Opioids for the Treatment of Chronic Pain: Mistakes Made, Lessons Learned, and Future Directions

E SPECIAL ARTICLE Opioids for the Treatment of Chronic Pain: Mistakes Made, Lessons Learned, and Future Directions

Jane C. Ballantyne, MD, FRCA

An overreliance on opioids has impacted all types of pain management, making it undoubtedly a root cause of the “epidemic” of prescription opioid abuse in the United States. Yet, an examination of the statistics that led the US Centers for Disease Control and Prevention to declare that prescription opioid abuse had reached epidemic levels shows that the abuse occurrences and deaths are arising outside the hospital or hospice setting, which strongly implicates the outpatient use of opioids to treat chronic pain. Such abuse and related deaths are occurring in chronic pain patients themselves and also through diversion. Overprescribing to outpatients has afforded distressed and vulnerable individuals access to these highly addictive drugs. The focus of this article is on what we have learned since opioid treatment of chronic pain was first popularized at the end of the 20th century and how this new information can guide chronic pain management in the future. (Anesth Analg 2017;125:1769–78)

he markedly increased prescribing of opioid analge- health care availability and access, promotional activities by sics in the United States beginning in the 1980s has the pharmaceutical industry, drug availability, drug regu- been a root cause of the US epidemic of prescription lations, and clinical practice standards. While it could be T 1 opioid abuse and deaths. This increase in opioid prescrib- argued that overprescribing is seemingly a uniquely North ing occurred mainly because of increased prescribing for American problem, the insights gained mainly from North chronic pain.2–5 Relatively small increases in prescribing for America can promote an understanding of the limits of acute pain concurrently occurred. While opioid prescribing opioid utility for treating chronic pain—lessons that are rel- for acute pain is typically finite and within the hospital set- evant to all continents and cultures. ting, increased prescribing for acute pain contributed to this As the pitfalls of prescribing opioids for chronic pain epidemic, largely because prescribing for acute pain can be have gradually emerged since its expansion in the past an inadvertent gateway to long-term prescribing. Chronic 30 years, there has been an evolution away from thinking pain is open-ended and ubiquitous and occurs outside the opioids were generally safe and had often been needlessly hospital or hospice. Unlike when opioids are administered denied to the current understanding that safety consider- in a hospital or hospice, outpatients control their own usage ations must be included in prescribing decisions. Initially, and can readily lose control of their opioid use. assumed rates of opioid abuse were in the order of 5%11; Although the United States is the only country to officially newer data suggest rates of 12%–25%.12–14 declare opioid abuse an epidemic,6 it is not the only coun- Initially, it was argued that most abuse occurred in indi- try either to recognize the problems associated with over- viduals obtaining prescription opioids through criminal or prescribing of opioids or to experience marked increases in careless diversion and that risk mitigation strategies only opioid prescribing and associated increases in prescription needed to keep prescription opioids from getting into the opioid abuse and deaths. Canada is close behind the United wrong hands. The degree to which pain patients them- States in its increased prescribing and related abuse and selves were being overtly harmed by inappropriate opioid death rates.7,8 Other developed nations have not seen their prescribing for chronic pain was being obscured by good levels of abuse and deaths rise, according to local govern- intentions and wishful thinking by clinicians. ment statistics, but they are seeing trends in prescribing that Against this backdrop, this article focuses on: (1) the are similar to the United States and Canada.9,10 evidence for chronic opioid therapy; (2) analgesic efficacy, In contrast, prescribing of opioids for chronic pain in dependence, and tolerance; (3) applying palliative care developing countries is rare. These international differences principles to chronic pain management; (4) opioids and the likely stem from differences in culture, health care systems, brain; and (5) adverse outcomes and inappropriate patient selection.

