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Eight principles for safer opioid prescribing and cautions with benzodiazepines a
b
Lynn R. Webster , Gary M. Reisfield & Nabarun Dasgupta
c
a 1
PRA Health Sciences, Salt Lake City, UT
b 2
Pain Management Services, Division of Addiction Medicine, Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL c 3
Injury Prevention Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Published online: 28 May 2015.
Click for updates To cite this article: Lynn R. Webster, Gary M. Reisfield & Nabarun Dasgupta (2015) Eight principles for safer opioid prescribing and cautions with benzodiazepines, Postgraduate Medicine, 127:1, 27-32 To link to this article: http://dx.doi.org/10.1080/00325481.2015.993276
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http://informahealthcare.com/pgm ISSN: 0032-5481 (print), 1941-9260 (electronic) Postgrad Med, 2015; 127(1): 27– 2015 Informa UK, Ltd. DOI: 10.1080/00325481.2015.993276
ORIGINAL RESEARCH
Eight principles for safer opioid prescribing and cautions with benzodiazepines Lynn R. Webster1, Gary M. Reisfield2 & Nabarun Dasgupta3 PRA Health Sciences, Salt Lake City, UT, 2Pain Management Services, Division of Addiction Medicine, Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL, and 3Injury Prevention Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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1
Abstract
Keywords:
The provision of long-term opioid analgesic therapy for chronic pain requires a careful risk/ benefit analysis followed by clinical safety measures to identify and reduce misuse, abuse, and addiction and their associated morbidity and mortality. Multiple data sources show that benzodiazepines, prescribed for comorbid insomnia, anxiety, and mood disorders, heighten the risk of respiratory depression and other adverse outcomes when combined with opioid therapy. Evidence is presented for hazards associated with coadministration of opioids and benzodiazepines and the need for caution when initiating opioid therapy for chronic pain. Clinical recommendations follow, as drawn from 2 previously published literature reviews, one of which proffers 8 principles for safer opioid prescribing; the other review presents risks associated with benzodiazepines, suggests alternatives for co-prescribing benzodiazepines and opioids, and outlines recommendations regarding co-prescribing if alternative therapies are ineffective.
opioid analgesics, benzodiazepines, chronic pain, mortality, drug overdose, therapeutic use
Introduction Opioid-related poisoning deaths have escalated in the United States, with data indicating that the majority involve the administration of additional substances that also depress the central nervous system, leading to respiratory depression [1]. Medications indicated for the treatment of psychiatric illnesses (eg, benzodiazepines, antidepressants, and antipsychotics) are often found postmortem in opioid-related overdose deaths; benzodiazepines are cited more than any other pharmaceutical in opioid-related deaths and are second only to opioids in their contribution to prescription-related deaths overall, as reported by the Centers for Disease Control and Prevention [1]. Of 22 134 prescription-related deaths in 2010, 16 651 (75%) involved opioids and 6497 (29%) involved benzodiazepines. This article presents clinical recommendations for clinicians who prescribe opioids or benzodiazepines in the course of treating chronic pain. Drawn from prior literature reviews, the evidence presented here elucidates patient risk factors, available alternatives, and steps to manage patients who present with pain conditions that require long-term opioid therapy. An ongoing question for researchers has been why clinical trials of opioids show safety with high doses of opioids, whereas epidemiological studies show increased risk for unintentional overdose at high doses. To address this issue, a prospective cohort study of North Carolina residents was Correspondence: Lynn R. Webster, MD, Vice President of Scientific Affairs, PRA International, 3838 South, 700 East, Suite 202, Salt Lake City, UT 84106, USA. Tel: +1 801 892 5140. E-mail: [email protected]
History Received 16 June 2014 Revised 17 July 2014 Accepted 3 September 2014 Published online 15 December 2014
conducted to examine dose-dependent overdose risk through matching dispensing data with medical examiner records of overdose deaths [2]. Using estimates obtained via regression models, a dose-dependent effect was found, with an overdose death rate 10 times higher among high-dose opioid recipients (defined as ‡ 200 mg/d of oral morphine equivalents) who were also receiving benzodiazepines [2]. [The dosage was derived from a cohort study of all North Carolina residents (N = 9 560 234) in 2010, using data from an electronic controlled substances prescription monitoring program that were then correlated with data from a separate study of overdose mortality conducted by the Division of Public Health]. Another finding was that 80% of patients prescribed highdose opioids were co-prescribed benzodiazepines (Figure 1), comprising a very different prescribing pattern than is observed in clinical trials. These trials routinely exclude subjects who use opioids in combination with other central nervous system depressants, presumably to avoid added toxicity. Benzodiazepine exposure was determined by receipt of ‡ 1 prescription for a benzodiazepine in 365 days prior to death or to the end of the study versus those who had no record of such a prescription. The reference group for incidence rate ratios is > 0 to 19.9 mg/day of average daily milligrams of morphine equivalents. The gray lines on the figure are the bounds of the 95% confidence interval. Incidence rate ratios and confidence intervals were estimated using Poisson regression, with person-days of exposure accrued in an intent-to-treat-type manner. The vertical axis is plotted on the log 10 scale. Average daily milligrams of morphine equivalents are plotted at the midpoint of each category range; the last point includes 500 through 5000 mg/day.
