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Refractory dependence on opioid analgesics

Ballantyne, Jane C.a,*; Sullivan, Mark D.b; Koob, George F.c

doi: 10.1097/j.pain.0000000000001680
Topical Review
Editor's Choice

aDepartments of Anesthesiology and Pain Medicine and

bPsychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, United States

cNational Institutes of Health, Bethesda, MD, United States

*Corresponding author. Address: Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Box 356540, Seattle, WA 98195-6560. Tel.: (206) 543 2568; fax: (206) 543 2958. E-mail address: (J.C. Ballantyne).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

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 this article on the journal's Web site (

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1. Introduction

In the present article, we argue that individuals with chronic pain on chronic opioids can develop a complex refractory dependence syndrome which we define here as Opioid Dependence. We further argue that Opioid Dependence is equivalent to the withdrawal/negative affect stage of the addiction cycle and should be recognized as a separate state from addiction.

Drug dependence suggests that an individual is dependent on the drug for well-being and often invokes the constructs of tolerance and drug opposite responses (withdrawal) when the drug is removed. Dependence and withdrawal can arise with any drug, but when the drug is addictive, the withdrawal symptoms contribute to the development and maintenance of the addiction. Long-term effects of substance misuse are understood as disorders of motivation that ultimately lead to deficits in executive function and pathological drug seeking42 (Fig. 1).

Figure 1.

Figure 1.

Defining drug dependence continues to be very confusing. Historically, dependence was defined by its physical withdrawal symptoms.67,68 Defined this way, and in current nosology, dependence and its associated withdrawal symptoms are associated with addiction, but remain a feature of, and not the same as, addiction. Moreover, these withdrawal symptoms are seen as reversible; in the case of opioids, they are expected to subside within days after discontinuation. By contrast, Substance Dependence was defined in DSM-IV as a syndrome equivalent to addiction where one needed to meet 3 of 7 criteria, tolerance being one, and withdrawal symptoms (also defined as dependence) being another.1 This labeling produced substantial confusion in conceptualization in the field. Partly as a result, DSM-5 adopted the term Substance Use Disorder (SUD) with tolerance and withdrawal still being criteria, except under conditions of medical use. For our purposes, there are 2 critical points which will frame our arguments. (1) Withdrawal after prolonged opioid use is multifaceted and often protracted. (2) For the rest of the article, we will use dependence with a little “d” as a general term for any drug dependence or the manifestation of any withdrawal syndrome for any drug. Should we use the term Substance or Opioid Dependence, we will use the capital “D” to refer to a severe persistent state and a specific syndrome (Fig. 2).

Figure 2.

Figure 2.

When opioids were first promoted as safe and effective treatment for chronic pain, the argument for safety relied on the argument that dependence would reverse within days, and the treatment could be easily stopped after a taper if necessary. But, experience does not bear this out.44,70 Attempts to taper in patients whose opioid therapy has become unhelpful or unsafe have exposed a new problem which we define as: refractory Dependence on opioid analgesics. For patients with this condition, tapering is extremely distressing, prolonged, and, in many cases, not tolerated (with the risk that patients seek opioids elsewhere).17 Early attempts at structuring treatment algorithms for the condition suggest an urgent need to provide a definition and a diagnostic label, so that the appropriate resources can be summoned and not hampered by confused terminology (Fig. 3). This topical review will examine the vexed question of how refractory Dependence on opioid analgesics fits into current understanding and terminology of addiction.

Figure 3.

Figure 3.

