Bridging the Gaps: Special Commentary
Assessing the prevalence of opioid misuse, abuse, and addiction in chronic pain Jane C. Ballantyne
n their systematic review, Vowles et al.16 tackle the debatably impossible task of estimating the prevalence of opioid misuse, abuse, and addiction in chronic pain. They make their assessments utilizing rate estimates from the literature (this literature happens to be mostly a United States literature). Why impossible—because it is hard to understand what addiction actually is when it arises during pain treatment with opioids. Rather sensibly, the authors use broad categories where “misuse” is using opioid not as prescribed, “abuse” is intentional use for nonmedical purpose, and “addiction” is compulsive use (see article for more complete descriptions). These definitions are based on recent consensus statements from expert panels and additional expert opinion.4,12,14–16 The authors do not get bogged down in language used in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and International Classification of Diseases where “abuse” and “dependence” carried different meanings to those generally understood and confused people’s understanding of addiction, as well confounding efforts to quantify addiction prevalence.1 Perhaps not surprisingly, given the difficulty we have with agreeing on definitions or understanding what addiction is when it arises during the treatment of pain with opioids, rates of problematic use extracted from studies are broad ranging (from ,1% to 81%). Abuse is reported in only one study, while average rates of misuse range from 21% to 29% and average rates of addiction range from 8% to 12%. This is useful information in terms of understanding the scale of misuse and addiction. But, could rates of addiction have been underestimated because there cannot be clear distinctions between misuse and addiction, despite the apparent clarity of the definitions? The neural processes of opioid addiction have been learned from animal and human studies in subjects that are receiving opioids not as pain treatment, but for other purposes. In the case of human studies, subjects have generally been using opioids for recreational purposes.11 What is known from such studies is that adaptations in the reward center in the brain (the mesocorticolimbic system) and in central noradrenergic nuclei result in the state of dependence whereby unpleasant psychological and physical symptoms result in a need to obtain opioid should levels decline or needs increase.6,8,11 Dependence is known to be a powerful driver of opioid-seeking behavior. In fact, established opioid addicts seek opioids not to provide euphoria but to avoid dysphoria and other unpleasant symptoms.8 What turns opioid seeking for
I
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA, USA PAIN 156 (2015) 567–568 © 2015 International Association for the Study of Pain http://dx.doi.org/10.1097/j.pain.0000000000000105
April 2015
·
Volume 156
·
Number 4
the relief of withdrawal into the state of compulsive opioid seeking that defines addiction is not fully understood, but irreversibility is a feature, and is believed to be due to the secondary process of memory formation (memory, ie, of obtaining or procuring drug) in structures such as the amygdala, hippocampus, and cerebral cortex.5,13 In the case of recreational or illicit use of opioids, dependence without addiction does not arise because the progression in this case is fairly clear from occasional use involving procurement but without dependence, through repeated procurement, to addiction with dependence. Because in the case of recreational or illicit use, the user must obtain or procure the drug, the clinical picture and the underlying drivers of addiction are relatively straightforward and well established.9 Not so in the case of opioid treatment of chronic pain. While there are similarities in that dependence will develop with continued use and will similarly be a powerful driver of opioid seeking (in fact dependence will be responsible for the state aptly described by patients themselves whereby they believe that they need opioids even when they have stopped providing good pain relief: “you see, they work, when I stop them, I get worse”).10 But in the case of chronic pain treatment, there are many other drivers of opioid seeking. Not least, of course, is seeking pain relief, but patients with pain could also be looking for relief of anxiety, depression, stress, or existential suffering. Patients having pain are typically prescribed opioids; therefore, they do not need to procure them. This has 2 implications: one that dependence may develop without addiction because there may be long-term use without aberrant behaviors; and second that the progression toward and the factors underlying addiction when it does occur are extremely complex.3 In fact, do we really know when the dependence that arises in opioid-treated pain patients becomes addiction? Does the absence of the defining characteristics of impaired control over drug use, compulsive use, continued use despite harm and craving mean as much in a person essentially maintained on opioids, as it does in a person needing to procure drug? And where in the large gray zone between clearly addicted and clearly not addicted, can a line be drawn that not only clearly defines addiction but would also define who is suitable for addiction treatment, or at least addictiontype treatment?2 Rather than trying to identify such a line or to distinguish between misuse, abuse, and addiction, it may be better to accept that the state of dependence (which could variously be manifest as misuse, abuse, or addiction), or what has been termed “complex persistent dependence” (a state of dependence that, like addiction, does not easily reverse), is akin to addiction and worthy of addiction-type treatment.3 Vowles et al.16 end their article with the comment that it is not certain whether the unclear benefits derived from opioids compensate for the additional burden of the “unintended” consequences to patients and health care systems. Adaptations www.painjournalonline.com
567
Copyright Ó 2015 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
568
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J.C. Ballantyne 156 (2015) 567–568
to continuous opioid use are responsible not only for dependence and all its consequences but also for diminished analgesic efficacy. If the result is much harm with little benefit, then we really do need to re-examine chronic opioid therapy in terms of who are suitable candidates and what are suitable precautions. The value of the Vowles et al.16 analysis is that it provides an estimate of the scope of misuse and addiction, although for the reasons already stated, it may actually underestimate addiction rates. All patients exhibiting misuse, abuse, or addiction, and the Vowles et al.16 analyses suggest there are many, are likely to improve in addiction-type programs such as program by Jamison et al, which provides a low-intensity intervention that includes mentoring and education.7,16 Hopefully more judicious prescribing will reduce unintended consequences, but in the meantime, those already afflicted by dependence, whether or not this is addiction, need appropriate care. The implication of the Vowles et al.16 findings is that a very large contingent needing care already exists in the United States specifically, and steps need to be taken urgently in the United States to provide such care.