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Incidence rate per 10,000 person-years
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Received benzodiazepine (s) No benzodiazepine (s)
80 70 60 50 40 30 20 10 0 0
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Average daily milligrams of morphine equivalents
Figure 1. Incidence rate ratios for overdose deaths involving opioid analgesics, by average milligrams of morphine equivalents and benzodiazepine prescription status, North Carolina Residents, 2010. Reprinted from Dasgupta [2], with permission.
Therefore, although it is difficult to discern from death investigations what proportion of decedents obtained medications via legitimate prescriptions, it is certain that benzodiazepines are frequently co-prescribed with opioids in patients with chronic noncancer pain—between 20% and 50% of patients by some estimates [3–7]. Furthermore, patients treated with opioids are more likely to receive benzodiazepines than are patients treated with other modalities for chronic pain [8], and the combination appears more common in patients with substance-use disorders [9]. A newer concern has emerged with evidence that the practice of benzodiazepine co-prescribing with opioids is increasing. Scientists at Stanford Hospital and Clinics in Palo Alto, CA, reviewed a national database of 3.1 billion primary care visits between 2002 and 2009 and found an annual increase of 12% in opioid and benzodiazepine co-prescribing [10]. Another concern involves prescribing in older adults. Benzodiazepines have been associated with falls and fractures in this population, both alone and in combination with opioids [11,12]. In addition to these prescribing patterns, benzodiazepines are favored by nonmedical users (ie, persons without a legitimate prescription or who otherwise demonstrate signs of illegal diversion), with or without opioids [13]. Emergency department visits involving nonmedical use of the benzodiazepine alprazolam doubled from 57 419 to 124 902 during the years 2005 to 2010 [14]. More people who enter substance-abuse treatment report abusing both benzodiazepines and opioids, with treatment episodes for the combination having increased 570%, from approximately 5000 admissions in 2000 to more than 33 000 admissions in 2010 [15]. According to the Drug Abuse Warning Network, from 2004 to 2008, benzodiazepines were involved in 26% of opioid-related visits to hospital emergency departments [16]. It is evident that opioid and benzodiazepine prescribing and misuse are closely linked.
Furthermore, a prescribing error by medical providers is one of many factors determined by expert consensus to be related to opioid deaths [17], suggesting a need for wide dissemination of best clinical practices to reduce adverse outcomes. Several clinical guidelines have been published to inform opioid prescribing for chronic pain; a systematic review gave high grades to a joint publication issued by the American Pain Society and American Academy of Pain Medicine and another by the Canadian National Opioid Use Guideline Group [18]. Though specifics differ among published clinical recommendations, a common core is to introduce opioids at the lowest rational dose, titrate slowly and carefully, and monitor individual patient response, taking care to avoid drug–drug interactions and being alert to comorbid medical and psychiatric illnesses, including sleep apnea, cardiopulmonary disease, existing or emerging substance-use disorders, and major depression, among other considerations. The aforementioned publications agree that additional research is necessary to ascertain the risk factors when prescribing opioids for chronic pain. Clinical information is lacking in some guidelines on managing chronic pain that coexists with insomnia, anxiety, and mood disorders for which benzodiazepines are frequently prescribed. It should be noted that interdisciplinary programs encompassing behavioral, pharmacological, rehabilitative, and other components provide the best evidence for the treatment of chronic pain, but little coverage for and access to these programs exists in the United States, a situation that is worsening [19,20].
Materials and methods Two articles and their references were summarized to develop clinical recommendations to reduce opioid-related overdose morbidity and mortality, and to heighten awareness of cautions when co-prescribing benzodiazepines [21,22]. The articles were recently published in Pain Medicine and were created via a literature search for prominent risk factors
DOI: 10.1080/00325481.2015.993276
Eight opioid principles and benzodiazepines
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Table I. Eight principles for safer opioid prescribing [21]. 1. 2. 3. 4. 5. 6. 7. 8.
