Ò
PAIN 155 (2014) 843–844
www.elsevier.com/locate/pain
Commentary
Will data destroy our faith in long-acting opioids? For those of us who trained in the 1980s, long-acting opioids were matter of faith. They just made sense, both pharmacologically and psychologically. Their pharmacological advantages included sustained blood levels of opioid, which took patients off the roller coaster of up-and-down blood levels produced by short-acting opioids. This was thought to provide more stable around-the-clock analgesia. Long-acting opioids produced slower increases and slower decreases in opioid blood levels, which was thought to reduce addiction risk. The psychological benefits of long-acting opioids were also widely touted. Pain psychology pioneer William Fordyce believed that time-contingent administration of longacting opioids protected patients against developing addiction or other opioid problems [7]. This was because time-contingent (on a schedule) administration of opioids did not reinforce pain behavior as did pain-contingent (‘‘PRN’’) administration of opioids. Patients on scheduled long-acting opioids were not preoccupied with monitoring their pain levels and then rescuing themselves with pain medication when the pain became severe. This all made sense to me. For years, I prescribed long-acting opioids and taught their advantages to my trainees. Most European guidelines for opioid treatment of chronic noncancer pain still recommend long-acting over short-acting opioids. American and Canadian guidelines do not include these recommendations. The empirical evidence for these recommendations is weak. Most studies comparing long-acting and short-acting opioids have found no difference in pain relief or adverse effects [11]. Many of these trials had significant flaws, so it is hard to infer that the few benefits of long-acting opioids that were found were due to their long-acting feature. Chou et al. [4] reviewed 16 randomized trials and 8 observational studies comparing long- and short-acting opioids. None of the randomized trials was rated as good quality, and the observational studies were generally of poorer quality than the trials. They concluded that there was insufficient evidence to determine whether long-acting opioids as a class are more effective or safer than short-acting opioids. The randomized trial of long-acting vs short-acting dihydrocodeine by Pedersen et al. published in this issue of PAINÒ is a welcome addition to this literature because it is a rigorous and careful study of the long-acting vs short-acting question [10]. The primary outcome of this trial was stability in pain intensity, measured as the difference between the highest and least pain intensity over 7 days. This difference was 2.71 in the group receiving long-acting opioids and 3.43 in the group receiving short-acting opioids. The difference favored the short-acting group, but it did not achieve statistical or clinical significance. Differences between the groups in maximum, minimum, and average pain also q
DOI of original article: http://dx.doi.org/10.1016/j.pain.2013.12.016
did not achieve statistical or clinical significance. Quality of life improved during the trial by a clinically significant 5 to 10 points on the SF-8 for both groups. None of the 8 scale scores or the 2 component scores were significantly different between the groups. There were also no significant differences in quality of sleep, depression, or episodes of breakthrough pain. This trial thus provides evidence that many of the purported benefits of long-acting opioids may not exist. This trial is not perfect and is not definitive on the issue of longacting vs short-acting opioids. The trial had a small sample size, although it was likely large enough to capture clinically significant effects. The group that received short-acting opioids had multiple characteristics that may have made them less responsive to opioid analgesia: younger age, higher body mass index, more years of pain, more years of opioid use, and a higher percentage of women. This higher percentage of women may have been associated with a higher prevalence of depression in the short-acting group because women are twice as likely to be depressed. The authors do not tell us baseline levels of depression in the 2 groups. This is important because depression has been associated with less opioid analgesia [8]. Furthermore, the trial examined dihydrocodeine, an unusual opioid more often used in cough syrup than in analgesic medications. A more informative comparison might have been made between sustained-release and immediate-release formulations of oxycodone or morphine. Other studies have produced evidence that adverse events are more frequent with long-acting rather than short-acting opioids. Contrary to the theory reviewed above, we found that long-term opioid