Conflict of interest statement The author has no conflicts of interest to declare. Article history: Received 13 January 2015 Accepted 16 January 2015 Available online 27 January 2015
References [1] Ballantyne JC, LaForge SL. Opioid dependence and addiction in opioid treated pain patients. PAIN 2007;129:235–55. [2] Ballantyne JC, Stannard C. New addiction criteria: diagnostic challenges persist in treating pain with opioids. PAIN 2013;21:1–7. [3] Ballantyne JC, Sullivan MD, Kolodny A. Opioid dependence vs addiction: a distinction without a difference? Arch Intern Med 2012;172:1342–3.
PAIN®
[4] Butler S. The IMMPACT factor or IMMPACT strikes again! PAIN 2013; 154:2243–4. [5] Hyman S, Malenka R. Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci 2001;2:695–703. [6] Hyman SE, Malenka RC, Nestler EJ. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 2006;29: 565–98. [7] Jamison RN, Ross EL, Michna E, Chen LQ, Holcomb C, Wasan AD. Substance misuse treatment for high-risk chronic pain patients on opioid therapy: a randomized trial. PAIN 2010;150:390–400. [8] Koob GF, Le Moal M. Drug addiction, dysregulation of reward, and allostasis. Neuropharm 2001;24:97–129. [9] Kreek MJ, Nielsen DA, Butelman ER, LaForge KS. Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nat Neurosci 2005;8:1450–7. [10] Moore N, Pariente A, Begaud B. Why Are Benzodiazepines Not Yet Controlled Substances? JAMA Psychiatry 2015;72:110–1. [11] Nestler EJ. Historical review: molecular and cellular mechanisms of opiate and cocaine addiction. Trends Pharmacol Sci 2004;25:210–8. [12] O’Connor AB, Turk DC, Dworkin RH, Katz NP, Colucci R, Haythornthwaite JA, Klein M, O’Brien C, Posner K, Rappaport BA, Reisfield G, Adams EH, Balster RL, Bigelow GE, Burke LB, Comer SD, Cone E, Cowan P, Denisco RA, Farrar JT, Foltin RW, Haddox JD, Hertz S, Jay GW, Junor R, Kopecky EA, Leiderman DB, McDermott MP, Palmer PP, Raja SN, Rauschkolb C, Rowbotham MC, Sampaio C, Setnik B, Smith SM, Sokolowska M, Stauffer JW, Walsh SL, Zacny JP. Abuse liability measures for use in analgesic clinical trials in patients with pain: IMMPACT recommendations. PAIN 2013;154:2324–34. [13] Robinson T, Berridge K. The neural incentive basis of drug craving: an incentive snsitization theory of addiction. Brain Res Rev 1993;18: 247–91. [14] Smith SM, Dart RC, Katz NP, Paillard F, Adams EH, Comer SD, Degroot A, Edwards RR, Haddox JD, Jaffe JH, Jones CM, Kleber HD, Kopecky EA, Markman JD, Montoya ID, O’Brien C, Roland CL, Stanton M, Strain EC, Vorsanger G, Wasan AD, Weiss RD, Turk DC, Dworkin RH. Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations. PAIN 2013;154:2287–96. [15] Sullivan M. Clarifying opioid misuse and abuse. PAIN 2013;154: 2239–40. [16] Vowles KE, McEntee ML, Julnes PS, Frohe T, Ney JP, van der Goes D. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. PAIN 2015;156:569–576.