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2. Dependence vs addiction

Is opioid dependence the same as opioid addiction, a feature of opioid addiction, or distinct from opioid addiction? These questions have produced a great deal of confusion, and indeed, there still are no completely satisfactory answers.7,16,51 Drug addiction has long been understood as compulsive use of a drug and loss of control over drug intake. When opioids began to be used much more widely for the treatment of chronic pain in the late 1980s, the confusion produced by designating drug addiction “Substance Dependence” in DSM-IV became all too apparent.6 Patients treated with opioid analgesics could develop dependence, since this was an inevitable consequence of the round-the-clock administration of opioids that had become popular, but this dependence did not necessarily fit criteria for addiction. One argument was that the withdrawal due to opioid dependence in patients with pain is merely “physical” and easily reversible.67,68 In part, confusion arises because “physical” can refer purely to reversible somatic symptoms such as muscle and joint pain, nausea and abdominal pain, agitation, and runny nose, leaving out other “emotional” symptoms; or the term “physical” or “physiological” can be used to encompass the more refractory withdrawal symptoms of pain, misery, irritability, dysphoria, and malaise.59 This broader understanding of “physical” subsumes “emotional” within “physical,” understanding that “emotional” withdrawal involves physical/physiological (molecular/neurochemical/neurocircuitry) changes in the brain's emotional and motivational systems. Nevertheless, the withdrawal seen in patients on established and continuous opioid therapy clearly consists of distressing and hard to reverse emotional as well as physical (somatic) symptoms.14,37,42,59 Is their dependence different from or simply a form of Opioid Use Disorder (OUD), and if different, should it receive its own diagnostic label?

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3. Opioid addiction in the spectrum of other drug addictions

All drugs of addiction have rewarding effects achieved either directly or indirectly through changes in reward neurocircuitry in the basal forebrain42 Drug effects on this neurocircuitry drive the initial positive reinforcing effects of addictive drugs, but positive reinforcement is gradually replaced by negative reinforcement or the need to continue taking the drug to avoid its negative effects. Here, neuroadaptations involve a compromised reward neurocircuitry and a recruited brain stress neurocircuitry. Thus, negative reinforcement is seen as a powerful factor driving continued drug seeking and drug use.27,28,40 Addiction research continues to be focused on the processes by which people become addicted and why the processes culminate in brain changes that are long term and persistent. Much of the early animal research has been now extended by advanced imaging and molecular genetics allowing for studies to be conducted in humans. What has been learned from the more sophisticated neurocircuitry studies is how the reward system is compromised, stress is activated, and executive function is dysregulated, leading to the development and intransigence of addiction, which arises through functional neuroplasticity in motivational systems extending anatomically beyond the basal forebrain, to the temporal lobe, and into the frontal cortex.8,12,31,33,42,45,66 (Fig. 1).

The 3 stages of addiction—binge/intoxication, withdrawal/negative affect, and preoccupation (“craving”)—are now seen as occurring in distinct neural circuits of the brain (Fig. 1).42,67 Although the initial stage of binge/intoxication results from changes in the basal ganglia, the second withdrawal/negative affect stage results from rebound negative effects in the same area together with recruitment of stress neurotransmitters such as corticotrophin releasing factor and dynorphin in the extended amygdala. The third preoccupation/anticipation stage involves dysregulation of key afferent projects to the basal ganglia and extended amygdala from the prefrontal cortex.19,39,41,72

Although most drug addictions fit into the three-stage cycle and share similar mechanisms, there are several ways in which opioid addiction is unique. Opioid addiction is inexorably bound with physical and emotional pain, where other drugs such as alcohol interact more with emotional pain than physical pain. Although nonopioid addictive drugs have their rewarding effects indirectly through endogenous opioids and dopamine, exogenous opioids produce their rewarding effects directly, a process that commandeers opioid receptors widely, may usurp the actions of endogenous opioid peptides, and alters the natural balance between intrinsic opioid reward and other opioid effects such as their pain-relieving effects. Although all addictive drugs serve to exaggerate incentive salience, pathological habits, and drug seeking,13,26,38 opioid drugs dramatically overwhelm natural pain relief and upend the physiological balance between pain and reward.53,60,61,71 Drug withdrawal is often painful, but the pain of opioid withdrawal is particularly powerful given the acute effects of opioids to relieve pain. The emergence or reemergence of pain (a drug opposite effect) is an important and relevant withdrawal phenomenon, and opioids, including illicit opioids, are often started to relieve such pain. In patients with chronic pain, this means that opioid-induced pain (withdrawal hyperalgesia) can be an important factor driving continued opioid use, thus driving a vicious cycle of both relieving and creating pain.52,55,56 In other words, one is taking opioids now to fix the problem (pain) that opioids caused (hyperalgesia). Even worse, such pain is not only physical but involves emotional pain, termed hyperkatifeia.37,59 Not only does opioid withdrawal tend to persist for longer than other drug withdrawals but also brain pain emotional systems are sensitized by repeated withdrawal, and the hyperkatifeia produced can persist into protracted abstinence.36,37,59,67

