TY - JOUR
AU - J, Ives, Timothy
AB - Abstract Setting There are no studies that exist within the primary care setting that address optimal opioid therapy in osteoarthritis patients. In light of the recently released US Centers for Disease Control and Prevention guidelines on opioid use in chronic noncancer pain, there is a pressing need to better characterize the effectiveness of long- and short-acting opioids. Objective To examine the effectiveness of short-acting opioids (SAO) vs long-acting opioids (LAO) and combination therapies (SAO and LAO) for treating chronic osteoarthritis pain in a retrospective trial. Methods Average and lowest pain scores approximately one to two weeks prior to patient appointments were collected and averaged for both SAO and LAO patients who were actively enrolled in a pain clinic at an academic medical center. Results There was no statistical difference between reported average and low pain scores for the SAO vs LAO groups (P = 0.201 and P = 0.296, respectively), although the SAO group on average had a significantly lower morphine equivalence (P < 0.001). Various covariates for both groups were tested in an adjusted model to look at trends in the use of nonopioid medications (i.e., acetaminophen, nonsteroidal anti-inflammatory drugs, antidepressants, and adjunct analgesic agents). No significant differences in pain scores existed when comparing covariates for the SAO vs LAO groups. Conclusions The study suggests that in addition to being effective, short-acting opioid medications may also provide a safer and cheaper alternative to long-acting opioid therapies in the treatment of chronic osteoarthritis. Perspective This article investigates the effectiveness of short-acting vs long-acting opioids for the treatment of chronic noncancer pain, specifically osteoarthritis. This information could potentially aid practitioners in primary care environments to design equally efficacious and less costly opioid regimens, while simultaneously enhancing patient safety. Osteoarthritis, Opioids, Short-Acting, Long-Acting, Chronic pain Introduction Over the past two decades, clinicians have been challenged to devise analgesic regimens that optimize patient outcomes. The reliance on opioids to treat chronic noncancer pain without compelling efficacy data has been strongly implicated with increases in “diversion, overdose, and addiction” [1]. From a societal standpoint, there has been an epidemic in nonmedical opioid use with attendant suffering, decreased productivity, and worse medical and mental health outcomes [2]. In addition, the dependence of opioid therapy for chronic pain has tended to obscure treatment of comorbid psychiatric illness and the importance of ultimately ensuring better functional outcomes. For example, major depression and chronic pain frequently coexist [3], and many pain-treating physicians contend that functional outcomes supersede somatic pain relief as the most important intended focus of pain management [4]. The expansion of opioid use in patients with chronic pain has been beneficial in the aggregate [5]; however, it has not been accompanied by a robust body of clinical trials to provide guidance on the current US Centers for Disease Control and Prevention (CDC) recommendations for the use of opioids in chronic noncancer pain [6]. The available clinical trials have serious limitations (e.g., randomization against placebo, short duration of intervention, outcomes focused exclusively on pain scores, exclusion of patients with psychiatric comorbidity, exclusion of medically complex patients, or the exclusion of pain related to malignancy, etc.), resulting in a dearth of actionable clinical research applicable to clinical settings [7,8]. This research is especially limited in general medical and primary care settings where there are many competing medical, mental