Assess patients for risk of nonmedical use or medical misuse before starting opioid therapy and manage accordingly Watch for and treat comorbid mental disease when it occurs Conventional conversion may cause harm when rotating (switching) from one opioid to another Avoid combining benzodiazepines with opioids, especially during sleep hours Use methadone as a secondary or tertiary agent, starting with a low dose and titrating very slowly Assess for sleep apnea in patients on high daily doses of methadone or other opioids and in patients with a predisposition Counsel patients on long-term opioid therapy to reduce opioid dose during upper respiratory infections or asthmatic episodes Avoid prescribing long-acting opioid formulations for acute, postoperative, or trauma-related pain
and best practices for the prescribing of opioids and the co-prescribing of opioids and benzodiazepines for chronic pain and associated mood, anxiety, and sleep disorders. The 8 principles [21] have the endorsement of the board of directors of the American Academy of Pain Medicine and appeared previously on the website of the former LifeSource Foundation [23]; in addition, a version was presented as part of a physician education program performed in Utah [24].
the equivalent dose when switching from one opioid to another to enhance or restore analgesia or to lessen side effects [37,38]. A recently published paradigm suggests slowly decreasing the current opioid while slowly titrating the new opioid to effect [39], a process that takes time but provides added safety. Expert consultation should be sought by practitioners who are unfamiliar with rotating opioids.
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Benzodiazepines add risk with opioids, especially for sleep
The eight principles The following 8 prescribing principles (Table I) were established to reduce adverse outcomes associated with long-term opioid therapy prescribed for chronic pain: Assessment for risk of misuse Risk management includes assessing patients for risk of developing opioid-related problems before beginning opioid therapy. Assessment tools are designed to stratify risk by measuring biological, social, and psychiatric risk factors [25–27] associated with misusing prescribed opioids [28–30]. Patients are managed according to risk category (ie, high, moderate, and low), with the understanding that moderate- to high-risk patients require more stringent monitoring measures and that patients may move between risk categories over time. Other tools may assist in the periodic reassessment and documentation that accompany prescribing of opioid therapy, including effects on analgesia, daily activities, adverse effects, aberrant drug-related behaviors, cognition, and quality of life [31,32]. Safe opioid prescribing depends on utilizing available tools such as state prescription monitoring databases and urine drug tests [33], monitoring progress toward therapeutic goals, and counseling patients to use, store, and dispose of medications safely. The importance of managing comorbid mental disease Mood and anxiety disorders often co-occur with chronic pain, and the use and misuse of benzodiazepines may heighten the risk of opioid overdose [1,34–36]. The presence of psychiatric disorders should be ascertained before initiating opioid therapy, and if no reasonable alternative to opioid therapy is possible, care should be coordinated with mental health practitioners on an ongoing basis as necessary. Possible harm when rotating (switching) opioids Dosing should be patient specific, and equianalgesic conversion tables, by themselves, are not sufficient to determine
As previously discussed, benzodiazepines interact pharmacodynamically with opioids to suppress breathing [14,40,41]. Alternatives for insomnia include melatonin, cognitivebehavioral therapy for insomnia, improved sleep hygiene, and medications such as trazodone, an anticonvulsant, or a low dose of a tricyclic antidepressant, which may be beneficial, especially when the pain is neuropathic in origin. Older patients should be managed cautiously and should be monitored for anticholinergic side effects. Options to treat anxiety disorders include cognitive-behavioral therapy, atypical antipsychotics, anticonvulsants, some antidepressants, exercise, and stress management. Alternative medications to benzodiazepines should be subject to a risk/benefit analysis, and potential side effects should be discussed with the patient. Initiating methadone (as a secondary or tertiary agent), with a low dose and slow titration A particular difficulty with methadone derives from a half-life (typically 8 to 59 hours and up to 130 hours) that outlasts its analgesic effect (4 to 8 hours) [42,43]. Because accumulation of methadone is unpredictable, a low dose is advised for initiating treatment: £ 15 mg per day in divided doses (q8h) [44]; dose increases should be done in increments no greater than 25% to 50%, and no more frequently than weekly. This holds true whether or not a patient is opioid naive. This recommendation is more conservative than that in guidelines available elsewhere. When in doubt, always consult with an experienced methadone prescriber first. Sleep apnea with high-dose methadone or other opioids or with a predisposition Sleep apnea and long-term opioid therapy are linked, and the data suggest a potentially dangerous relationship, especially at higher opioid doses [40,45]. Sleep evaluation is recommended at doses > 50 mg/day of methadone or > 150 mg/ day morphine equivalents of other opioids. All patients with a predisposition or risk factors should be assessed for sleep
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Table II. Clinical recommendations regarding combination opioid and benzodiazepine therapy in patients with chronic pain [22]. Near-absolute contraindications Strong relative contraindications
New use or nonpsychiatric prescription of benzodiazepines