Copyright Ó 2015 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
Assessing the prevalence of opioid misuse, abuse, and addiction in chronic pain Jane C. Ballantyne
n their systematic review, Vowles et al.16 tackle the debatably impossible task of estimating the prevalence of opioid misuse, abuse, and addiction in chronic pain. They make their assessments utilizing rate estimates from the literature (this literature happens to be mostly a United States literature). Why impossible—because it is hard to understand what addiction actually is when it arises during pain treatment with opioids. Rather sensibly, the authors use broad categories where “misuse” is using opioid not as prescribed, “abuse” is intentional use for nonmedical purpose, and “addiction” is compulsive use (see article for more complete descriptions). These definitions are based on recent consensus statements from expert panels and additional expert opinion.4,12,14–16 The authors do not get bogged down in language used in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and International Classification of Diseases where “abuse” and “dependence” carried different meanings to those generally understood and confused people’s understanding of addiction, as well confounding efforts to quantify addiction prevalence.1 Perhaps not surprisingly, given the difficulty we have with agreeing on definitions or understanding what addiction is when it arises during the treatment of pain with opioids, rates of problematic use extracted from studies are broad ranging (from ,1% to 81%). Abuse is reported in only one study, while average rates of misuse range from 21% to 29% and average rates of addiction range from 8% to 12%. This is useful information in terms of understanding the scale of misuse and addiction. But, could rates of addiction have been underestimated because there cannot be clear distinctions between misuse and addiction, despite the apparent clarity of the definitions? The neural processes of opioid addiction have been learned from animal and human studies in subjects that are receiving opioids not as pain treatment, but for other purposes. In the case of human studies, subjects have generally been using opioids for recreational purposes.11 What is known from such studies is that adaptations in the reward center in the brain (the mesocorticolimbic system) and in central noradrenergic nuclei result in the state of dependence whereby unpleasant psychological and physical symptoms result in a need to obtain opioid should levels decline or needs increase.6,8,11 Dependence is known to be a powerful driver of opioid-seeking behavior. In fact, established opioid addicts seek opioids not to provide euphoria but to avoid dysphoria and other unpleasant symptoms.8 What turns opioid seeking for
I
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA, USA PAIN 156 (2015) 567–568 © 2015 International Association for the Study of Pain http://dx.doi.org/10.1097/j.pain.0000000000000105
April 2015
·
Volume 156
·
Number 4
the relief of withdrawal into the state of compulsive opioid seeking that defines addiction is not fully understood, but irreversibility is a feature, and is believed to be due to the secondary process of memory formation (memory, ie, of obtaining or procuring drug) in structures such as the amygdala, hippocampus, and cerebral cortex.5,13 In the case of recreational or illicit use of opioids, dependence without addiction does not arise because the progression in this case is fairly clear from occasional use involving procurement but without dependence, through repeated procurement, to addiction with dependence. Because in the case of recreational or illicit use, the user must obtain or procure the drug, the clinical picture and the underlying drivers of addiction are relatively straightforward and well established.9 Not so in the case of opioid treatment of chronic pain. While there are similarities in that dependence will develop with continued use and will similarly be a powerful driver of opioid seeking (in fact dependence will be responsible for the state aptly described by patients themselves whereby they believe that they need opioids even when they have stopped providing good pain relief: “you see, they work, when I stop them, I get worse”).10 But in the case of chronic pain treatment, there are many other drivers of opioid seeking. Not least, of course, is seeking pain relief, but patients with pain could also be looking for relief of anxiety, depression, stress, or existential suffering. Patients having pain are typically prescribed opioids; therefore, they do not need to procure them. This has 2 implications: one that dependence may develop without addiction because there may be long-term use without aberrant behaviors; and second that the progression toward and the factors underlying addiction when it does occur are extremely complex.3 In fact, do we really know when the dependence that arises in opioid-treated pain patients becomes addiction? Does the absence of the defining characteristics of impaired control over drug use, compulsive use, continued use despite harm and craving mean as much in a person essentially maintained on opioids, as it does in a person needing to procure drug? And where in the large gray zone between clearly addicted and clearly not addicted, can a line be drawn that not only clearly defines addiction but would also define who is suitable for addiction treatment, or at least addictiontype treatment?2 Rather than trying to identify such a line or to distinguish between misuse, abuse, and addiction, it may be better to accept that the state of dependence (which could variously be manifest as misuse, abuse, or addiction), or what has been termed “complex persistent dependence” (a state of dependence that, like addiction, does not easily reverse), is akin to addiction and worthy of addiction-type treatment.3 Vowles et al.16 end their article with the comment that it is not certain whether the unclear benefits derived from opioids compensate for the additional burden of the “unintended” consequences to patients and health care systems. Adaptations www.painjournalonline.com
567
Copyright Ó 2015 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
568
·
J.C. Ballantyne 156 (2015) 567–568
to continuous opioid use are responsible not only for dependence and all its consequences but also for diminished analgesic efficacy. If the result is much harm with little benefit, then we really do need to re-examine chronic opioid therapy in terms of who are suitable candidates and what are suitable precautions. The value of the Vowles et al.16 analysis is that it provides an estimate of the scope of misuse and addiction, although for the reasons already stated, it may actually underestimate addiction rates. All patients exhibiting misuse, abuse, or addiction, and the Vowles et al.16 analyses suggest there are many, are likely to improve in addiction-type programs such as program by Jamison et al, which provides a low-intensity intervention that includes mentoring and education.7,16 Hopefully more judicious prescribing will reduce unintended consequences, but in the meantime, those already afflicted by dependence, whether or not this is addiction, need appropriate care. The implication of the Vowles et al.16 findings is that a very large contingent needing care already exists in the United States specifically, and steps need to be taken urgently in the United States to provide such care.