health, and pharmacologic priorities. Despite a lack of evidence and rigorous testing, a common dosing strategy for patients receiving opioids for chronic noncancer pain is a regimen consisting of long-acting opioids for basal analgesia with supplemental short-acting opioids for breakthrough pain, rather than a regimen based on potent short-acting opioids to be used either regularly or as needed [9]. This approach has led to the use of very high doses of opioids that have not been validated for effectiveness in clinical trials [10]. On a public health level, the use of high-dose opioids to treat chronic pain has fueled the epidemic of opioid-related deaths in the Unites States [11]. In addition to contributing to the rise of opioid-related deaths, the use of high doses of opioid analgesics may be countertherapeutic in other ways. Opioid-induced hyperalgesia may aggravate pain management, and mental health and functional outcomes may also be adversely affected [10]. The evidence on how to best manage chronic noncancer pain in primary care settings is sparse. No single opioid regimen has been found to be superior to another at equianalgesic doses [12]. Moreover, the use of long-acting basal opioid regimens supplemented with short-acting opioids has not been demonstrated to be superior to using short-acting opioids, either scheduled continuously or as needed. There are no randomized clinical trials that compare long-acting basal regimens with short-acting as-needed regimens in patients with noncancer chronic pain. Additionally, in the primary care setting, no studies exist that address optimal opioid therapy in osteoarthritis patients. In light of the recently released CDC guidelines on opioid use in chronic noncancer pain, there is a pressing need to better characterize the effectiveness of long- and short-acting opioids in primary care settings [6]. The aim of this study was to compare SAO therapy versus LAOs or combination therapies for treatment of chronic osteoarthritis. Additionally, opioid dose intensity was examined between the two groups. This analysis was performed to investigate the analgesic effectiveness, not efficacy, of the different opioid regimens in a population of patients enrolled in a primary care pain management program. Methods Patients The study population consisted of patients enrolled in the UNC Internal Medicine Pain Service (IMPS). This program has been in existence since 2002, and its structure has been previously described, including pain outcomes and the prevalence of substance misuse in this population [13,14]. Patient study data were obtained from the University of North Carolina (UNC) Health Care System electronic medical record system. Data were retrieved from the electronic health record for patient visits to the IMPS over a 15-month period between April 4, 2014, and June 30, 2015. Patients taking SAO, LAO, or combination regimens were identified, of which 114 (66.6%) were Caucasian, 53 (31%) were African American, two (1.2%) were Hispanic, and two (1.2%) refused to answer. LAO and combination regimen data were then combined and analyzed as a single variable against the SAO data. From the specific opioid (or opioids) used for each regimen, the morphine mg equivalent (MME) for each patient was calculated [15]. Additional covariates included patient age, gender, ethnicity, smoking status, and osteoarthritis pain sites. Also, use of any adjunct analgesics (e.g., acetaminophen, gabapentin, pregabalin, nonsteroidal anti-inflammatory drugs (NSAIDs; prescription and over-the-counter formulations), or antidepressant medication was identified. Dependent variables and outcomes of interest were pain scores on the Brief Pain Inventory (BPI) and a comparison of relative opioid dose intensity among opioid regimens. Eligibility Criteria Inclusion criteria were as follows: a diagnosis of moderate to severe osteoarthritis, enrollment in the UNC IMPS during the specified time range, and receipt of opioid prescriptions for chronic pain management for more than six months. Patients were excluded from the study if they had a diagnosis of nonosteoarthritic pain, use of non-opioid pain medications, medication contract violations (e.g., presence of inappropriate urine toxicological screenings with evidence of illicit drug use), an active malignancy, were pregnant or breastfeeding, no reported pain scores, or were deceased (Figure 1). Figure 1 View largeDownload slide Patients excluded from retrospective analysis. *No reported pain scores and/or less than two visits within the time frame. IMPS = University of North Carolina Internal Medicine Pain Service; OA = osteoarthritis. Figure 1 View largeDownload slide Patients excluded from retrospective analysis. *No reported pain scores and/or less than two visits within the time frame. IMPS = University of North Carolina Internal Medicine Pain Service; OA = osteoarthritis. Statistical Analysis Average pain scores, average morphine equivalents, and all other statistical analyses were calculated using Stata 14 (v. 14.1, StataCorp, College Station, TX, USA). Bivariate and multivariate analyses were performed using chi-square, one-way analysis of variance, and linear regression tests. The study was approved by the Institutional Review Board at the University of North Carolina at Chapel Hill. Results Of the 324 active patients in the IMPS, 171 patients (52.8%) met the inclusion criteria. The study population was predominantly white (66.6%) and female (68.4%). The mean age was 59.7 years (range = 32–83 years). Patients averaged 4.5 clinic visits during this time frame (range = 2–7 visits). The collective means of the patient’s reported lowest and average pain scores from one to two weeks prior to the pain appointment were compared for patients taking SAOs vs LAOs. The differences in mean pain scores were not significant (P = 0.201) when comparing the SAO group (mean = 5.67) with the LAO group (mean = 5.35). The differences in lowest reported pain scores were also not significant (P = 0.296) for SAOs (mean = 3.83) and LAOs (mean = 3.52). The aggregate MMEs for SAO (mean = 52.4) vs LAO (mean = 97.0) achieved significance (P < 0.001). Multivariate analysis was performed across groups receiving SAOs and LAOs, controlling for age, gender, smoking status, and medication use: acetaminophen, adjunct (i.e., neuropathic agents such as tricyclic agents, gabapentin, topiramate, etc.), oral NSAIDs, topical patches and ointments (i.e., topical NSAIDs, lidocaine), and antidepressants. No significant differences existed by age, gender, and race between groups. Although SAO patients were more likely to be receiving neuropathic analgesic agents and to smoke (Table 1), it did not alter the results in adjusted analyses. Adjusting for topical agents and antidepressants also did not affect the analyses when comparing the two groups. Acetaminophen use was higher in the SAO group than the LAO group, as SAOs are typically combined with this drug. Table 1 SAO vs LAO/Combination therapy regimens compared with pain scores for primary osteoarthritis pain sites and bivariate analysis of covariates Outcomes Short-Acting Opioids Long-Acting Opioids P Population data, No. (%)  Number of patients (171) 118 (69.0) 53 (31.0) –  Male (54) 33 (28.0) 21 (39.6) 0.129  Female (117) 85 (72.0) 32 (60.4) Age, y, mean ± SD 59.6 ± 10.32 59.9 ± 8.83 0.196 Averaged pain scores, mean ± SD  Average score 5.67 ± 1.47 5.35 ± 1.49 0.201  Lowest score 3.83 ± 1.80 3.52 ± 1.77 0.296  Mean morphine mg equivalence 52.4 ± 37.7 97.0 ± 65.5 <0.001 Covariates, No. (%)  Smoking 48 (40.68) 14 (26.42) 0.073  APAP 87 (73.73) 25 (47.17) 0.001  Adjunct analgesic agents 54 (45.76) 15 (28.30) 0.031  