From the Department of Anesthesiology and Pain Medicine, University of EVIDENCE BASE FOR CHRONIC OPIOID THERAPY Washington School of Medicine, Seattle, Washington. Because opioids have been recognized as effective analgesics Accepted for publication August 18, 2017. for thousands of years, there was no great urgency to con- Funding: None. firm their efficacy with clinical trials. That was until the mid- The author declares no conflicts of interest. 20th century, when the pharmaceutical industry introduced Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of new opioids and formulations, whose efficacy needed to be this article on the journal’s website (www.anesthesia-analgesia.org). compared to the efficacy of a standard like morphine to be Reprints will not be available from the author. approved for clinical use. They also needed to be tested in Address correspondence to Jane C. Ballantyne, MD, FRCA, Department of patients with chronic pain diagnoses, since before the mid- Anesthesiology and Pain Medicine, Box 356540, University of Washington School of Medicine, Seattle, WA 98195. Address e-mail to [email protected]. 20th century, opioids were generally considered unsafe and 15 Copyright © 2017 International Anesthesia Research Society ineffective for chronic pain. So began an era during which DOI: 10.1213/ANE.0000000000002500 the number of randomized trials of opioids for chronic pain

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increased several fold, subsequently leading to a new evi- warnings that the rates of opioid-related abuse and deaths dence base of systematic reviews and meta-analyses.16–19 have increased to epidemic levels in the United States.2–4,6,22 The evidence from these individual trials and systematic In addition to providing these warnings, many prospec- reviews/meta-analyses confirms that opioids are effective tive population studies have now demonstrated that the and safe analgesics for many chronic pain diagnoses—at long-term analgesic and health effects of chronic opioid least during the conduct of controlled trials. No conclu- therapy are poor.23–30 One must ask why the outcomes in sions can be made about associated abuse and addiction prospective population studies are so much worse than the risk, and findings on functional improvement and health- outcomes in retrospective observational studies. Likely con- related quality of life are mixed. Furthermore, there are tributing factors to this difference are: (1) the more diverse several limitations to currently available randomized tri- population in population studies, not necessarily treated in als in assessing the utility of chronic opioid therapy. Their the highly structured and constrained environment of a ret- duration is not long enough to be able to assess long-term rospective observational study; (2) the mix of patients doing efficacy or adverse outcomes. The study populations are well and those doing poorly, whereas many patients doing highly selected and thus not representative of the general poorly drop out of observational studies; (3) the length of population. Most importantly, to be eligible, study patients treatment tends to be much longer in population studies; cannot be at risk for substance abuse. Many analgesic trials and (4) variations in practice, including use of monitoring utilize enriched enrollment, whereby patients who do not and risk mitigation, occurring in population studies. respond to the study drug during preenrollment are elim- Concerns about prescription opioid abuse has triggered inated from the trial. All told, existing randomized trials, renewed efforts in many countries to examine the evi- and the systematic reviews and meta-analyses upon which dence on chronic opioid effects, both positive and negative. they are based, confirm early analgesic efficacy but do not Accepting that the risk of abuse is much greater than origi- provide information about real-world opioid utility for the nally purported (>20% in several recent studies),14,31–33 this treatment of chronic pain.20,21 begs the question: Do opioids actually work well in provid- Not surprisingly, since there were very few randomized ing long-term pain relief? The US Centers for Disease Control trials available when chronic opioid therapy was initially and Prevention (CDC) commissioned 2 separate efforts to promoted in the 1980s, the supporting evidence consisted update the evidence, one a well-designed, intensive system- mainly of small-scale observational studies, the potential atic review of available trials34 and the other a contextual weakness of which is now widely recognized. Looking review of population-level data.35 In both efforts, evidence back, it is somewhat surprising that an entire medical com- could not be found to support long-term efficacy, although munity was convinced by such marginal evidence. there was strong evidence of harm, particularly at high doses. A representative 1986 paper by Portenoy and Foley11 was As troubling as the lack of evidence to support long-term seminal in promoting chronic opioid therapy in the 1980s effectiveness, there was also no evidence that interventions and 1990s. It was a retrospective observational study of 38 intended to improve safety (eg, risk mitigation strategies). cancer survivors with unrelated noncancer chronic pain Nevertheless, there are patients who do well on chronic who had been treated with opioids for up to 6 years. The opioid therapy and whose lives are positively transformed majority of patients obtained