Conflict of interest statement The author has no conflicts of interest to declare. Article history: Received 13 January 2015 Accepted 16 January 2015 Available online 27 January 2015
References [1] Ballantyne JC, LaForge SL. Opioid dependence and addiction in opioid treated pain patients. PAIN 2007;129:235–55. [2] Ballantyne JC, Stannard C. New addiction criteria: diagnostic challenges persist in treating pain with opioids. PAIN 2013;21:1–7. [3] Ballantyne JC, Sullivan MD, Kolodny A. Opioid dependence vs addiction: a distinction without a difference? Arch Intern Med 2012;172:1342–3.
PAIN®
[4] Butler S. The IMMPACT factor or IMMPACT strikes again! PAIN 2013; 154:2243–4. [5] Hyman S, Malenka R. Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci 2001;2:695–703. [6] Hyman SE, Malenka RC, Nestler EJ. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 2006;29: 565–98. [7] Jamison RN, Ross EL, Michna E, Chen LQ, Holcomb C, Wasan AD. Substance misuse treatment for high-risk chronic pain patients on opioid therapy: a randomized trial. PAIN 2010;150:390–400. [8] Koob GF, Le Moal M. Drug addiction, dysregulation of reward, and allostasis. Neuropharm 2001;24:97–129. [9] Kreek MJ, Nielsen DA, Butelman ER, LaForge KS. Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nat Neurosci 2005;8:1450–7. [10] Moore N, Pariente A, Begaud B. Why Are Benzodiazepines Not Yet Controlled Substances? JAMA Psychiatry 2015;72:110–1. [11] Nestler EJ. Historical review: molecular and cellular mechanisms of opiate and cocaine addiction. Trends Pharmacol Sci 2004;25:210–8. [12] O’Connor AB, Turk DC, Dworkin RH, Katz NP, Colucci R, Haythornthwaite JA, Klein M, O’Brien C, Posner K, Rappaport BA, Reisfield G, Adams EH, Balster RL, Bigelow GE, Burke LB, Comer SD, Cone E, Cowan P, Denisco RA, Farrar JT, Foltin RW, Haddox JD, Hertz S, Jay GW, Junor R, Kopecky EA, Leiderman DB, McDermott MP, Palmer PP, Raja SN, Rauschkolb C, Rowbotham MC, Sampaio C, Setnik B, Smith SM, Sokolowska M, Stauffer JW, Walsh SL, Zacny JP. Abuse liability measures for use in analgesic clinical trials in patients with pain: IMMPACT recommendations. PAIN 2013;154:2324–34. [13] Robinson T, Berridge K. The neural incentive basis of drug craving: an incentive snsitization theory of addiction. Brain Res Rev 1993;18: 247–91. [14] Smith SM, Dart RC, Katz NP, Paillard F, Adams EH, Comer SD, Degroot A, Edwards RR, Haddox JD, Jaffe JH, Jones CM, Kleber HD, Kopecky EA, Markman JD, Montoya ID, O’Brien C, Roland CL, Stanton M, Strain EC, Vorsanger G, Wasan AD, Weiss RD, Turk DC, Dworkin RH. Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations. PAIN 2013;154:2287–96. [15] Sullivan M. Clarifying opioid misuse and abuse. PAIN 2013;154: 2239–40. [16] Vowles KE, McEntee ML, Julnes PS, Frohe T, Ney JP, van der Goes D. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. PAIN 2015;156:569–576.
Copyright Ó 2015 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