NSAID/topical 61 (51.69) 29 (54.72) 0.714  Antidepressants 50 (42.37) 28 (52.83) 0.204 Outcomes Short-Acting Opioids Long-Acting Opioids P Population data, No. (%)  Number of patients (171) 118 (69.0) 53 (31.0) –  Male (54) 33 (28.0) 21 (39.6) 0.129  Female (117) 85 (72.0) 32 (60.4) Age, y, mean ± SD 59.6 ± 10.32 59.9 ± 8.83 0.196 Averaged pain scores, mean ± SD  Average score 5.67 ± 1.47 5.35 ± 1.49 0.201  Lowest score 3.83 ± 1.80 3.52 ± 1.77 0.296  Mean morphine mg equivalence 52.4 ± 37.7 97.0 ± 65.5 <0.001 Covariates, No. (%)  Smoking 48 (40.68) 14 (26.42) 0.073  APAP 87 (73.73) 25 (47.17) 0.001  Adjunct analgesic agents 54 (45.76) 15 (28.30) 0.031  NSAID/topical 61 (51.69) 29 (54.72) 0.714  Antidepressants 50 (42.37) 28 (52.83) 0.204 APAP = Acetaminophen; LAO = long-acting opioid; NSAID = nonsteroidal anti-inflammatory drug; SAO = short-acting opioid. Table 1 SAO vs LAO/Combination therapy regimens compared with pain scores for primary osteoarthritis pain sites and bivariate analysis of covariates Outcomes Short-Acting Opioids Long-Acting Opioids P Population data, No. (%)  Number of patients (171) 118 (69.0) 53 (31.0) –  Male (54) 33 (28.0) 21 (39.6) 0.129  Female (117) 85 (72.0) 32 (60.4) Age, y, mean ± SD 59.6 ± 10.32 59.9 ± 8.83 0.196 Averaged pain scores, mean ± SD  Average score 5.67 ± 1.47 5.35 ± 1.49 0.201  Lowest score 3.83 ± 1.80 3.52 ± 1.77 0.296  Mean morphine mg equivalence 52.4 ± 37.7 97.0 ± 65.5 <0.001 Covariates, No. (%)  Smoking 48 (40.68) 14 (26.42) 0.073  APAP 87 (73.73) 25 (47.17) 0.001  Adjunct analgesic agents 54 (45.76) 15 (28.30) 0.031  NSAID/topical 61 (51.69) 29 (54.72) 0.714  Antidepressants 50 (42.37) 28 (52.83) 0.204 Outcomes Short-Acting Opioids Long-Acting Opioids P Population data, No. (%)  Number of patients (171) 118 (69.0) 53 (31.0) –  Male (54) 33 (28.0) 21 (39.6) 0.129  Female (117) 85 (72.0) 32 (60.4) Age, y, mean ± SD 59.6 ± 10.32 59.9 ± 8.83 0.196 Averaged pain scores, mean ± SD  Average score 5.67 ± 1.47 5.35 ± 1.49 0.201  Lowest score 3.83 ± 1.80 3.52 ± 1.77 0.296  Mean morphine mg equivalence 52.4 ± 37.7 97.0 ± 65.5 <0.001 Covariates, No. (%)  Smoking 48 (40.68) 14 (26.42) 0.073  APAP 87 (73.73) 25 (47.17) 0.001  Adjunct analgesic agents 54 (45.76) 15 (28.30) 0.031  NSAID/topical 61 (51.69) 29 (54.72) 0.714  Antidepressants 50 (42.37) 28 (52.83) 0.204 APAP = Acetaminophen; LAO = long-acting opioid; NSAID = nonsteroidal anti-inflammatory drug; SAO = short-acting opioid. Table 2 Types of primary osteoarthritis pain sites Osteoarthritis Pain Site No. (%) Lumbar 71 (41.5) Knees 39 (22.8) Hips/legs 28 (16.4) Cervical 15 (8.8) Hands 10 (5.8) Feet 7 (4.1) Shoulder 1 (0.6) Osteoarthritis Pain Site No. (%) Lumbar 71 (41.5) Knees 39 (22.8) Hips/legs 28 (16.4) Cervical 15 (8.8) Hands 10 (5.8) Feet 7 (4.1) Shoulder 1 (0.6) Table 2 Types of primary osteoarthritis pain sites Osteoarthritis Pain Site No. (%) Lumbar 71 (41.5) Knees 39 (22.8) Hips/legs 28 (16.4) Cervical 15 (8.8) Hands 10 (5.8) Feet 7 (4.1) Shoulder 1 (0.6) Osteoarthritis Pain Site No. (%) Lumbar 71 (41.5) Knees 39 (22.8) Hips/legs 28 (16.4) Cervical 15 (8.8) Hands 10 (5.8) Feet 7 (4.1) Shoulder 1 (0.6) No evidence was found that the practice of using LAOs and combination therapies is superior to using SAOs alone. For long-acting and combination therapies, the mean morphine equivalence was 97 ± 65.5 mg, which was 45.98% higher than the short-acting equivalence (mean = 52.4 ± 37.7 mg). When comparing study groups, SAOs provided statistically comparable analgesia (P = 0.201) to LAOs/Combination therapy while providing a statistically significant (P < 0.001) lower opioid equivalent requirement. Patients who were taking SAOs (i.e., oxycodone, hydrocodone, and morphine) had slightly higher averaged pain scores than patients who were taking extended-release or combination therapies (5.67 vs 5.35), but the