satisfactory analgesia through- by the treatment. This is supported by multiple anecdotal out the study period and only 2 patients developed control reports. What is not clear, and an important area for future issues. These authors and others reported substance abuse research, is which patients can be predicted to have good rates of only 1% to 5%. The Portenoy and Foley11 study was outcomes versus those for whom opioids should be avoided. not the only observational study used to support chronic In summary, there is strong evidence to support short- opioid therapy in the 1980s; however, it was widely cited term analgesic efficacy of opioids for chronic pain, and and was confirmed by other similar observational studies. there is weak evidence to support longer-term analgesic Opioids seemed to offer satisfactory analgesia for up to 6 efficacy. However, population studies reveal significant years, with low rates of opioid abuse, albeit with mixed safety concerns and lack of long-term analgesic efficacy findings on function and health-related quality of life— across the wider population. Whether long-term opioid overall supporting chronic opioid therapy.20,21 therapy improves function and health-related quality of life It was not until a decade or so after chronic opioid ther- is uncertain. There is no convincing evidence of long-term apy became widely adopted in the United States and sev- analgesic efficacy and strong evidence of harm, especially at eral other countries that an accumulation of larger scale, high doses of >100 morphine milligram equivalents per day. population-level data began to suggest that there were problems with the therapy. Although prospective longitudi- ANALGESIC EFFICACY, DEPENDENCE, AND nal population studies (like other quantitative observational TOLERANCE studies) can be fraught with systematic bias and confound- Clinicians often encounter patients on long-term chronic ing, they have several major advantages. They can assess opioid therapy, even at high doses, who still self-report what is happening in the real world, over many years, and 10/10 pain. This would seem to be a clear treatment fail- they can provide an alert to problems. There will always ure. Yet these patients, and often their prescribing providers be uncertainty about true causation versus simple associa- as well, believe that the opioid is the only thing preventing tion, but with enough consistent data, this type of evidence even worse pain or a return to the pain levels before start- becomes convincing. In fact, it has been well-designed pop- ing the opioid. Whatever else is happening, it would appear ulation studies that have almost exclusively provided the that the opioid is failing as an analgesic.

There may be a substantial difference between continu- produced pain relief is now operating in a hyperalgesic ous and intermittent opioid use. In the drug addiction litera- state, whereby only exogenous and not endogenous opi- ture, somewhat misleadingly, the word “abuse” was applied oid can restore the normal or pain-free state.46 A proposed when drug use was intermittent and reversible (Diagnostic mechanism for failed analgesia is that patients taking opi- and Statistical Manual [DSM] IV).36–38 Intermittent use was a oids chronically are in a continuous state of withdrawal.47 precursor to continuous use or “addiction” (again, mislead- Some investigators have proposed that chronic pain itself, ingly named “substance dependence”), in which physical even without the addition of exogenous opioids, is a state of dependence and tolerance coupled with aberrant behaviors dependence, tolerance, and continuous withdrawal because characterize the disorder. These distinctions are no longer of the endogenous opioid response to chronic pain.48 used in the latest addiction criteria (DSM V).39 Nevertheless, Opioid dependence is understood to be an adapta- the long-established observation that dependence and toler- tion that causes withdrawal when the level of opioid use ance go hand in hand with continuous use is relevant not is reduced. Withdrawal comprises certain physical symp- only to addiction but also when opioids are used continu- toms, such as agitation, nausea, diarrhea, pupillary dilation, ously and long term for pain treatment. Dependence and and pain (withdrawal hyperalgesia), as well as psychologi- tolerance are inevitable neuroadaptations to continuous opi- cal symptoms such as anhedonia. For pain patients, with- oid use, and these adaptations could account in large part drawal hyperalgesia and anhedonia may be key drivers of for analgesic failure.40,41 At the same time, it is possible that their efforts to restore homeostasis through consuming opi- because these adaptations do not occur with intermittent or oid because pain, anxiety, and fear motivated them to take occasional use of opioids, analgesic efficacy may be better opioids in the first place. Tolerance to opioids is the need preserved if opioids are not used continuously. Preliminary to take higher doses to achieve the same effect. Tolerance evidence supports that intermittent use provides equivalent is far from simple. There are hundreds of molecular and or better analgesia and is preferred by patients.42–44 cellular mechanisms occurring along pain pathways and Extrapolating once more from addiction medicine, when in the “pain connectome,”49 the areas of the brain where people transition from occasional use to continuous use, simple nociception is converted into action, that account for instead of providing