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4. Why opioid use as pain treatment is different

The argument that the dependence developed by patients with pain consists only of physical symptoms that will reverse within days or can be avoided by a slow taper is based on the clinical experience in patients with acute, subacute, or short-lived pain, whose pain is more straightforward and predictable, usually people with low risk of developing addiction. In these cases, there may be symptoms of withdrawal upon rapid cessation or tapering, but they will resolve within days.32,40,67 This short-lived withdrawal depends upon the risks being low, the circumstances and motivations for opioid use being uncomplicated, and the usage being relatively short-lived. However, there are other circumstances in which the trajectory is more complicated and unpredictable. Take the individual with high risk, which includes adolescents and young adults who may not display comorbid risk factors because of their young age, and who carry extra risk because they are more willing to take risks, to experiment with drugs, and to be subject to peer pressure.11,29,47,48,57 They can rapidly develop escalating use once exposed to pain treatment and thus be set on a pathway towards addiction.

However, there is another more common pathway that is more insidious, which is the pathway taken by many patients treated with opioids for chronic pain. Continued use of opioids is actually the exception rather than the rule, and studies show that in the order of 60% of those starting chronic opioid treatment abandon the treatment.34,62,69 Patients who continue use tend to have a more complex presentation and have often had stressful lives characteristically plagued by psychological trauma, especially childhood abuse.21,58 Similar to the above, comorbid psychiatric disorders such as depression, anxiety, and post-traumatic stress disorder are common.18,35,63 Chronic pain also may be a result of dysfunctional learning that involves emotions more than sensations.2–4,30,49,54,64,65 Some researchers have gone so far as to propose that addiction risk becomes embedded in the neurophysiology of chronic pain as it becomes entwined with depression and reward deficiency.9,10,20–22,73 All told, the circumstances and motivations that lead patients with chronic pain into chronic continuous opioid use are tremendously varied, which means that the ways in which their dependence on opioids is manifest are also tremendously varied. Yet, their dependence is rarely manifest simply as reversible somatic symptoms and is much more likely to be manifest as refractory physical and emotional distress. Although the 3 stages of addiction have historically been seen as a progression or a spiral where each stage progresses in succession, the entry point theoretically could be through any of the 3 stages.38,40,41 We argue here that for patients using opioid analgesics long-term and continuously, the withdrawal/negative affect stage (stage 2) of addiction is the main entry point. This hypothesis is supported considering that the complex and refractory dependence we now see in patients receiving long-term opioids (such long-term usage for pain being unprecedented) shares many of the characteristics of opioid addiction that arise during stage 2 (Fig. 1) and further reinforced, considering that the hypernegative emotional state (hyperkatifeia) does not end with acute withdrawal and can extend into prolonged abstinence.36,59 It is also proposed that long-term continuous medical opioid use, through similar neuroadaptations seen in nonmedical opioid abuse, can exacerbate comorbidities of chronic pain such as depression, reward deficiency, and social isolation. It should be noted that long-term continuous medical opioid use has become much more common since the introduction of extended-release opioids which are designed to be given round-the-clock. We would argue that this state is similar to addiction and shares many of the characteristics of addiction, including long-term persistence. One also sees a rapid transition into the preoccupation/anticipation stage, with profound craving, if opioid analgesics are withheld too rapidly.

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5. Is the Opioid Dependence of patients with pain different from or simply a form of Opioid Use Disorder?

Advances in neurobiological research have helped us understand how the brain adapts to exogenous opioids beyond their relatively simple reinforcing effects to their usurping of circuits involved in executive function, motivation, and stress. These adaptations evolve over time as a product of learning based on the motivations for, and results of, drug use. Are these changes unique to individuals whose drug use is nonmedical, or could they also arise in individuals who are prescribed opioids for the treatment of pain?