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If coadministration adjudged clinically necessary
Active misuse, abuse, or addiction to benzodiazepines, opioids, alcohol, and/or other central nervous system depressants History of any substance use disorder (poor or recent recovery indicates stronger contraindication) involving benzodiazepines, opioids, alcohol, or other central nervous system depressants Unstable mood, anxiety, or thought disorders Personality disorders, particularly “Cluster B” disorders (ie, antisocial personality disorder, characterized by failure to conform to social norms, deceitfulness, impulsivity, reckless disregard for the safety of self or others, and consistent irresponsibility; and borderline personality disorder, characterized by impulsivity, recurrent suicidal behavior, gestures, or threats, and affective instability) Certain medical comorbidities (ie, obesity, sleep-disordered breathing, chronic obstructive pulmonary disease, and hepatic or renal dysfunction) Older adults and others at elevated fall risk Strongly consider psychiatric consultation Examine risks of coadministration specific to patient Consider benzodiazepine alternatives Use each drug class at lowest effective dose Use each drug for shortest effective period Coordinate care between prescribing physician and psychiatrist (imperative) Absent compelling rationale, opioid should NOT be methadone Counsel patients to risks of the combination, obtain informed consent
apnea, and at-risk patients may need inpatient evaluation of the safety of opioid therapy. Danger with upper respiratory infections or asthmatic episodes Patients experiencing events with acute respiratory tract compromise (eg, flu, pneumonia, upper respiratory infections, cigarette use, chronic obstructive pulmonary disease) should be counseled to reduce their daily opioid doses, particularly their evening doses, by ‡ 30% [46]. Long-acting opioids not for acute, postoperative, or trauma-related pain Long-acting opioids, including transdermal patches [47], are for patients who have developed tolerance to opioids and in whom intermediate- or long-term opioid treatment is anticipated. Tolerant patients are those who take regular, daily, around-the-clock opioids [47].
Indications and recommendations regarding benzodiazepines In view of the evidence that benzodiazepines are frequently prescribed together with opioids, it would be well to summarize some effectiveness findings regarding this class of medications. Benzodiazepines show effectiveness when used short term for anxiety disorders (eg, panic disorder, generalized anxiety disorder), but evidence for long-term effectiveness is mostly empirical [48]. Some effectiveness is demonstrated early in depressive disorders, but long-term effectiveness has not been shown. In major depressive disorder, treatment guidelines recommend reserving benzodiazepines for patients with pronounced anxiety or insomnia that is inadequately controlled with selective serotonin reuptake inhibitors or serotonin-norepinephrine uptake inhibitors. Patients
who took benzodiazepines for insomnia and who also suffered from chronic pain saw no benefit from benzodiazepines in an older study [3]. In light of the potential for adverse outcomes with the co-prescribing of opioids and benzodiazepines, there are considerations and contraindications that can guide clinical decision making, including cautions for new or nonpsychiatric uses of benzodiazepines and for clinically necessary coadministration (Table II). The fourth of the 8 principles cited above suggests alternatives to benzodiazepines for sleep or co-occurring anxiety disorders. Table II further describes safety measures if alternatives to benzodiazepines are not possible. It is important to assess each patient individually and to seek expert consultation in pain, psychiatry, substance abuse, or other relevant fields when necessary to coordinate goals of therapy, specific pharmacologic agents, dosage levels, and adjustments; to gauge response to therapy; and to monitor adverse effects, including the misuse and abuse of, or addiction to, either drug.
Conclusion Opioid- and benzodiazepine-related morbidity and mortality present a serious public health problem and therapeutic challenge that could be reduced if prescribers recognize risk factors and follow literature-based recommendations. Particular caution is necessary when pain is complicated by comorbid medical or psychiatric illness or when clinical presentation suggests possible aberrant use of either or both classes of medications. More research is necessary to evaluate long-term opioids for safety and effectiveness, including their effects on hormonal and immune systems and their risks for abuse, misuse, addiction, and associated adverse outcomes. Benzodiazepine contributions to opioid-related deaths must be appreciated, and their co-prescribing requires proper patient selection, judicious dosing, and risk-appropriate monitoring.
Eight opioid principles and benzodiazepines
DOI: 10.1080/00325481.2015.993276
Acknowledgments
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Special thanks to Nabarun Dasgupta, PhD, for providing portions of his dissertation, which was approved by the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Epidemiology. Beth Dove of Dove Medical Communications, LLC, Salt Lake City, Utah, provided technical writing and editorial assistance for this manuscript. Declaration of interest: Lynn R. Webster has disclosed a relevant financial relationship with Acura Pharmaceuticals, AstraZeneca, BioDelivery Sciences International, BristolMyers Squibb, CVS Caremark, Depomed, Egalet, Grunenthal USA, Inspirion Pharmaceuticals, Insys Therapeutics, Jazz Pharmaceuticals, Kaleo, Mallinckrodt Pharmaceuticals, Nektar Therapeutics, Nevro Corporation, Orexo Pharmaceuticals, Signature Therapeutics, Synchrony Healthcare, Teva Pharmaceuticals and Travena. Gary M. Reisfield and Nabarun Dasgupta have no conflicts of interest to declare.