euphoria, each dose is needed to avoid tolerance.50 dysphoria.45 The adaptation is an attempt to restore hedonic It is especially difficult for the clinician to know how homeostasis in the face of continued exogenous drug use. to respond to changes in opioid efficacy because many of There is a shift from the normal state, in which normal the processes that produce tolerance are shared between endogenous responses are enough to maintain mood within opioid-induced hyperalgesia (associated with high-dose or a normal range, to the dysphoric state, in which only more high-potency opioid treatment), withdrawal hyperalgesia drug can shift the dysphoria back to normal (Figure 1). (associated with continuous opioid therapy), psychological Consistent with this model, a similar process may occur or associative tolerance,51,52 and pharmacological or nonas- with the analgesic effects of opioids. Again, in an attempt sociative tolerance (Table 1).53–55 to maintain homeostasis, exogenous opioid that once Both dependence and tolerance are adaptations to continuous opioid use, and they cannot be separated. If tolerance develops, whether because of psychological and/or pharmacological factors, withdrawal symptoms, including a worsening of pain, will persist unless the opioid dose is increased (Figure 2). Each dose escalation will restore analgesic efficacy, but multiple dose escalations may be needed, leading to the distressing but all too common state in which no dose is enough. Thus, we return to the question posed at the beginning of this section: What is happening when we see patients on long-term, continuous opioid therapy, possibly at high doses, who are still reporting 10/10 pain, yet they (and perhaps we) are convinced that their opioid treatment is the only thing that prevents their pain being even worse? The most likely explanation is that they have developed depen- Figure 1. Natural progression of opioid dependence. When people move from occasional use to continuous use, each dose (instead of dence and tolerance, which are impeding their ability to providing euphoria) is needed to avoid dysphoria. The adaptation is get pain relief from their opioid treatment. The idea that an attempt to restore hedonic homeostasis in the face of continued these patients are in a state of continuous withdrawal may exogenous drug use. There is a shift from the normal state where explain this clinical scenario, and it is gaining credibility as normal endogenous responses are enough to keep feelings within a 47,48 normal range to the dysphoric state, where only more drug can shift we learn more about natural endogenous opioid actions. the dysphoria back to normal. Using this model, it is proposed that a similar process occurs with the analgesic effects of opioids. Again, APPLYING PALLIATIVE CARE PRINCIPLES TO in an attempt to maintain homeostasis, exogenous opioid that once CHRONIC PAIN MANAGEMENT produced pain relief is now operating in a hyperalgesic state where The impetus to more widely prescribe opioids for chronic only exogenous and not endogenous opioid can restore the normal or pain-free state. This proposed mechanism for failed analgesia is pain initially came from palliative care; and then from the based on the idea that people taking opioids continuously are in a pharmaceutical industry. Palliative care specialists argued continuous state of withdrawal. that because cancer pain could be effectively treated with

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Table 1. Tolerance to Opioids and Related Definitions Tolerance The need for higher doses to achieve the same effect. Tolerance develops to both the euphoric and the analgesic effects of opioid but by different mechanisms and at different rates. The below-listed mechanisms could all contribute to a clinical picture of opioid tolerance. Opioid-induced hyperalgesia A state of nociceptive sensitization caused by exposure to opioids. Often manifests as allodynia. Withdrawal hyperalgesia A cardinal sign of physical withdrawal from opioids. Often manifests as flu-like aches and pains or worsening of underlying chronic pain. Associative (psychological) tolerance Can arise in the case of all the central effects of opioids, including euphoria and dysphoria, sedation, analgesia, and nausea. This type of tolerance involves learning, and its development is linked to environmental or contextual cues.51,52 Nonassociative (pharmacological) tolerance Occurs as a result of cellular and molecular adaptations. May involve receptor internalization, recycling, desensitization, or downregulation.53–55

cancer patients would need breakthrough pain medication to treat whatever pain episodes were not prevented by the long-acting opioid soon followed.58,59 When the use of opioids for chronic, noncancer pain began to be encouraged, long-acting opioids began to be promoted with the claim that they would produce better analgesia with less addiction risk (because the steady state avoided peaks and troughs, and thus euphoria and dysphoria). Shortly thereafter, the concept of breakthrough pain was also applied to chronic pain. Chronic pain came to be treated with opioids based on not only the moral principles but also the treatment principles of palliation. Unfortunately, applying these treatment principles did not have the predicted positive effects of better analgesia with less misuse, abuse, and addiction risk, but instead, adverse consequences. Unlike treatment for cancer pain in the 1980s, treatment was needed for long enough that doses