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      Benefit-Risk Analysis of Buprenorphine for Pain Management

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          Abstract

          Health care providers in the United States are facing challenges in selecting appropriate medication for patients with acute and chronic pain in the midst of the current opioid crisis and COVID-19 pandemic. When compared with conventional opioids, the partial µ-opioid receptor agonist buprenorphine has unique pharmacologic properties that may be more desirable for pain management. The formulations of buprenorphine approved by the US Food and Drug Administration for pain management include intravenous injection, transdermal patch, and buccal film. A comparison of efficacy and safety data from studies of buprenorphine and conventional opioids suggests that buprenorphine may be a better-tolerated treatment option for many patients that provides similar or superior analgesia. Our benefit-risk assessment in this narrative review suggests that health care providers should consider that buprenorphine may be an appropriate alternative for pain management over other opioids.

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          Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone).

          SUMMARY OF CONSENSUS: 1. The use of opioids in cancer pain: The criteria for selecting analgesics for pain treatment in the elderly include, but are not limited to, overall efficacy, overall side-effect profile, onset of action, drug interactions, abuse potential, and practical issues, such as cost and availability of the drug, as well as the severity and type of pain (nociceptive, acute/chronic, etc.). At any given time, the order of choice in the decision-making process can change. This consensus is based on evidence-based literature (extended data are not included and chronic, extended-release opioids are not covered). There are various driving factors relating to prescribing medication, including availability of the compound and cost, which may, at times, be the main driving factor. The transdermal formulation of buprenorphine is available in most European countries, particularly those with high opioid usage, with the exception of France; however, the availability of the sublingual formulation of buprenorphine in Europe is limited, as it is marketed in only a few countries, including Germany and Belgium. The opioid patch is experimental at present in U.S.A. and the sublingual formulation has dispensing restrictions, therefore, its use is limited. It is evident that the population pyramid is upturned. Globally, there is going to be an older population that needs to be cared for in the future. This older population has expectations in life, in that a retiree is no longer an individual who decreases their lifestyle activities. The "baby-boomers" in their 60s and 70s are "baby zoomers"; they want to have a functional active lifestyle. They are willing to make trade-offs regarding treatment choices and understand that they may experience pain, providing that can have increased quality of life and functionality. Therefore, comorbidities--including cancer and noncancer pain, osteoarthritis, rheumatoid arthritis, and postherpetic neuralgia--and patient functional status need to be taken carefully into account when addressing pain in the elderly. World Health Organization step III opioids are the mainstay of pain treatment for cancer patients and morphine has been the most commonly used for decades. In general, high level evidence data (Ib or IIb) exist, although many studies have included only few patients. Based on these studies, all opioids are considered effective in cancer pain management (although parts of cancer pain are not or only partially opioid sensitive), but no well-designed specific studies in the elderly cancer patient are available. Of the 2 opioids that are available in transdermal formulation--fentanyl and buprenorphine--fentanyl is the most investigated, but based on the published data both seem to be effective, with low toxicity and good tolerability profiles, especially at low doses. 2. The use of opioids in noncancer-related pain: Evidence is growing that opioids are efficacious in noncancer pain (treatment data mostly level Ib or IIb), but need individual dose titration and consideration of the respective tolerability profiles. Again no specific studies in the elderly have been performed, but it can be concluded that opioids have shown efficacy in noncancer pain, which is often due to diseases typical for an elderly population. When it is not clear which drugs and which regimes are superior in terms of maintaining analgesic efficacy, the appropriate drug should be chosen based on safety and tolerability considerations. Evidence-based medicine, which has been incorporated into best clinical practice guidelines, should serve as a foundation for the decision-making processes in patient care; however, in practice, the art of medicine is realized when we individualize care to the patient. This strikes a balance between the evidence-based medicine and anecdotal experience. Factual recommendations and expert opinion both have a value when applying guidelines in clinical practice. 