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Postgraduate Medicine Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ipgm20
Eight principles for safer opioid prescribing and cautions with benzodiazepines a
b
Lynn R. Webster , Gary M. Reisfield & Nabarun Dasgupta
c
a 1
PRA Health Sciences, Salt Lake City, UT
b 2
Pain Management Services, Division of Addiction Medicine, Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL c 3
Injury Prevention Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Published online: 28 May 2015.
Click for updates To cite this article: Lynn R. Webster, Gary M. Reisfield & Nabarun Dasgupta (2015) Eight principles for safer opioid prescribing and cautions with benzodiazepines, Postgraduate Medicine, 127:1, 27-32 To link to this article: http://dx.doi.org/10.1080/00325481.2015.993276
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
http://informahealthcare.com/pgm ISSN: 0032-5481 (print), 1941-9260 (electronic) Postgrad Med, 2015; 127(1): 27– 2015 Informa UK, Ltd. DOI: 10.1080/00325481.2015.993276
ORIGINAL RESEARCH
Eight principles for safer opioid prescribing and cautions with benzodiazepines Lynn R. Webster1, Gary M. Reisfield2 & Nabarun Dasgupta3 PRA Health Sciences, Salt Lake City, UT, 2Pain Management Services, Division of Addiction Medicine, Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL, and 3Injury Prevention Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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1
Abstract
Keywords:
The provision of long-term opioid analgesic therapy for chronic pain requires a careful risk/ benefit analysis followed by clinical safety measures to identify and reduce misuse, abuse, and addiction and their associated morbidity and mortality. Multiple data sources show that benzodiazepines, prescribed for comorbid insomnia, anxiety, and mood disorders, heighten the risk of respiratory depression and other adverse outcomes when combined with opioid therapy. Evidence is presented for hazards associated with coadministration of opioids and benzodiazepines and the need for caution when initiating opioid therapy for chronic pain. Clinical recommendations follow, as drawn from 2 previously published literature reviews, one of which proffers 8 principles for safer opioid prescribing; the other review presents risks associated with benzodiazepines, suggests alternatives for co-prescribing benzodiazepines and opioids, and outlines recommendations regarding co-prescribing if alternative therapies are ineffective.
opioid analgesics, benzodiazepines, chronic pain, mortality, drug overdose, therapeutic use
Introduction Opioid-related poisoning deaths have escalated in the United States, with data indicating that the majority involve the administration of additional substances that also depress the central nervous system, leading to respiratory depression [1]. Medications indicated for the treatment of psychiatric illnesses (eg, benzodiazepines, antidepressants, and antipsychotics) are often found postmortem in opioid-related overdose deaths; benzodiazepines are cited more than any other pharmaceutical in opioid-related deaths and are second only to opioids in their contribution to prescription-related deaths overall, as reported by the Centers for Disease Control and Prevention [1]. Of 22 134 prescription-related deaths in 2010, 16 651 (75%) involved opioids and 6497 (29%) involved benzodiazepines. This article presents clinical recommendations for clinicians who prescribe opioids or benzodiazepines in the course of treating chronic pain. Drawn from prior literature reviews, the evidence presented here elucidates patient risk factors, available alternatives, and steps to manage patients who present with pain conditions that require long-term opioid therapy. An ongoing question for researchers has been why clinical trials of opioids show safety with high doses of opioids, whereas epidemiological studies show increased risk for unintentional overdose at high doses. To address this issue, a prospective cohort study of North Carolina residents was Correspondence: Lynn R. Webster, MD, Vice President of Scientific Affairs, PRA International, 3838 South, 700 East, Suite 202, Salt Lake City, UT 84106, USA. Tel: +1 801 892 5140. E-mail: [email protected]
History Received 16 June 2014 Revised 17 July 2014 Accepted 3 September 2014 Published online 15 December 2014
conducted to examine dose-dependent overdose risk through matching dispensing data with medical examiner records of overdose deaths [2]. Using estimates obtained via regression models, a dose-dependent effect was found, with an overdose death rate 10 times higher among high-dose opioid recipients (defined as ‡ 200 mg/d of oral morphine equivalents) who were also receiving benzodiazepines [2]. [The dosage was derived from a cohort study of all North Carolina residents (N = 9 560 234) in 2010, using data from an electronic controlled substances prescription monitoring program that were then correlated with data from a separate study of overdose mortality conducted by the Division of Public Health]. Another finding was that 80% of patients prescribed highdose opioids were co-prescribed benzodiazepines (Figure 1), comprising a very different prescribing pattern than is observed in clinical trials. These trials routinely exclude subjects who use opioids in combination with other central nervous system depressants, presumably to avoid added toxicity. Benzodiazepine exposure was determined by receipt of ‡ 1 prescription for a benzodiazepine in 365 days prior to death or to the end of the study versus those who had no record of such a prescription. The reference group for incidence rate ratios is > 0 to 19.9 mg/day of average daily milligrams of morphine equivalents. The gray lines on the figure are the bounds of the 95% confidence interval. Incidence rate ratios and confidence intervals were estimated using Poisson regression, with person-days of exposure accrued in an intent-to-treat-type manner. The vertical axis is plotted on the log 10 scale. Average daily milligrams of morphine equivalents are plotted at the midpoint of each category range; the last point includes 500 through 5000 mg/day.