escalated to sometimes unsafe and toxic levels. There is now overwhelming evidence that many of the adverse outcomes of chronic opioid therapy can be linked to high doses.3,28,60–63 This is true of abuse and death rates as well as cognitive impairment, falls and fractures, infertility, loss of libido and drive, and social dysfunction, including inability to work (Table 2; Supplemental Digital Content, Document, http://links.lww.com/AA/C19). Figure 2. Tolerance and dependence work together. Both tolerance These are important downsides to prescribing opioids for and dependence are adaptations to continuous opioid use, and they cannot be separated. If tolerance arises, whether because of psy- chronic pain. The intention is that the pain relief with opi- chological or pharmacological factors or both, withdrawal symptoms, oids will improve rather than worsen dysfunction associ- including a worsening of pain, will persist unless the opioid dose is ated with chronic pain, which may occur if opioids are increased. Each dose escalation will restore analgesics efficacy, but used in a way that does improve pain. But it appears that multiple dose escalations may be needed, leading to the distressing but all too common state where no dose is enough. paradoxically, high-dose opioids often do not improve pain, and may even make pain worse. This is not a simple matter of high-dose opioids producing opioid-induced opioids, chronic pain, which caused equal suffering, should hyperalgesia. There are many processes that contribute also be treated with opioids.11 This was largely a moral to hyperalgesia, related to pain itself and its chronicity, argument. The pharmaceutical industry was concomitantly opioid use, endogenous opioid effects, and withdrawal developing and promoting new long-acting opioid formula- effects.50 It is beyond the scope of the present article to tions like MS Contin (Purdue Pharma LP, Abingdon, MD). describe these processes in detail, but whatever the The goals of palliative care and industry naturally coincided. underlying cause, there are shared cellular and molecular The principles of cancer pain treatment suited both stake- mechanisms for the hyperalgesia. Given the present state holders and their causes. of knowledge, one cannot assuredly implicate opioids as First proposed in the 1986 World Health Organization causing or worsening pain, because it is not possible to analgesic ladder approach for cancer pain, the titrate-to- unravel what is happening in an individual patient who effect principle (matching dose with effect) was predicated is not experiencing pain relief. However, based on both on analgesic doses being escalated to reduce pain levels as clinical experience and an understanding of basic mecha- much as possible, with no upper dose limit for opioids.56,57 nisms, lowering the dose for a patient on high-dose opioid Long-acting opioids were developed so that cancer patients therapy will not cause any worsening of pain other than would have more sustained pain relief. The concept that on a short-term basis.

Table 2. Adverse Events Associated With High Table 3. Proposed Pain and Reward Concepts and Dose Related Terminology Higher rates of overdose and death1–4 Pain Terms Reward Terms Less likelihood of being able to wean if necessary Perceived pain Pleasure, hedonia, euphoria Difficulty controlling acute pain, surgical recovery, and terminal pain (pain that is felt) (reward that is felt) Continued use during pregnancy—neonatal abstinence Physiological pain, nociception Reward (not necessarily felt) Higher rates of mental health and substance use disorder, less able (not necessarily felt) to control usage5–13 Persistent or pathological Addiction (a maladaptation of a Higher rates of falls and fractures in the elderly14 pain (a maladaptation of a physiological state) Less likelihood of returning to function or work15–20 physiological state) Higher rates of endocrinopathy affecting fertility, libido, and drive21–23 Higher rates of immune dysfunction24–27 High doses should be considered >90 mg morphine equivalent daily dose. longer postulated that opioid-induced pain relief and addic- The full list of references for this table is included in Supplemental Digital Content, Document, http://links.lww.com/AA/C19. tion occur as distinct processes in distinct areas of the brain. There are many ways in which pain and reward operate The other side of the dose/effect equation is perhaps together to maintain homeostasis, calculate pain salience, even more important than the titrate-to-effect principle, and produce learned protective and survival behaviors, tending over time to lead to higher doses that are neither both on an evolutionary and an individual basis.66,71–73 What effective nor safe. The effect, a lowering of the pain inten- follows is that whether or not pain relief is the goal of opioid sity, may be the wrong goal for chronic pain treatment. It treatment, opioid drugs used continuously will have effects has been argued that a lowering of pain intensity per se is far beyond simple analgesia. Addiction is not inevitable, but neither sufficient nor necessary for reducing the suffering alterations in hedonic tone, ability to feel pleasure, ability associated with chronic pain.64,65 Reducing a unidimen- to socialize, and ability to evaluate and prioritize will all be sional pain score using opioids may be the wrong focus, compromised.46,74 selects the wrong patients, and misunderstands chronic pain. For example, if using increasing doses of opioids