3. The use of opioids in neuropathic pain: The role of opioids in neuropathic pain has been under debate in the past but is nowadays more and more accepted; however, higher opioid doses are often needed for neuropathic pain than for nociceptive pain. Most of the treatment data are level II or III, and suggest that incorporation of opioids earlier on might be beneficial. Buprenorphine shows a distinct benefit in improving neuropathic pain symptoms, which is considered a result of its specific pharmacological profile. 4. The use of opioids in elderly patients with impaired hepatic and renal function: Functional impairment of excretory organs is common in the elderly, especially with respect to renal function. For all opioids except buprenorphine, half-life of the active drug and metabolites is increased in the elderly and in patients with renal dysfunction. It is, therefore, recommended that--except for buprenorphine--doses be reduced, a longer time interval be used between doses, and creatinine clearance be monitored. Thus, buprenorphine appears to be the top-line choice for opioid treatment in the elderly. 5. Opioids and respiratory depression: Respiratory depression is a significant threat for opioid-treated patients with underlying pulmonary condition or receiving concomitant central nervous system (CNS) drugs associated with hypoventilation. Not all opioids show equal effects on respiratory depression: buprenorphine is the only opioid demonstrating a ceiling for respiratory depression when used without other CNS depressants. The different features of opioids regarding respiratory effects should be considered when treating patients at risk for respiratory problems, therefore careful dosing must be maintained. 6. Opioids and immunosuppression: Age is related to a gradual decline in the immune system: immunosenescence, which is associated with increased morbidity and mortality from infectious diseases, autoimmune diseases, and cancer, and decreased efficacy of immunotherapy, such as vaccination. The clinical relevance of the immunosuppressant effects of opioids in the elderly is not fully understood, and pain itself may also cause immunosuppression. Providing adequate analgesia can be achieved without significant adverse events, opioids with minimal immunosuppressive characteristics should be used in the elderly. The immunosuppressive effects of most opioids are poorly described and this is one of the problems in assessing true effect of the opioid spectrum, but there is some indication that higher doses of opioids correlate with increased immunosuppressant effects. Taking into consideration all the very limited available evidence from preclinical and clinical work, buprenorphine can be recommended, while morphine and fentanyl cannot. 7. Safety and tolerability profile of opioids: The adverse event profile varies greatly between opioids. As the consequences of adverse events in the elderly can be serious, agents should be used that have a good tolerability profile (especially regarding CNS and gastrointestinal effects) and that are as safe as possible in overdose especially regarding effects on respiration. Slow dose titration helps to reduce the incidence of typical initial adverse events such as nausea and vomiting. Sustained release preparations, including transdermal formulations, increase patient compliance.
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            Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults — United States, 2016

            Chronic pain, one of the most common reasons adults seek medical care ( 1 ), has been linked to restrictions in mobility and daily activities ( 2 , 3 ), dependence on opioids ( 4 ), anxiety and depression ( 2 ), and poor perceived health or reduced quality of life ( 2 , 3 ). Population-based estimates of chronic pain among U.S. adults range from 11% to 40% ( 5 ), with considerable population subgroup variation. As a result, the 2016 National Pain Strategy called for more precise prevalence estimates of chronic pain and high-impact chronic pain (i.e., chronic pain that frequently limits life or work activities) to reliably establish the prevalence of chronic pain and aid in the development and implementation of population-wide