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Incidence rate per 10,000 person-years
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Figure 1. Incidence rate ratios for overdose deaths involving opioid analgesics, by average milligrams of morphine equivalents and benzodiazepine prescription status, North Carolina Residents, 2010. Reprinted from Dasgupta [2], with permission.
Therefore, although it is difficult to discern from death investigations what proportion of decedents obtained medications via legitimate prescriptions, it is certain that benzodiazepines are frequently co-prescribed with opioids in patients with chronic noncancer pain—between 20% and 50% of patients by some estimates [3–7]. Furthermore, patients treated with opioids are more likely to receive benzodiazepines than are patients treated with other modalities for chronic pain [8], and the combination appears more common in patients with substance-use disorders [9]. A newer concern has emerged with evidence that the practice of benzodiazepine co-prescribing with opioids is increasing. Scientists at Stanford Hospital and Clinics in Palo Alto, CA, reviewed a national database of 3.1 billion primary care visits between 2002 and 2009 and found an annual increase of 12% in opioid and benzodiazepine co-prescribing [10]. Another concern involves prescribing in older adults. Benzodiazepines have been associated with falls and fractures in this population, both alone and in combination with opioids [11,12]. In addition to these prescribing patterns, benzodiazepines are favored by nonmedical users (ie, persons without a legitimate prescription or who otherwise demonstrate signs of illegal diversion), with or without opioids [13]. Emergency department visits involving nonmedical use of the benzodiazepine alprazolam doubled from 57 419 to 124 902 during the years 2005 to 2010 [14]. More people who enter substance-abuse treatment report abusing both benzodiazepines and opioids, with treatment episodes for the combination having increased 570%, from approximately 5000 admissions in 2000 to more than 33 000 admissions in 2010 [15]. According to the Drug Abuse Warning Network, from 2004 to 2008, benzodiazepines were involved in 26% of opioid-related visits to hospital emergency departments [16]. It is evident that opioid and benzodiazepine prescribing and misuse are closely linked.
Furthermore, a prescribing error by medical providers is one of many factors determined by expert consensus to be related to opioid deaths [17], suggesting a need for wide dissemination of best clinical practices to reduce adverse outcomes. Several clinical guidelines have been published to inform opioid prescribing for chronic pain; a systematic review gave high grades to a joint publication issued by the American Pain Society and American Academy of Pain Medicine and another by the Canadian National Opioid Use Guideline Group [18]. Though specifics differ among published clinical recommendations, a common core is to introduce opioids at the lowest rational dose, titrate slowly and carefully, and monitor individual patient response, taking care to avoid drug–drug interactions and being alert to comorbid medical and psychiatric illnesses, including sleep apnea, cardiopulmonary disease, existing or emerging substance-use disorders, and major depression, among other considerations. The aforementioned publications agree that additional research is necessary to ascertain the risk factors when prescribing opioids for chronic pain. Clinical information is lacking in some guidelines on managing chronic pain that coexists with insomnia, anxiety, and mood disorders for which benzodiazepines are frequently prescribed. It should be noted that interdisciplinary programs encompassing behavioral, pharmacological, rehabilitative, and other components provide the best evidence for the treatment of chronic pain, but little coverage for and access to these programs exists in the United States, a situation that is worsening [19,20].
Materials and methods Two articles and their references were summarized to develop clinical recommendations to reduce opioid-related overdose morbidity and mortality, and to heighten awareness of cautions when co-prescribing benzodiazepines [21,22]. The articles were recently published in Pain Medicine and were created via a literature search for prominent risk factors
DOI: 10.1080/00325481.2015.993276
Eight opioid principles and benzodiazepines
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Table I. Eight principles for safer opioid prescribing [21]. 1. 2. 3. 4. 5. 6. 7. 8.