to Pain Chronification in the Brain achieve repeated but nonsustained reductions in pain inten- There are many processes that contribute to chronic pain: sity comes at the price of less ability to function, such dose inflammatory, neuropathic, central, and psychological. escalation and titrating to effect has not improved health- Whatever the contributing causes of chronic pain, the con- related quality of life. Had the focus instead been on func- tinuous stress of chronic pain will produce responses in the tion and not on pain intensity, excessive dose escalation brain that can now be measured with functional magnetic would probably have been avoided. resonance imaging, combined with psychophysical, genetic, A patient’s self-report of high pain intensity may be as and other approaches. much a cry for help as it is an indication that a dose increase Accumulating evidence suggests that in chronic pain or even any opioid will help. By ignoring the patient behind states, the brain undergoes extensive reorganization sec- the pain score, we often miss that the patient with the great- ondary to aberrant learning.67,75–81 It has been proposed that est distress is likely to be the patient with the greatest risk experienced or perceived chronic pain results from dysfunc- for aberrant behavior and poor outcomes. This is the patient tional learning, which has been likened to the dysfunctional who may do better with alternative approaches. learning that converts functional rewards into the craving Finally, and most complex, we misunderstand chronic that defines addiction82–84 (Table 3). In both cases, the learn- pain if we oversimplify, or think that its intensity is all there ing is occurring in overlapping reward, limbic, and corti- is to it. Chronic pain comes in many guises, some of which cal centers, and is mediated by endogenous opioids and have obvious solutions such as primary disease manage- dopamine. This has led some investigators to propose that ment, surgery, injections, or physical therapy. But for the chronic pain is less a sensory problem and more a reward complex chronic pain patient, who is the most likely to enter problem.46 into chronic opioid therapy, pain has become chronicified The aim of the central processes and endogenous opioid largely through adaptations in the brain. These adaptations systems is to maintain homeostasis. For some individuals, involve the endogenous opioid system in reward, limbic, this successfully suppresses the pain experience; for other and cortical areas, now termed the “pain connectome” or more vulnerable individuals, it does not.85,86 A recent study “pain saliency network.”49,66–70 Endogenous and exogenous in patients with chronic back pain demonstrated how pain opioids have a greater effect on the emotional component of can shift from expected sensory regions in the brain into pain than the sensory, and that, in this respect, the salience limbic areas like the medial prefrontal cortex and amyg- or meaning of pain is more important than its intensity. dala.87 Germane to the use of opioids to treat persistent pain is that both endogenous and exogenous opioids suppress OPIOIDS AND THE BRAIN pain mainly through their effects in the emotional areas of Despite thousands of years of using plant-derived opiates the brain to which pain shifts as it chronicifies, with result- to treat pain, that opioids work via an endogenous opioid ing almost negligible effects on sensory transmission.71,88–90 system was not confirmed until as late as the 1970s. Since It follows that when an opioid is used to treat chronic pain, that discovery, however, our understanding of what opi- it is mainly treating the affective and not the sensory com- oids do to the brain has advanced rapidly, and completely ponent of pain. The treated patient may care less about pain, altered the way we think about pain and its treatment. It is but the pain itself is unaltered.

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Reward Deficiency and Chronic Pain has fortuitously produced a wealth of data from which Expanding upon that chronic pain is less a sensory prob- the United States and other countries can learn. One clear lem and more a reward problem, Elman and Borsook46 have message is that the patients taking high opioid doses are suggested that neural changes are similar between chronic the same people who could be predicted to have poor pain and long-term substance abuse; thus, the proclivity outcomes. In other words, their comorbidities predict out- for addictive behavior is ingrained in pain neuropathology. comes such as problematic opioid use, loss of control over Chronic pain produces a state of reward deficiency or anhe- use, opioid use disorder, accidental overdose, suicide, and donia, meaning that chronic pain patients have a reduced analgesic failure.23 These specific comorbidities include capacity to experience pleasure, similar to long-term sub- depression, anxiety, posttraumatic stress disorder, personal- stance abusers.74,91 Not only are the dopamine-mediated ity disorder, prior substance use disorder, and family his- wanting and opioid-mediated liking of normal rewards like tory of substance use disorder.27–30,99–103 food and sex diminished, the reward and salience associ- Patients who are taking high doses of opioids and are at ated with pain relief are increased. This sets the chronic pain risk of adverse outcomes are a self-selected high-risk group. patient up for incentive sensitization and craving, which This phenomenon has been