pain interventions ( 5 ). National estimates of high-impact chronic pain can help differentiate persons with limitations in major life domains, including work, social, recreational, and self-care activities from those who maintain normal life activities despite chronic pain, providing a better understanding of the population in need of pain services. To estimate the prevalence of chronic pain and high-impact chronic pain in the United States, CDC analyzed 2016 National Health Interview Survey (NHIS) data. An estimated 20.4% (50.0 million) of U.S. adults had chronic pain and 8.0% of U.S. adults (19.6 million) had high-impact chronic pain, with higher prevalences of both chronic pain and high-impact chronic pain reported among women, older adults, previously but not currently employed adults, adults living in poverty, adults with public health insurance, and rural residents. These findings could be used to target pain management interventions. NHIS is a cross-sectional, in-person, household health survey of the civilian noninstitutionalized U.S. population, conducted by the National Center for Health Statistics (NCHS).* Data from the 2016 Sample Adult Core for adults aged ≥18 years (33,028; response rate = 54.3%) † were analyzed. Information about pain was collected through responses to the following questions: “In the past six months, how often did you have pain? Would you say never, some days, most days, or every day?” and “Over the past six months, how often did pain limit your life or work activities? Would you say never, some days, most days, or every day?” Chronic pain was defined as pain on most days or every day in the past 6 months, as recommended by the International Association for the Study of Pain, § modified to account for intermittent pain, and used in both the National Pain Strategy and National Institutes of Health Task Force on Chronic Back Pain ( 6 ). As suggested in the National Pain Strategy, high-impact chronic pain was defined as chronic pain that limited life or work activities on most days or every day during the past 6 months ( 5 ). The prevalence of chronic pain and high-impact chronic pain (both crude and age-adjusted, with 95% confidence intervals) were estimated for the U.S. adult population overall and by various sociodemographic characteristics. These characteristics, collected with the Family Core questionnaire, included age, sex, race/ethnicity, education level, current employment status, ¶ poverty status (calculated using NHIS imputed income files),** veteran status, health insurance coverage type (reported separately for adults aged <65 and ≥65 years), and urbanicity. All prevalence estimates met NCHS reliability standards. †† Because pain prevalence varies by age, age-adjusted estimates were used in comparisons of chronic pain and high-impact chronic pain between subgroups. Based on two-tailed Z-tests, all reported differences between subgroups are statistically significant (unless otherwise noted; p<0.05). Analyses were conducted using statistical software that accounts for the stratification and clustering of households in the NHIS sampling design. Estimates incorporated the final sample adult weights adjusted for nonresponse and calibrated to population control totals to enable generalization to the civilian noninstitutionalized population aged ≥18 years. In 2016, an estimated 20.4% of U.S. adults (50.0 million) had chronic pain and 8.0% of U.S. adults (19.6 million) had high-impact chronic pain (Table), with higher prevalence associated with advancing age. Age-adjusted prevalences of both chronic pain and high-impact chronic pain were significantly higher among women, adults who had worked previously but were not currently employed, adults living in or near poverty, and rural residents. In addition, the age-adjusted prevalences of chronic pain and high-impact chronic pain were significantly lower among adults with at least a bachelor’s degree compared with all other education levels. TABLE Prevalence of chronic pain* and high impact chronic pain † among U.S. adults aged ≥18 years, by sociodemographic characteristics—National Health Interview Survey, 2016 Characteristic Chronic pain* High-impact chronic pain† Estimated no.§ Crude
% (95% CI) Age-adjusted¶
% (95% CI) Estimated no.§ Crude
% (95% CI) Age-adjusted¶