Assess patients for risk of nonmedical use or medical misuse before starting opioid therapy and manage accordingly Watch for and treat comorbid mental disease when it occurs Conventional conversion may cause harm when rotating (switching) from one opioid to another Avoid combining benzodiazepines with opioids, especially during sleep hours Use methadone as a secondary or tertiary agent, starting with a low dose and titrating very slowly Assess for sleep apnea in patients on high daily doses of methadone or other opioids and in patients with a predisposition Counsel patients on long-term opioid therapy to reduce opioid dose during upper respiratory infections or asthmatic episodes Avoid prescribing long-acting opioid formulations for acute, postoperative, or trauma-related pain
and best practices for the prescribing of opioids and the co-prescribing of opioids and benzodiazepines for chronic pain and associated mood, anxiety, and sleep disorders. The 8 principles [21] have the endorsement of the board of directors of the American Academy of Pain Medicine and appeared previously on the website of the former LifeSource Foundation [23]; in addition, a version was presented as part of a physician education program performed in Utah [24].
the equivalent dose when switching from one opioid to another to enhance or restore analgesia or to lessen side effects [37,38]. A recently published paradigm suggests slowly decreasing the current opioid while slowly titrating the new opioid to effect [39], a process that takes time but provides added safety. Expert consultation should be sought by practitioners who are unfamiliar with rotating opioids.
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Benzodiazepines add risk with opioids, especially for sleep
The eight principles The following 8 prescribing principles (Table I) were established to reduce adverse outcomes associated with long-term opioid therapy prescribed for chronic pain: Assessment for risk of misuse Risk management includes assessing patients for risk of developing opioid-related problems before beginning opioid therapy. Assessment tools are designed to stratify risk by measuring biological, social, and psychiatric risk factors [25–27] associated with misusing prescribed opioids [28–30]. Patients are managed according to risk category (ie, high, moderate, and low), with the understanding that moderate- to high-risk patients require more stringent monitoring measures and that patients may move between risk categories over time. Other tools may assist in the periodic reassessment and documentation that accompany prescribing of opioid therapy, including effects on analgesia, daily activities, adverse effects, aberrant drug-related behaviors, cognition, and quality of life [31,32]. Safe opioid prescribing depends on utilizing available tools such as state prescription monitoring databases and urine drug tests [33], monitoring progress toward therapeutic goals, and counseling patients to use, store, and dispose of medications safely. The importance of managing comorbid mental disease Mood and anxiety disorders often co-occur with chronic pain, and the use and misuse of benzodiazepines may heighten the risk of opioid overdose [1,34–36]. The presence of psychiatric disorders should be ascertained before initiating opioid therapy, and if no reasonable alternative to opioid therapy is possible, care should be coordinated with mental health practitioners on an ongoing basis as necessary. Possible harm when rotating (switching) opioids Dosing should be patient specific, and equianalgesic conversion tables, by themselves, are not sufficient to determine
As previously discussed, benzodiazepines interact pharmacodynamically with opioids to suppress breathing [14,40,41]. Alternatives for insomnia include melatonin, cognitivebehavioral therapy for insomnia, improved sleep hygiene, and medications such as trazodone, an anticonvulsant, or a low dose of a tricyclic antidepressant, which may be beneficial, especially when the pain is neuropathic in origin. Older patients should be managed cautiously and should be monitored for anticholinergic side effects. Options to treat anxiety disorders include cognitive-behavioral therapy, atypical antipsychotics, anticonvulsants, some antidepressants, exercise, and stress management. Alternative medications to benzodiazepines should be subject to a risk/benefit analysis, and potential side effects should be discussed with the patient. Initiating methadone (as a secondary or tertiary agent), with a low dose and slow titration A particular difficulty with methadone derives from a half-life (typically 8 to 59 hours and up to 130 hours) that outlasts its analgesic effect (4 to 8 hours) [42,43]. Because accumulation of methadone is unpredictable, a low dose is advised for initiating treatment: £ 15 mg per day in divided doses (q8h) [44]; dose increases should be done in increments no greater than 25% to 50%, and no more frequently than weekly. This holds true whether or not a patient is opioid naive. This recommendation is more conservative than that in guidelines available elsewhere. When in doubt, always consult with an experienced methadone prescriber first. Sleep apnea with high-dose methadone or other opioids or with a predisposition Sleep apnea and long-term opioid therapy are linked, and the data suggest a potentially dangerous relationship, especially at higher opioid doses [40,45]. Sleep evaluation is recommended at doses > 50 mg/day of methadone or > 150 mg/ day morphine equivalents of other opioids. All patients with a predisposition or risk factors should be assessed for sleep
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Table II. Clinical recommendations regarding combination opioid and benzodiazepine therapy in patients with chronic pain [22]. Near-absolute contraindications Strong relative contraindications
New use or nonpsychiatric prescription of benzodiazepines
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If coadministration adjudged clinically necessary