termed “adverse selection.”104 It could ultimately lead to addiction. This is one of many cred- is possible that adverse outcomes are occurring not because ible reasons that rather than protecting from addiction, as of the high opioid doses per se but because of the risk factors we once thought, chronic pain is a risk factor for addiction. in the patients that tend to be prescribed high doses. They are not the patients taking stable low to moderate doses of Social Functions of Opioids opioids that are not escalated. They are also not the up to Interestingly, as organisms become more dependent on 40% of people who are started on chronic opioid treatment social functions, endogenous opioids play an increasing but discontinue them because they do not like the effects.16,17 role in socialization. In amphibians, endogenous opioids Why is this important? First, because it suggests that the have analgesic functions only. In mammals, endogenous pain patients who contribute to the sobering statistics of opioids play an additional and increasingly complex role abuse and deaths start out being at risk, and it is their risk in social behaviors that are crucial to survival. In humans, factors that put them on the trajectory to high and unsafe this extends to socialization necessary for the survival of the dosing. Second, because it ties in with what new research species, not just the immediate family or social circle. Carr92 is discovering, namely, that people with complex refrac- has recently argued that pain modulation by endogenous tory chronic pain tend to have reward deficiencies that put opioids is secondary in importance for humans to “behav- them at high risk for craving opioids, losing control of their ioral fine-tuning to help the population as a whole survive opioid use, becoming socially isolated, and being unable to threats beyond trauma to the individual.” carry out normal social functions. Human social interactions trigger the release of endog- It could be said that the US epidemic of prescription enous opioids. Recent human studies have concluded that opioid abuse and deaths has occurred because we have put the reward of social touch is mediated by endogenous opi- highly addictive drugs into the hands of a distressed popu- oids.93,94 The administration of a μ-opioid receptor antago- lation that is at high risk for not being able to control their nist decreases interest in social relationships, highlighting usage.105 The question should now be: can we control the the importance of endogenous opioids in social interac- epidemic by being more selective about who receives opi- tions.95 Separation elicits distress through low opioid recep- oid pain treatment? tor activity, while reunion elicits comfort through high Many lines of evidence support that it is increased pre- opioid receptor activity.96 Given that social function is so scribing for chronic pain that has produced the epidemic, important for human survival, the reinforcement of social not prescribing for acute pain or pain at the end of life. But bonds through opioid reward is an essential opioid function. this is because the amount of opioid used for chronic pain, Individuals who experience repeated social rejection which is open-ended, is necessarily much higher than the or abuse, particularly in childhood, may develop dys- amount used for acute or end-of-life pain, which are time- functional opioid regulation, which is thought to underlie limited.5 Moreover, prescribing for chronic pain generally many neuropsychiatric diseases, including posttraumatic gives control of opioids to patients themselves, whereas stress disorder, chronic pain, substance abuse, and depres- prescribing for acute and end-of-life pain is generally more sion.48,97,98 Early research on “opioidergic” tone suggest that controlled. Nevertheless, the treatment of acute pain with the innate properties of the endogenous opioids system opioids is a common gateway for long-term opioid prescrib- coupled with adaptations that could arise as an individual ing and, after surgery or trauma, has been a common source is confronted with stress could contribute to vulnerability of excess opioids in people’s homes. State governments are and resilience.85,86 Social rejection is thereby a common pre- now taking matters into their own hands and introducing cursor to risk for opioid craving, use, and abuse. dose limits for chronic opioid therapy106,107 and duration limits for acute pain.108 But if we understand adverse selec- ADVERSE OUTCOMES AND ADVERSE SELECTION tion and the effects of chronic pain and opioids on the brain, It has already been highlighted that many of the adverse will either of these initiatives actually control the epidemic? outcomes of chronic opioid treatment can be linked to high doses (Table 2).3,28,60–63 The United States may be the CONCLUSIONS only country where overprescribing of opioids has led to This article is written within the context of articles that relate an epidemic of abuse and deaths. This overprescribing the practice of anesthesia and pain medicine to the opioid