% (95% CI) Total 50,009,000 20.4 (19.7–21.0) 19.4 (18.7–20.0) 19,611,000 8.0 (7.6–8.4) 7.5 (7.1–7.9) Age group (yrs) 18–24 2,082,000 7.0 (5.8–8.5) —** 446,000 1.5 (0.9–2.3) —** 25–44 11,042,000 13.2 (12.3–14.1) —** 3,681,000 4.4 (3.9–5.0) —** 45–64 23,269,000 27.8 (26.6–29.0) —** 10,044,000 12.0 (11.2–12.9) —** 65–84 11,808,000 27.6 (26.4–29.0) —** 4,578,000 10.7 (9.9–11.6) —** ≥85 1,766,000 33.6 (30.1–37.3) —** 830,000 15.8 (13.2–18.9) —** Sex Male 21,989,000 18.6 (17.7–19.5) 17.8 (17.0–18.7) 8,276,000 7.0 (6.5–7.6) 6.7 (6.2–7.3) Female 28,049,000 22.1 (21.2–23.0) 20.8 (19.9–21.6) 11,296,000 8.9 (8.4–9.4) 8.2 (7.7–8.7) Race/Ethnicity Hispanic 5,856,000 15.1 (13.6–16.7) 16.7 (15.2–18.4) 2,754,000 7.1 (6.0–8.3) 7.9 (6.9–9.2) White, non-Hispanic 36,226,000 23.0 (22.2–23.8) 21.0 (20.3–21.8) 13,230,000 8.4 (7.9–8.9) 7.4 (7.0–7.9) Black, non-Hispanic 5,148,000 17.9 (16.4–19.6) 17.8 (16.3–19.4) 2,387,000 8.3 (7.2–9.4) 8.1 (7.1–9.2) Other, non-Hispanic†† 2,774,000 13.8 (12.1–15.7) 14.4 (12.7–16.3) 1,326,000 6.6 (5.3–8.1) 7.0 (5.7–8.5) Education Less than high school 7,809,000 26.1 (24.2–28.2) 23.7 (21.7–25.7) 4,069,000 13.6 (12.3–15.2) 12.1 (10.7–13.7) High school/GED 14,441,000 23.7 (22.5–25.0) 22.6 (21.2–23.9) 5,910,000 9.7 (9.0–10.6) 9.1 (8.4–10.0) Some college 17,129,000 22.6 (21.5–23.8) 22.9 (21.8–24.0) 6,518,000 8.6 (7.9–9.4) 8.7 (8.0–9.5) Bachelor's degree or higher 10,383,000 13.4 (12.6–14.3) 12.4 (11.7–13.3) 2,944,000 3.8 (3.4–4.3) 3.5 (3.1–4.0) Employment status Employed 22,085,000 14.7 (14.1–15.5) 14.5 (13.8–15.2) 5,108,000 3.4 (3.1–3.8) 3.2 (2.9–3.6) Not employed; worked previously 25,737,000 31.5 (30.3–32.7) 29.2 (27.8–30.6) 13,318,000 16.3 (15.4–17.2) 16.1 (15.0–17.3) Not employed; never worked 2,083,000 15.9 (13.8–18.2) 18.7 (16.1–21.6) 1,192,000 9.1 (7.6–10.9) 11.1 (9.1–13.4) Poverty status <100% FPL 8,017,000 25.8 (24.2–27.6) 29.6 (27.9–31.3) 4,630,000 14.9 (13.6–16.4) 17.5 (16.1–19.0) 100% ≤FPL<200% 11,357,000 26.2 (24.5–27.9) 25.9 (24.2–27.7) 5,375,000 12.4 (11.3–13.6) 12.3 (11.2–13.5) 200% ≤FPL<400% 14,181,000 20.3 (19.2–21.4) 19.3 (18.3–20.4) 5,100,000 7.3 (6.7–8.1) 6.9 (6.2–7.6) ≥400% FPL 16,441,000 16.3 (15.4–17.2) 14.6 (13.8–15.5) 4,438,000 4.4 (4.0–4.9) 3.9 (3.5–4.4) Veteran Yes 6,379,000 29.1 (27.1–31.2) 26.0 (23.5–28.7) 2,258,000 10.3 (9.1–11.8) 9.2 (7.7–11.1) No 43,519,000 19.5 (18.9–20.2) 19.0 (18.4–19.7) 17,407,000 7.8 (7.4–8.2) 7.5 (7.1–7.9) Health insurance coverage§§ Age <65 yrs Private 20,539,000 15.1 (14.3–15.8) 14.0 (13.3–14.8) 5,713,000 4.2 (3.8–4.7) 3.8 (3.4–4.2) Medicaid and other public coverage 8,215,000 29.3 (27.3–31.5) 30.0 (28.0–32.2) 4,822,000 17.2 (15.6–19.0) 17.8 (16.2–19.6) Other 3,860,000 43.5 (40.0–47.2) 34.8 (31.2–38.7) 2,263,000 25.5 (22.5–28.8) 19.3 (16.4–22.5) Uninsured 3,683,000 16.2 (14.4–18.2) 17.0 (15.2–19.0) 1,319,000 5.8 (4.7–7.2) 6.2 (5.0–7.6) Age ≥65 yrs Private 5,606,000 28.0 (26.3–29.9) 28.1 (26.3–30.0) 1,842,000 9.2 (8.1–10.5) 9.3 (8.2–10.6) Medicare and Medicaid 1,428,000 42.5 (37.6–47.5) 42.5 (37.6–47.5) 816,000 24.3 (20.4–28.6) 24.3 (20.4–28.6) Medicare Advantage 3,094,000 25.5 (23.1–28.1) 25.8 (23.4–28.4) 1,226,000 10.1 (8.5–11.8) 10.3 (8.7–12.1) Medicare only, excluding Medicare Advantage 2,115,000 25.9 (23.1–28.9) 25.9 (23.1–28.9) 939,000 11.5 (9.5–13.7) 11.5 (9.5–13.7) Other 1,229,000 31.6 (27.2–36.3) 31.8 (27.4–36.5) 545,000 14.0 (11.3–17.3) 14.3 (11.5–17.7) Uninsured 106,000 —¶¶ —¶¶ 59,000 —¶¶ —¶¶ Urbanicity*** Urban 38,401,000 19.0 (18.3–19.7) 18.4 (17.7–19.0) 14,754,000 7.3 (6.9–7.8) 7.0 (6.6–7.4) Rural 11,575,000 26.9 (25.4–28.5) 24.0 (22.5–25.6) 4,776,000 11.1 (10.2–12.2) 9.8 (8.8–10.9) Abbreviations: CI = confidence interval; FPL = federal poverty level; GED = General Educational Development certification. * Pain on most days or every day in the past 6 months. † Chronic pain limiting life or work activities on most days or every day in the past 6 months. § The estimated numbers, rounded to 1,000s, were annualized based on the 2016 data. Counts for adults of unknown status (responses coded as “refused,” “don’t know,” or “not ascertained”) with respect to chronic pain and high-impact chronic pain are not shown separately in the table, nor are they included in the calculation of percentages (as part of either the denominator or the numerator), to provide a more straightforward presentation of the data. ¶ Estimates are age-adjusted using the projected 2000 U.S. population as the standard population and five age groups: 18–29, 30–39, 40–49, 50–59, and ≥60 years. ** Not applicable. †† Non-Hispanic other includes non-Hispanic American Indian and Alaska Native only, non-Hispanic Asian only, non-Hispanic Native Hawaiian and Pacific Islander only, and non-Hispanic multiple race. §§ Based on a hierarchy of mutually exclusive categories. Adults reporting both private and Medicare Advantage coverage were assigned to the Medicare Advantage category. “Uninsured” includes adults who had no coverage as well as those who had only Indian Health Service coverage or had only a private plan that paid for one type of service such as accidents or dental care. “Other” comprises military health care including TRICARE, VA, and CHAMP-VA, and certain types of local and state