recipients receiving time-contingent long-acting opioids had more opioid control concerns than those receiving pain contingent short-acting opioids [12]. A study of opioid-related deaths in Ontario showed that these deaths increased significantly after the introduction of long-acting oxycodone to the provincial drug formulary. Most of the deaths were deemed unintentional [5]. Use of long-acting opioids has been associated with increased risk of overdose in other studies as well [2]. This has led the US Food and Drug Administration (FDA) to issue a class-wide Risk Evaluation and Mitigation Strategy for long-acting and extended-release opioids. The FDA is now also requiring changes to the labels of all long-acting and extended-release opioids. These new labels will state that these medications are indicated only when a patient requires daily, around-the-clock, long-term opioid therapy. The new labels must also caution that there is a risk of addiction, abuse, misuse, overdose, and death with use of these medications, even at recommended doses [9]. Long-acting opioids have none of the dose limits that are typical of short-acting combination products. Prescribers often combine long-acting opioids with short-acting opioids to target breakthrough pain. Continuous exposure to
http://dx.doi.org/10.1016/j.pain.2014.01.032 0304-3959/$36.00 Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
844
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Commentary / PAIN 155 (2014) 843–844
opioids may promote more rapid development of opioid tolerance [1]. These features lead users of long-acting opioids to receive higher daily opioid doses, which is a known risk factor for opioid overdose [6]. Our faith in long-acting opioids is thus under assault from multiple directions. Claims of improved efficacy, safety, pain stability, sleep, and quality of life have not been supported by studies to date. Furthermore, many patients prefer short-acting opioids because these opioids allow them to target, control, and limit their opioid use. They report an increased sense of control with paincontingent use of short-acting opioids. This pain-contingent use of short-acting opioids may result in intermittent rather than continuous exposure of the patient to opioids. It is possible that intermittent rather than continuous use of opioids may protect against opioid tolerance, hyperalgesia, and hypogonadism [3]. Additional studies are needed to explore and confirm these findings. However, we should expect further challenges to our faith in long-acting opioids. Conflict of interest statement The author has received a grant from the REMS Program Committees to provide continuing medical education concerning safe prescribing of extended-release and long-acting opioids (ie, the Web-based COPE-REMS program) in accord with the FDA REMS on ER/LA opioids. References [1] Ballantyne JC, Shin NS. Efficacy of opioids for chronic pain: a review of the evidence. Clin J Pain 2008;24:469–78. [2] Braden JB, Russo J, Fan MY, Edlund MJ, Martin BC, DeVries A, Sullivan MD. Emergency department visits among recipients of chronic opioid therapy. Arch Intern Med 2010;170:1425–32.
[3] Brennan MJ. The effect of opioid therapy on endocrine function. Am J Med 2013;126:S12–8. [4] Chou R, Clark E, Helfand M. Comparative efficacy and safety of long-acting oral opioids for chronic non-cancer pain: a systematic review. J Pain Symptom Manage 2003;26:1026–48. [5] Dhalla IA, Mamdani MM, Sivilotti ML, Kopp A, Qureshi O, Juurlink DN. Prescribing of opioid analgesics and related mortality before and after the introduction of long-acting oxycodone. CMAJ 2009;181:891–6. [6] Dunn KM, Saunders KW, Rutter CM, Banta-Green CJ, Merrill JO, Sullivan MD, Weisner CM, Silverberg MJ, Campbell CI, Psaty BM, Von Korff M. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med 2010;152:85–92. [7] Fordyce W. Behavioral methods for chronic pain and illness. St. Louis, MO: Mosby Year Book; 1976. [8] Jamison RN, Edwards RR, Liu X, Ross EL, Michna E, Warnick M, Wasan AD. Relationship of negative affect and outcome of an opioid therapy trial among low back pain patients. Pain Pract 2013;13:173–81. [9] Kuehn BM. FDA tightens indications for using long-acting and extendedrelease opioids to treat chronic pain. JAMA 2013;310:1547–8. [10] Pedersen L, Borchgrevink PC, Breivik HP, Søndenå Fredheim OM. A randomized, double-blind, double-dummy comparison of short- and longacting dihydrocodeine in chronic non-malignant pain. PAINÒ 2014;155:881–8. [11] Rauck RL. What is the case for prescribing long-acting opioids over shortacting opioids for patients with chronic pain? A critical review. Pain Pract 2009;9:468–79. [12] Von Korff M, Merrill J, Rutter C, Sullivan M, Campbell C, Weisner C. Timescheduled versus pain-contingent opioid dosing in chronic opioid therapy. PAINÒ 2011;152:1256–62.