absolute difference in pain scores was not statistically significant (P = 0.201), nor clinically significant, based upon patient reports during their clinic visits. Based upon study results, factors such as smoking, adjunct analgesics, age, and gender did not statistically impact pain scores when switching regimens from LAOs to SAOs (Table 1). Discussion The study data do not support the common practice of prescribing LAOs, with or without SAOs for breakthrough pain, in patients with chronic pain. Although intuitively appealing, a provision of basal opioid analgesia does not appear to be superior to using SAOs alone. Prescribing LAOs adds to the cost of chronic pain care, and these regimens also increase the medical risk to the patient by exposing them to higher doses of potent opioids, thereby increasing the risk of overdose and death [16]. In addition, higher doses of opioids may increase the incidence of less lethal but still bothersome adverse drug events, most notably constipation and cognitive impairment [17]. When used to manage chronic osteoarthritis pain, the use of SAOs can achieve comparable analgesia at a reduced risk for adverse effects. Such a practice standard, if applied to the ∼100 million patients receiving opioids for chronic pain [18], would also have public health implications in terms of potentially mitigating the risk of opioid overdose that is linked with increased MMEs. Opioid prescription overdose, the leading cause of accidental death in the United States, was responsible for 47,055 deaths in 2014 alone [19]. Limitations This study was nonrandomized and retrospective. It is possible that the two groups differed in ways that could not be accounted for statistically (i.e., unmeasured confounders). It was not an a priori analysis of drug efficacy. It represents a view of analgesic effectiveness in a closely monitored, highly regimented care setting for patients receiving opioids. Other limitations include a small sample size and an analysis limited to patients with osteoarthritis pain sites (Table 2). Also, short-acting opioids are often compounded with acetaminophen. Because we included short-acting agents without stratification for acetaminophen content, we were unable to quantify and estimate the impact that acetaminophen might have on pain control and our results. Conclusion In a cohort of primary care patients with chronic pain due to osteoarthritis, SAOs provided comparable analgesia to LAOs, with a lower opioid equivalence requirement. The absolute differences in pain scores between the two groups were not clinically significant. Results were unaffected in an adjusted model. This analysis does not support the superiority of long-acting basal opioid treatment, either with or without SAOs, over SAOs alone, although this is commonly considered to be a standard of care. Use of SAOs, rather than LAOs, may decrease the cost of treatment, and it may also decrease the risk of overdose and mortality. More rigorous randomized trials are needed to ascertain whether LAOs offer any advantage to SAOs in the management of chronic osteoarthritis pain. Acknolwedgments The research team would like to acknowledge the providers and patients of the Internal Medicine Pain Service. The authors have all contributed equally to the completion of this project. Funding sources: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflicts of interest: The authors have no conflicts of interest to declare. References 1 Volkow ND , McLellan AT. Opioid abuse in chronic pain—misconceptions and mitigation strategies . N Engl J Med 2016 ; 374 : 1253 – 63 . Google Scholar Crossref Search ADS PubMed 2 Eisenberg DM , Davis RB , Ettner SL , et al. . Trends in alternative medicine use in the United States, 1990–1997: Results of a follow-up national survey . JAMA 1998 ; 280 : 1569 – 75 . Google Scholar Crossref