governmental coverage, not including the Children’s Health Insurance Program. ¶¶ Estimates are considered unreliable according to the National Center for Health Statistics’ standards of reliability. *** Based on U.S. Census Bureau definitions of urban and rural areas (https://www2.census.gov/geo/pdfs/reference/ua/Defining_Rural.pdf). Whereas non-Hispanic white adults had a significantly higher age-adjusted prevalence of chronic pain than did all other racial and ethnic subgroups, no significant differences in high-impact chronic pain prevalence by race/ethnicity were observed. Similarly, the age-adjusted prevalence of chronic pain was significantly higher among veterans than among nonveterans, but no significant difference was observed in the prevalence of high-impact chronic pain. Among adults aged <65 years, the age-adjusted prevalences of chronic pain and high-impact chronic pain were higher among those with Medicaid and other public health care coverage or other insurance (e.g., Veteran’s Administration, certain local and state government) than among adults with private insurance or those who were uninsured. Among adults aged ≥65 years, those with both Medicare and Medicaid had higher age-adjusted prevalences of chronic pain and high-impact chronic pain than did adults with all other types of coverage. Discussion Pain is a component of many chronic conditions, and chronic pain is emerging as a health concern on its own, with negative consequences to individual persons, their families, and society as a whole ( 4 , 5 ). Healthy People 2020 (https://www.healthypeople.gov/), the nation’s science-based health objectives, has a developmental objective to “decrease the prevalence of adults having high-impact chronic pain.” This analysis extends previous national studies of chronic pain prevalence by identifying adults with high-impact chronic pain. In 2016, approximately 20% of U.S. adults had chronic pain (approximately 50 million), and 8% of U.S. adults (approximately 20 million) had high-impact chronic pain. This estimate of high-impact chronic pain is similar to or slightly lower than estimates reported in the few studies that have looked at pain using a similar construct. For example, a recent study that used a measure of high-impact chronic pain similar to the one used in this study reported an estimate of 13.7% among a sample of U.S. adult health plan enrollees ( 7 ). Similarly, a 2001 study of adults from a region in Scotland found that 14.1% of survey participants reported significant chronic pain, and 6.3% reported severe chronic pain, and a 2001 study of Australian adults reported that 11.0% of men and 13.5% of women reported chronic pain that interfered, to some degree, with daily life activities ( 3 , 8 ). The results of subgroup analyses in the current study were consistent with findings in these studies ( 3 , 8 ) insofar as the prevalence of high-impact chronic pain was higher among women, adults who had achieved lower levels of education, and those who were not employed at the time of the survey, and was lower among adults with private health insurance compared with public and other types of coverage. In addition, high-impact chronic pain was also found to be higher among adults living in poverty and among rural residents. Socioeconomic status appears to be a common factor in many of the subgroup differences in high-impact chronic pain prevalence reported here. Indicators of socioeconomic status such as education, poverty, and health insurance coverage have been determined to be associated with both general health status and the presence of specific health conditions ( 9 ) as well as with patients’ success in navigating the health care system ( 9 ). Identifying populations at risk is necessary to inform efforts for developing and targeting quality pain services. The findings in this report are subject to at least five limitations. First, data are self-reported and subject to recall bias. Second, data are cross-sectional, precluding drawing causal inferences. This might be particularly relevant for socioeconomic status, which can be both a risk factor for and a consequence of chronic pain or high-impact chronic pain, or both. Third, no information is available on treatment for chronic pain to assess the prevalence of chronic pain and high-impact chronic pain among those with and without treatment. Fourth, NHIS excludes important populations, such as active duty military and residents of long-term care facilities or prisons. And finally, NHIS does not collect data on chronic pain or high-impact chronic pain in children. Despite these limitations, three strengths of this study are that it used a large, nationally representative data source to produce estimates of chronic