achieve adequate pain control. However, studies to measure OrCC are scarce and the evidence of OUD in CNCP in countries with relatively low opioid consumption is practically unavailable. The up to date literature on OUD is characterized by great variability of definitions, measurements, demographics, and opioid use duration. Moreover, an overwhelming majority of the studies took place in the United Stated of America (US), the country with the highest opioid consumption and a current opioid crisis. Despite their over-consumption, however, studies in those countries showed that CNCP is still undertreated and even suggested that OUD might not be related to the prescription to pain patients. From a different angle, stringent restrictions and regulations to prevent OUD may result in inadequate pain control and insufficient opioid therapy, especially in countries with relatively low- moderate opioid consumption rates. Therefore, to strike a balance when treating pain with opioids, it is indispensable to determine the characteristics of OUD in CNCP patients with LtOT in countries with low-moderate opioid consumption. Moreover, in S. Korea there are not available statistics regarding the OUD occurrence in CNCP patients and national guidelines on LtOT in CNCP have not been developed. In this study, we will perform a national, multicenter, observational cross-sectional study to address the current status of opioid treatment and OUD for CNCP in S. Korea, a country with moderate opioid consumption since 2010. The availability of up-to-date data on OUD is necessary for the development of national guidelines to prevent severe harms of opioids, enhance patients and physicians' satisfaction, potentiate opioid's benefits, and guaranty adequate pain control in the CNCP population. The ultimate aims of this study are to estimate the frequency of OUD (such as OrCC), to evaluate the patient's functional and psychiatric characteristics, and to determine the risk factors associated with OUD in CNCP patients receiving LtOT. The results of this study will help to seize the occurrence of OUD in countries with low-moderate opioid consumption thus it will approach the real risk effect of LtOT in CNCP.

Official Title
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Addressing the Risks of Long-Term Opioid Therapy in Chronic Noncancer Pain: A National, Multicenter, and Observational Cross-sectional Study in South Korea

Conditions
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Chronic Noncancer Pain, Opioid-Related Disorders

Participation Criteria
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Eligibility Criteria
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Inclusion criteria were as follows: 1) patients at age equal or greater than 18 years; 2) patients with a diagnosis of chronic pain defined by the American Chronic Pain Association (ACPA) as an ongoing or recurrent pain, lasting beyond the usual course of acute illness or injury or more than 3 months, and which adversely affected the individuals' well-being; 3) patients with CNCP with opioid medication for treatment and/or control of chronic pain; 4) patients who were receiving long-term opioid therapy defined as the use of opioids on most days for a period of time greater than 3 months; and 5) patients who complete the screening tools and questionnaires evaluated in the study. Exclusion criteria were as follows: 1) patients with diagnosis and/or ongoing cancer treatment or palliative or receiving end-of-life care; 2) patients younger than 18 years of age; 3) patients without current opioid therapy for the treatment and/or control of chronic pain; 4) patients with chronic pain that received opioid therapy intermittently or for less than 3 months; 5) serious systemic diseases (Myasthenia Gravis, decreased lung function, severe liver problems, severe renal impairment, shock, hypo- or hyperpotassemia) or psychiatric disorders (schizophrenia and acute anxiety) that compromise the patients safety or the completion of the survey; or 6) patients with intellectual impairment to answer the tools and questionnaires evaluated.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of opioid-related chemical coping | Prevalence of chemical coping with opioids in the study population by the pain specialists participating in the study through a questionnaire that contained the per-protocol definition of chemical coping and seven different aberrant behaviors related to chemical coping proposed by a panel of experts. One or more affirmative answers were considered as positive | The assessment took place during a routine outpatient clinic 1 day visit. The presence of chemical coping was evaluated by pain specialist through the questionnaire immediately after the routine visit of each patient. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sociodemographic characteristics of chronic noncancer pain patients using long-term opioid therapy | Patients' demographic data (sex, age, ethnicity, body mass index, marital status, education, and employment status), pain characteristics [duration, intensity using an 11-pointed numerical rating pain scale (NRS) score ranged from 0 (no pain) to 10 (pain as bad as you can imagine), etiology, location, and type of pain such as nociceptive, neuropathic, functional pain syndrome (fibromyalgia, temporomandibular disorder, etc.), and mixed, co-morbid psychiatric disease, substance abuse history, secondary morbid gain, ongoing litigation, history of taken prescription drugs with alcohol, and suicidal ideation] were collected. | The data was collected from the start of the study up to 3 months after finishing recruitment. The NRS was assessed in each patient during the routine visit with a pain specialist. | 
| Characteristic of opioid's use in chronic noncancer pain in South Korea | Opioid information including duration of administration, opioid types (long-acting vs. short-acting), route of administration (oral, transdermal, mucosal, or intravenous), Morphine Equivalent Daily Dosage (MEDD, mg/day), the initial prescriber, number of visits per year to an opioid prescriber, and history of Emergency room (ER) visits seeking for opioids, as well as concomitant use of benzodiazepines and other medication such as antidepressants, anticonvulsants, and/or topical agents were obtained. | The data was collected from the start of the study up to 3 months after finishing recruitment. | 
| Risk factors associated to long-term opioid therapy and opioid-related chemical coping | The assessment was conducted through a survey in the outpatient setting of each pain clinic. The survey contained a number of questionnaires including 1) the Cut, Annoyed, Guilty, Eye-opener - Adapted to Include Drugs (CAGE-AID); 2) the Brief Pain Inventory-Short Form (BPI-SF); 3) Pain Catastrophizing Scale; 4) Hospital Anxiety and Depression Scale (HADS); 5) Insomnia Severity Index (ISI); 6) Korean Instrumental Activities of Daily Living Scale (K-IADL); 7) Korean-Connor-Davidson Resilience Scale (K-CD-RISC); and 8) Patient Global Impression of Change Scale. | The patients answered to the questionnaires and tools before a routine 1 day visit. Each patient finished the evaluation on the same day of the visit. The record of answers will take place from the start to the finish of recruitment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chemical coping, Long-term opioid therapy, Risk factors, Predictive tools, Frequency