One could argue that any patient who takes opioids continuously and long-term, more than likely at high doses, will develop a complex Dependence equivalent to the withdrawal/negative affect stage of addiction which should be recognized as a separate state from addiction/OUD, which we define here as Opioid Dependence, In fact, clinical experience strongly supports that patients treated with a long-term course of opioids do develop a complex Dependence with negative affect, stress-like symptoms, reward deficiencies, feelings of unease and not feeling “hedonically normal,” social isolation, and difficulty tapering (Fig. 2).37,59 Many patients who struggle to taper do not fit neatly into DSM-V criteria, and whether or not their symptoms meet criteria for OUD can be a matter of interpretation.

Since the earliest attempts to define drug addiction at the beginning of the 20th century, it has been necessary to develop new criteria in response to emerging knowledge. Drug addiction criteria, terminology, and definitions in DSM-IV (1994) and DSM-V (2013) differed substantially from each other and from previous versions, in no small part because of a changing experience of using opioids for the treatment of chronic pain. Accommodations were made for patients with pain who were treated with opioids, but unfortunately, even DSM-V criteria1 are problematic when we try to apply them to patients with pain. In part, DSM-V criteria are problematic in these patients because the behaviors listed are not the behaviors seen in patients with pain who are dependent on opioids. In part, the criteria are problematic because they force a binary choice between having an OUD, whether mild, moderate, or severe, and not having an OUD. This binary choice between having and not having an OUD diagnosis consequently affects the pain treatment that can be offered, which treatments will be covered by insurance, which treatments can be used without fear of censure, and possibly patient employment and child custody. And, in part, they are problematic because they discount tolerance and withdrawal which are central to, and in fact define, the disorder Opioid Dependence. We believe that Opioid Dependence exists as a state that is distinct from OUD as currently defined, and that when diagnostic criteria are next revisited, consideration should be given to making opioid Dependence its own diagnostic category, so that treatments can be better tailored to the condition.

The question of whether or not to use the label Opioid Dependence also has significant practical implications. It is beyond the scope of the present article to describe how refractory analgesic Opioid Dependence should be treated, suffice it to say that current treatment aims to reduce opioid dose to within recommended limits, or maintain with buprenorphine if tapering fails, using counseling as an indispensable adjunct24,25,43,50 (Fig. 2).

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6. Conclusion

Perhaps, the strongest reason for rethinking opioid dependence has been the recent experience of trying to taper patients who have received opioids, often at high dose, and for many years. It is estimated that there are millions of these patients in the United States at least, likely also in other countries such as Canada, where opioid treatment of chronic pain with open-ended dosing became common practice.15,23 Now that the dangers and ineffectiveness of high-dose opioid treatment have been recognized, patients are being offered a taper, especially if stable and effective use cannot be established (Fig. 3). Although some patients tolerate a taper well, especially those at the lower end of the dose range, many patients suffer distressing and painful withdrawal symptoms, and if tapering is undertaken too rapidly, pathological opioid-seeking behaviors and/or depression with suicidal ideation may emerge. The taper appears to unmask brain adaptations that were created and suppressed by continuous opioid therapy, just as they are during opioid maintenance treatment for addiction.

As the number of patients grows who have difficulty tapering their opioids despite poor pain control, the pain and addiction fields have moved closer to accepting that withdrawal from opioid pain treatment is not simple or easily reversed.39,42,59 To make matters worse, the neuroadaptations of withdrawal contribute to tolerance and likely account for many opioid analgesic failures,5,7,46,56 a topic that will be explored elsewhere. Neurobiological research has revealed vulnerabilities associated with complex chronic pain that make it likely that long-term users of opioid pain treatment adapt to continuous use in much the same way as nonmedical users, albeit with different motivations and behaviors. Our recent experience from the current era of high-dose prolonged opioid pain therapy has revealed many similarities to prolonged illicit use both from a neurobiological perspective, and from its clinical manifestations. We support the use of the term Opioid Dependence because it is less stigmatizing than OUD and can be accepted as a state with similarities to OUD and requiring of treatment. The case that Opioid Dependence is a state independent of OUD, and deserving of its own diagnosis and its own treatment algorithms is strongly supported (Fig. 3).

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M.D. Sullivan has received educational grants from Pfizer and Covidien and served on an advisory board for Janssen. Dr Ballantyne is a paid consultant in opioid litigation. The remaining authors have no conflicts of interest to declare.

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