Mark Sullivan Department of Psychiatry and Behavioral Sciences, University of Washington, Box 356560, Seattle, WA 98195, USA Tel.: +1 206 685 3184. E-mail address: [email protected]
PAIN 155 (2014) 843–844
www.elsevier.com/locate/pain
Commentary
Will data destroy our faith in long-acting opioids? For those of us who trained in the 1980s, long-acting opioids were matter of faith. They just made sense, both pharmacologically and psychologically. Their pharmacological advantages included sustained blood levels of opioid, which took patients off the roller coaster of up-and-down blood levels produced by short-acting opioids. This was thought to provide more stable around-the-clock analgesia. Long-acting opioids produced slower increases and slower decreases in opioid blood levels, which was thought to reduce addiction risk. The psychological benefits of long-acting opioids were also widely touted. Pain psychology pioneer William Fordyce believed that time-contingent administration of longacting opioids protected patients against developing addiction or other opioid problems [7]. This was because time-contingent (on a schedule) administration of opioids did not reinforce pain behavior as did pain-contingent (‘‘PRN’’) administration of opioids. Patients on scheduled long-acting opioids were not preoccupied with monitoring their pain levels and then rescuing themselves with pain medication when the pain became severe. This all made sense to me. For years, I prescribed long-acting opioids and taught their advantages to my trainees. Most European guidelines for opioid treatment of chronic noncancer pain still recommend long-acting over short-acting opioids. American and Canadian guidelines do not include these recommendations. The empirical evidence for these recommendations is weak. Most studies comparing long-acting and short-acting opioids have found no difference in pain relief or adverse effects [11]. Many of these trials had significant flaws, so it is hard to infer that the few benefits of long-acting opioids that were found were due to their long-acting feature. Chou et al. [4] reviewed 16 randomized trials and 8 observational studies comparing long- and short-acting opioids. None of the randomized trials was rated as good quality, and the observational studies were generally of poorer quality than the trials. They concluded that there was insufficient evidence to determine whether long-acting opioids as a class are more effective or safer than short-acting opioids. The randomized trial of long-acting vs short-acting dihydrocodeine by Pedersen et al. published in this issue of PAINÒ is a welcome addition to this literature because it is a rigorous and careful study of the long-acting vs short-acting question [10]. The primary outcome of this trial was stability in pain intensity, measured as the difference between the highest and least pain intensity over 7 days. This difference was 2.71 in the group receiving long-acting opioids and 3.43 in the group receiving short-acting opioids. The difference favored the short-acting group, but it did not achieve statistical or clinical significance. Differences between the groups in maximum, minimum, and average pain also q
DOI of original article: http://dx.doi.org/10.1016/j.pain.2013.12.016
did not achieve statistical or clinical significance. Quality of life improved during the trial by a clinically significant 5 to 10 points on the SF-8 for both groups. None of the 8 scale scores or the 2 component scores were significantly different between the groups. There were also no significant differences in quality of sleep, depression, or episodes of breakthrough pain. This trial thus provides evidence that many of the purported benefits of long-acting opioids may not exist. This trial is not perfect and is not definitive on the issue of longacting vs short-acting opioids. The trial had a small sample size, although it was likely large enough to capture clinically significant effects. The group that received short-acting opioids had multiple characteristics that may have made them less responsive to opioid analgesia: younger age, higher body mass index, more years of pain, more years of opioid use, and a higher percentage of women. This higher percentage of women may have been associated with a higher prevalence of depression in the short-acting group because women are twice as likely to be depressed. The authors do not tell us baseline levels of depression in the 2 groups. This is important because depression has been associated with less opioid analgesia [8]. Furthermore, the trial examined dihydrocodeine, an unusual opioid more often used in cough syrup than in analgesic medications. A more informative comparison might have been made between sustained-release and immediate-release formulations of oxycodone or morphine. Other studies have produced evidence that adverse events are more frequent with long-acting rather than short-acting opioids. Contrary to the theory reviewed above, we found that long-term opioid recipients