Search ADS PubMed 3 Bair MJ , Robinson RL , Katon W , Kroenke K. Depression and pain comorbidity: A literature review . Arch Intern Med 2003 ; 163 : 2433 – 45 . Google Scholar Crossref Search ADS PubMed 4 Kroenke K , Bair MJ , Damush TM , et al. . Optimized antidepressant therapy and pain self-management in primary care patients with depression and musculoskeletal pain: A randomized controlled trial . JAMA 2009 ; 301 : 2099. Google Scholar Crossref Search ADS PubMed 5 McQuay H. Opioids in pain management . Lancet 1999 ; 353 ( 9171 ): 2229 – 32 . Google Scholar Crossref Search ADS PubMed 6 Dowell D , Haegerich TM , Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016 . JAMA 2016 ; 315 ( 15 ): 1624 – 45 . Google Scholar Crossref Search ADS PubMed 7 Mao J. Current challenges in translational pain research . Trends Pharm Sci 2012 ; 33 ( 11 ): 568 – 73 . Google Scholar Crossref Search ADS PubMed 8 Colvin LA , Rowbotham DJ. I. Managing pain: Recent advances and new challenges . Br J Anaesth 2013 ; 111 : 1 – 3 . Google Scholar Crossref Search ADS PubMed 9 Turk DC , Wilson HD , Cahana A. Treatment of chronic non-cancer pain . Lancet 2011 ; 377 : 2226. Google Scholar Crossref Search ADS PubMed 10 Ballantyne JC , Mao J. Opioid therapy for chronic pain . N Engl J Med 2003 ; 349 : 1943. Google Scholar Crossref Search ADS PubMed 11 Kolodny A , Courtwright DT , Hwang CS , et al. . The prescription opioid and heroin crisis: A public health approach to an epidemic of addition . Annu Rev Public Health 2015 ; 36 : 559 – 74 . Google Scholar Crossref Search ADS PubMed 12 Martell B , O'Connor PG , Kerns RD , et al. . Systematic review: Opioid treatment for chronic back pain: Prevalence, efficacy, and association with addiction . Ann Int Med 2007 ; 146 : 116. Google Scholar Crossref Search ADS PubMed 13 Chelminski PR , Ives TJ , Felix KM , et al. . A primary care, multi-disciplinary disease management program for opioid-treated patients with chronic non-cancer pain and a high burden of psychiatric comorbidity . BMC Health Serv Res 2005 ; 5 ( 1 ): 3 – 10 . Google Scholar Crossref Search ADS PubMed 14 Ives TJ , Chelminski PR , Hammett-Stabler CA , et al. . Predictors of opioid misuse in patients with chronic pain: A prospective cohort study . BMC Health Serv Res 2006 ; 6 : 46. Google Scholar Crossref Search ADS PubMed 15 Von Korff M , Saunders K , Thomas Ray G , et al. . De facto long-term opioid therapy for noncancer pain . Clin J Pain 2008 ; 24 : 521 – 7 . Google Scholar Crossref Search ADS PubMed 16 Ray WA , Chung CP , Murray KT , Hall K , Stein CM. Prescription of long-acting opioids and mortality in patients with chronic noncancer pain . JAMA 2016 ; 315 ( 22 ): 2415 – 23 . Google Scholar Crossref Search ADS PubMed 17 Benyamin R , Trescot AM , Datta S , et al. . Opioid complications and side effects . Pain Physician 2008 ; 11 (2 Suppl) : S105 – 20 . Google Scholar PubMed 18 Pizzo P , Clark N. Institute of Medicine Report from the Committee on Advancing Pain Research, Care, and Education: Relieving Pain in America, a Blueprint for Transforming Prevention, Care, Education and Research . Washington (DC) : National Academies Press (US) ; 2011 . 19 Rudd RA , Aleshire N , Zibbell JE , Gladden RM. Increases in drug and opioid overdose deaths—United States, 2000–2014 . MMWR Morb Mortal Wkly Rep 2016 ; 64 ( 50–51 ): 1378 – 82 . Google Scholar Crossref Search ADS PubMed © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Short-Acting Opioids Are Associated with Comparable Analgesia to Long-Acting Opioids in Patients with Chronic Osteoarthritis with a Reduced Opioid Equivalence Dosing
JF - Pain Medicine
DO - 10.1093/pm/pnx245
DA - 2018-11-01
UR - https://www.deepdyve.com/lp/oxford-university-press/short-acting-opioids-are-associated-with-comparable-analgesia-to-long-RIXnSXiUjs
SP - 2191
VL - 19
IS - 11
DP - DeepDyve
ER -