pain and high-impact chronic pain across many demographic subgroups, it used standard broad definitions of pain that were not limited to one or more specific health conditions (e.g., headache or arthritis), and it used the standard case definition for high-impact chronic pain proposed by the National Pain Strategy. Chronic pain contributes to an estimated $560 billion each year in direct medical costs, lost productivity, and disability programs ( 4 ). The National Pain Strategy, which is the first national effort to transform how the population burden of pain is perceived, assessed, and treated, recognizes the need for better data to inform action and calls for estimates of chronic pain and high-impact chronic pain in the general population ( 5 ). This report helps fulfill this objective and provides data to inform policymakers, clinicians, and researchers focused on pain care and prevention. Summary What is already known about this topic? Chronic pain has been linked to numerous physical and mental conditions and contributes to high health care costs and lost productivity. A limited number of studies estimate that the prevalence of chronic pain ranges from 11% to 40%. What is added by this report? In 2016, an estimated 20.4% of U.S. adults had chronic pain and 8.0% of U.S. adults had high-impact chronic pain. Both were more prevalent among adults living in poverty, adults with less than a high school education, and adults with public health insurance. What are the implications for public health practice? This report helps fulfill a National Pain Strategy objective of producing more precise estimates of chronic pain and high-impact chronic pain.
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              Current knowledge of buprenorphine and its unique pharmacological profile.

              Despite the increasing clinical use of transdermal buprenorphine, questions have persisted about the possibility of a ceiling effect for analgesia, its combination with other μ-opioid agonists, and the reversibility of side effects. In October 2008, a consensus group of experts met to review recent research into the pharmacology and clinical use of buprenorphine. The objective was to achieve consensus on the conclusions to be drawn from this work. It was agreed that buprenorphine clearly behaves as a full μ-opioid agonist for analgesia in clinical practice, with no ceiling effect, but that there is a ceiling effect for respiratory depression, reducing the likelihood of this potentially fatal adverse event. This is entirely consistent with receptor theory. In addition, the effects of buprenorphine can be completely reversed by naloxone. No problems are encountered when switching to and from buprenorphine and other opioids, or in combining them. Buprenorphine exhibits a pronounced antihyperalgesic effect that might indicate potential advantages in the treatment of neuropathic pain. Other beneficial properties are the compound's favorable safety profile, particularly in elderly patients and those with renal impairment, and its lack of effect on sex hormones and the immune system. The expert group agreed that these properties, as well as proven efficacy in severe pain and favorable tolerability, mean that buprenorphine can be considered a safe and effective option for treating chronic cancer and noncancer pain. © 2010 World Institute of Pain.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                jpr
                jpainres
                Journal of Pain Research
                Dove
                1178-7090
                24 May 2021
                2021
                : 14
                : 1359-1369
                Affiliations
                [1 ]Gold Coast Research, LLC , Plantation, FL, 33317, USA
                [2 ]Department of Clinical Pharmacy, West Virginia University School of Pharmacy , Morgantown, WV, 26505, USA
                [3 ]University of Arizona College of Pharmacy , Tucson, AZ, 85721, USA
                [4 ]Department of Pharmaceutical Sciences, Temple University School of Pharmacy , Philadelphia, PA, 19140, USA
                Author notes
                Correspondence: Robert B Raffa Email robert.raffa@gmail.com
                Article
                305146
                10.2147/JPR.S305146
                8163969
                © 2021 Hale et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

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                Figures: 0, Tables: 0, References: 88, Pages: 11
                Categories
                Review

                Anesthesiology & Pain management

                opioids, pain, analgesia, buprenorphine buccal film, buprenorphine

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