Active misuse, abuse, or addiction to benzodiazepines, opioids, alcohol, and/or other central nervous system depressants History of any substance use disorder (poor or recent recovery indicates stronger contraindication) involving benzodiazepines, opioids, alcohol, or other central nervous system depressants Unstable mood, anxiety, or thought disorders Personality disorders, particularly “Cluster B” disorders (ie, antisocial personality disorder, characterized by failure to conform to social norms, deceitfulness, impulsivity, reckless disregard for the safety of self or others, and consistent irresponsibility; and borderline personality disorder, characterized by impulsivity, recurrent suicidal behavior, gestures, or threats, and affective instability) Certain medical comorbidities (ie, obesity, sleep-disordered breathing, chronic obstructive pulmonary disease, and hepatic or renal dysfunction) Older adults and others at elevated fall risk Strongly consider psychiatric consultation Examine risks of coadministration specific to patient Consider benzodiazepine alternatives Use each drug class at lowest effective dose Use each drug for shortest effective period Coordinate care between prescribing physician and psychiatrist (imperative) Absent compelling rationale, opioid should NOT be methadone Counsel patients to risks of the combination, obtain informed consent
apnea, and at-risk patients may need inpatient evaluation of the safety of opioid therapy. Danger with upper respiratory infections or asthmatic episodes Patients experiencing events with acute respiratory tract compromise (eg, flu, pneumonia, upper respiratory infections, cigarette use, chronic obstructive pulmonary disease) should be counseled to reduce their daily opioid doses, particularly their evening doses, by ‡ 30% [46]. Long-acting opioids not for acute, postoperative, or trauma-related pain Long-acting opioids, including transdermal patches [47], are for patients who have developed tolerance to opioids and in whom intermediate- or long-term opioid treatment is anticipated. Tolerant patients are those who take regular, daily, around-the-clock opioids [47].
Indications and recommendations regarding benzodiazepines In view of the evidence that benzodiazepines are frequently prescribed together with opioids, it would be well to summarize some effectiveness findings regarding this class of medications. Benzodiazepines show effectiveness when used short term for anxiety disorders (eg, panic disorder, generalized anxiety disorder), but evidence for long-term effectiveness is mostly empirical [48]. Some effectiveness is demonstrated early in depressive disorders, but long-term effectiveness has not been shown. In major depressive disorder, treatment guidelines recommend reserving benzodiazepines for patients with pronounced anxiety or insomnia that is inadequately controlled with selective serotonin reuptake inhibitors or serotonin-norepinephrine uptake inhibitors. Patients
who took benzodiazepines for insomnia and who also suffered from chronic pain saw no benefit from benzodiazepines in an older study [3]. In light of the potential for adverse outcomes with the co-prescribing of opioids and benzodiazepines, there are considerations and contraindications that can guide clinical decision making, including cautions for new or nonpsychiatric uses of benzodiazepines and for clinically necessary coadministration (Table II). The fourth of the 8 principles cited above suggests alternatives to benzodiazepines for sleep or co-occurring anxiety disorders. Table II further describes safety measures if alternatives to benzodiazepines are not possible. It is important to assess each patient individually and to seek expert consultation in pain, psychiatry, substance abuse, or other relevant fields when necessary to coordinate goals of therapy, specific pharmacologic agents, dosage levels, and adjustments; to gauge response to therapy; and to monitor adverse effects, including the misuse and abuse of, or addiction to, either drug.
Conclusion Opioid- and benzodiazepine-related morbidity and mortality present a serious public health problem and therapeutic challenge that could be reduced if prescribers recognize risk factors and follow literature-based recommendations. Particular caution is necessary when pain is complicated by comorbid medical or psychiatric illness or when clinical presentation suggests possible aberrant use of either or both classes of medications. More research is necessary to evaluate long-term opioids for safety and effectiveness, including their effects on hormonal and immune systems and their risks for abuse, misuse, addiction, and associated adverse outcomes. Benzodiazepine contributions to opioid-related deaths must be appreciated, and their co-prescribing requires proper patient selection, judicious dosing, and risk-appropriate monitoring.
Eight opioid principles and benzodiazepines
DOI: 10.1080/00325481.2015.993276
Acknowledgments
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Special thanks to Nabarun Dasgupta, PhD, for providing portions of his dissertation, which was approved by the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Epidemiology. Beth Dove of Dove Medical Communications, LLC, Salt Lake City, Utah, provided technical writing and editorial assistance for this manuscript. Declaration of interest: Lynn R. Webster has disclosed a relevant financial relationship with Acura Pharmaceuticals, AstraZeneca, BioDelivery Sciences International, BristolMyers Squibb, CVS Caremark, Depomed, Egalet, Grunenthal USA, Inspirion Pharmaceuticals, Insys Therapeutics, Jazz Pharmaceuticals, Kaleo, Mallinckrodt Pharmaceuticals, Nektar Therapeutics, Nevro Corporation, Orexo Pharmaceuticals, Signature Therapeutics, Synchrony Healthcare, Teva Pharmaceuticals and Travena. Gary M. Reisfield and Nabarun Dasgupta have no conflicts of interest to declare.
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