receiving time-contingent long-acting opioids had more opioid control concerns than those receiving pain contingent short-acting opioids [12]. A study of opioid-related deaths in Ontario showed that these deaths increased significantly after the introduction of long-acting oxycodone to the provincial drug formulary. Most of the deaths were deemed unintentional [5]. Use of long-acting opioids has been associated with increased risk of overdose in other studies as well [2]. This has led the US Food and Drug Administration (FDA) to issue a class-wide Risk Evaluation and Mitigation Strategy for long-acting and extended-release opioids. The FDA is now also requiring changes to the labels of all long-acting and extended-release opioids. These new labels will state that these medications are indicated only when a patient requires daily, around-the-clock, long-term opioid therapy. The new labels must also caution that there is a risk of addiction, abuse, misuse, overdose, and death with use of these medications, even at recommended doses [9]. Long-acting opioids have none of the dose limits that are typical of short-acting combination products. Prescribers often combine long-acting opioids with short-acting opioids to target breakthrough pain. Continuous exposure to
http://dx.doi.org/10.1016/j.pain.2014.01.032 0304-3959/$36.00 Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
844
Ò
Commentary / PAIN 155 (2014) 843–844
opioids may promote more rapid development of opioid tolerance [1]. These features lead users of long-acting opioids to receive higher daily opioid doses, which is a known risk factor for opioid overdose [6]. Our faith in long-acting opioids is thus under assault from multiple directions. Claims of improved efficacy, safety, pain stability, sleep, and quality of life have not been supported by studies to date. Furthermore, many patients prefer short-acting opioids because these opioids allow them to target, control, and limit their opioid use. They report an increased sense of control with paincontingent use of short-acting opioids. This pain-contingent use of short-acting opioids may result in intermittent rather than continuous exposure of the patient to opioids. It is possible that intermittent rather than continuous use of opioids may protect against opioid tolerance, hyperalgesia, and hypogonadism [3]. Additional studies are needed to explore and confirm these findings. However, we should expect further challenges to our faith in long-acting opioids. Conflict of interest statement The author has received a grant from the REMS Program Committees to provide continuing medical education concerning safe prescribing of extended-release and long-acting opioids (ie, the Web-based COPE-REMS program) in accord with the FDA REMS on ER/LA opioids. References [1] Ballantyne JC, Shin NS. Efficacy of opioids for chronic pain: a review of the evidence. Clin J Pain 2008;24:469–78. [2] Braden JB, Russo J, Fan MY, Edlund MJ, Martin BC, DeVries A, Sullivan MD. Emergency department visits among recipients of chronic opioid therapy. Arch Intern Med 2010;170:1425–32.
[3] Brennan MJ. The effect of opioid therapy on endocrine function. Am J Med 2013;126:S12–8. [4] Chou R, Clark E, Helfand M. Comparative efficacy and safety of long-acting oral opioids for chronic non-cancer pain: a systematic review. J Pain Symptom Manage 2003;26:1026–48. [5] Dhalla IA, Mamdani MM, Sivilotti ML, Kopp A, Qureshi O, Juurlink DN. Prescribing of opioid analgesics and related mortality before and after the introduction of long-acting oxycodone. CMAJ 2009;181:891–6. [6] Dunn KM, Saunders KW, Rutter CM, Banta-Green CJ, Merrill JO, Sullivan MD, Weisner CM, Silverberg MJ, Campbell CI, Psaty BM, Von Korff M. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med 2010;152:85–92. [7] Fordyce W. Behavioral methods for chronic pain and illness. St. Louis, MO: Mosby Year Book; 1976. [8] Jamison RN, Edwards RR, Liu X, Ross EL, Michna E, Warnick M, Wasan AD. Relationship of negative affect and outcome of an opioid therapy trial among low back pain patients. Pain Pract 2013;13:173–81. [9] Kuehn BM. FDA tightens indications for using long-acting and extendedrelease opioids to treat chronic pain. JAMA 2013;310:1547–8. [10] Pedersen L, Borchgrevink PC, Breivik HP, Søndenå Fredheim OM. A randomized, double-blind, double-dummy comparison of short- and longacting dihydrocodeine in chronic non-malignant pain. PAINÒ 2014;155:881–8. [11] Rauck RL. What is the case for prescribing long-acting opioids over shortacting opioids for patients with chronic pain? A critical review. Pain Pract 2009;9:468–79. [12] Von Korff M, Merrill J, Rutter C, Sullivan M, Campbell C, Weisner C. Timescheduled versus pain-contingent opioid dosing in chronic opioid therapy. PAINÒ 2011;152:1256–62.
Mark Sullivan Department of Psychiatry and Behavioral Sciences, University of Washington, Box 356560, Seattle, WA 98195, USA Tel.: +1 206 685 3184. E-mail address: [email protected]
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