abuse epidemic. Hence, the author has chosen to review 4. Individuals who most want or need opioids are at new evidence on chronic pain and opioid mechanisms that the highest risk of poor outcomes, including inad- could help inform why the epidemic happened, how to stop equate pain relief despite repeated dose escalation, it, and how to avoid it in the future. problematic use, abuse, and death. Additional topics such as how-to-use-opioids-for- chronic-pain are not discussed here, since this information Principles for Opioid Prescribing in the Case of is available in multiple papers, guidelines, text books, web- Chronic Pain based educational materials, and the US Food and Drug Opioids are neither effective nor safe enough to warrant their Administration Risk Evaluation and Mitigation Strategies widespread use.34,35,109 We should begin to think of opioid (available online for prescribers of long-acting opioids). treatment for chronic pain as the exception rather than the The principles of safe prescribing of opioids for rule. The question of who the best candidates are for chronic chronic pain are summarized in Table 4. This article also opioid therapy is not simple, and not one that has achieved does not describe treatment approaches for the millions consensus. However, we can turn to early evidence that for of patients already dependent on opioids, often taking many common chronic pain conditions, such as nonstruc- doses that are higher than those currently recommended, tural low back pain and central pain states (typified by fibro- for example, by the US CDC. Although we are learning myalgia), alternatives to opioids, particularly behavioral and how difficult it is to motivate patients to taper or dis- physical treatments, appear to afford superior efficacy and continue opioid treatment, that not all individuals can greater safety.110–115 This suggests that for these common pain be tapered without risk of relapse, that buprenorphine/ conditions, opioids should not be used at all.116 naloxone is proving to be a useful tool for stabilizing An approach that the author finds helpful is that chronic opioid-dependent people, and that these patients need opioids should be reserved for cases that require comfort counseling as much as they need an opioid stabilization care and not functional restoration.117 This idea is based on regime, we do not yet have enough experience to know if what is now strong evidence that, again, contrary to what we are correct in this approach. This is an area in which we once believed, chronic opioid therapy delays rather than research is desperately needed. promotes functional recovery and return to work.118–123 This approach tends to eliminate young people who have many What We Can Learn From Existing Basic Science alternative approaches they can use, some tapping into their and Clinical Data own powerful endogenous opioid systems. 1. Opioid analgesic efficacy often declines with contin- We also now have the benefit of a wealth of new science uous use because of the adaptations of dependence that provides insight into what actually happens to the and tolerance, theoretically producing a state of con- brain when pain becomes chronic, how connected pain and tinuous withdrawal. This may not be true if opioids reward systems are through the endogenous opioid system, are taken intermittently. how this affects basic motivations and social functions, and 2. Applying the treatment principles of palliative care what happens to the brain when we use exogenous opioids. to chronic pain management, namely titrate-to-effect This all points to what was an emphasis in this article—that and breakthrough pain principles, has resulted in brain adaptations to exogenous opioids are more likely to very high-dose usage. High doses have been shown arise with continuous than intermittent opioid use. There to be unsafe and ineffective. are other reasons to avoid long-acting round-the-clock opi- 3. Chronic pain should be thought of as a stress oids when treating chronic pain, and this indeed has been response involving the endogenous opioid system a recommendation of the CDC,34,106 but the most fundamen- in reward, limbic, and cortical areas of the brain. tal reason is that if we put people into a state of continu- Contrary to previous beliefs, people with refractory ous withdrawal, we do not help their pain, we compromise complex chronic pain are at high risk of abuse. safety, and we change their motivations and beliefs. E

ACKNOWLEDGMENTS Table 4. General Principles for Safe Chronic Opioid The author acknowledges Thomas Vetter for his review and Prescribing input to the manuscript. 1. Start with full H&P, including making diagnosis and assessment of risk versus benefit. DISCLOSURES 2. Obtain a written agreement or “contract” with established goals. Name: Jane C. Ballantyne, MD, FRCA. 3. Risk stratify, and stratify monitoring and treatment accordingly. Contribution: This author was solely responsible for the 4. Check the prescription monitoring data (PDMP) with each manuscript. prescription. This manuscript was handled by: Honorio T. Benzon, MD. 5. Check a baseline UDT. Thereafter, check UDT, do pill counts, etc, REFERENCES as indicated. 1. Okie S. A flood of opioids, a rising tide of deaths. N Engl J Med. 6. Be prepared to taper and discontinue if goals are not met. 2010;363:1981–1985. 7. Use extra caution at high doses. 2. Gomes T, Mamdani MM, Dhalla IA, Paterson JM, Juurlink DN. 8. Prescribe naloxone if dose is high. Opioid dose and drug-related mortality in patients with non- 9. Do not use concomitant sedative hypnotics. malignant pain. Arch Intern Med. 2011;171:686–691. 10. Document. 3. Dunn KM, Saunders KW, Rutter CM, et al. Opioid prescriptions Abbreviations: H&P, history and physical examination; PDMP, prescription for chronic pain and overdose: a cohort study. Ann Intern Med. drug monitoring program; UDT, urine drug test. 2010;152:85–92.

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