Thursday, August 23, 2012
The onerous specter of addiction resulting from the long-term administration of opioid analgesics in patients with chronic pain has often been raised in reports from various sources and in sensational news stories. In actuality, “addiction” is probably one of the most overused and misunderstood terms in medicine, and the absolute risks of addiction newly emerging during analgesic therapy are still uncertain. Now, a recent article suggests that addiction might be better understood in patients receiving opioid therapy as a complex persistent opioid dependence; however, this may be an oversimplification.
Illicit opioids, like heroin, are well-known to produce an addiction disorder in persons who repeatedly abuse the substances for their mood-altering effects. At the same time, medicinal opioids are powerful analgesics that, when properly prescribed and used, can provide vital relief of physical pain and emotional suffering. Within the medical community there is ongoing concern about how opioid analgesics can be safely prescribed long-term for treating chronic pain without the unintended consequence of new (de novo) addiction arising as a direct result of the therapy (iatrogenic).
Writing in an early online edition of the Archives of Internal Medicine, Jane Ballantyne, MD, Mark Sullivan, MD, PhD, and Andrew Kolodny, MD, present their opinions regarding addiction in persons who are administered opioid analgesics continuously and long-term [Ballantyne et al. 2012]. In these patients, they contend that, “biologically, opioid addiction can be understood in terms of neuroadaptations,” with two of those being tolerance and dependence.
- Tolerance, they note, is the need for increasing opioid dose to maintain the same effects. It may develop for both the euphoric and analgesic effects of opioids, and it can be influenced by psychological as well as pharmacological factors.
- Dependence is the physiologic response either to an uncompensated increase in tolerance or to the withdrawal of a drug. The latter is revealed as unpleasant symptoms — eg, sweating, anxiety, insomnia — as well as hyperalgesia (increased pain sensation) and anhedonia (inability to feel pleasure). Withdrawal hyperalgesia and anhedonia may explain the worsening of pain and mood that is seen during an opioid taper or after detoxification; although, pain may be augmented by psychosocial stressors that influence a perceived need for more opioid medication.
The authors assert that withdrawal symptoms are powerful drivers of opioid seeking. In this regard, addiction is further defined by aberrant behaviors that, when persistent, “result in irreversible changes in the brain.”
The authors concede that “standard drug addiction criteria have long been unsatisfactory when attempting to assess iatrogenic addiction in persons with pain.” For the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [discussed in prior UPDATE here], tolerance and withdrawal — classified as “physical dependence” — will be specifically excluded from the diagnostic criteria for iatrogenic substance-use disorder (eg, addiction), so that the diagnosis will be based solely on behavioral factors denoting aberrant drug seeking and use.
However, the authors further acknowledge that drug-seeking behaviors in patients with pain are different from those listed in standard substance-use disorder criteria, and are focused on obtaining opioids from prescribers. Therefore, they claim such “aberrancy” might include “doctor shopping, frequent lost prescriptions, and repeated requests for early prescriptions.” Meanwhile, behaviors listed in DSM-5, and the present DSM-IV, such as “failure to fulfill major role obligations at work, school or home,” can readily be attributed to pain rather than to addiction.
In fact, they state, “pain patients who are treated continuously with opioids may not manifest any aberrant behaviors because they are effectively receiving maintenance therapy, which suppresses craving.” However, the authors believe that opioid craving and addiction behaviors may emerge if opioids are suddenly not available, tolerance occurs, or attempts are made to taper the medication.
In the past, such behaviors have been attributed to “pseudoaddiction,” which Ballantyne and colleagues assert is “a misleading term that suggests that aberrant opioid seeking is predominantly a consequence of inadequate pain relief and should be addressed by increasing opioid dose.” As a concept, pseudoaddiction implies that opioid seeking will cease if an “adequate dose is reached,” but the authors assert that this is not apparent in the long-term treatment of chronic pain with opioids.
To exemplify their position, the authors point to fairly recently implemented opioid prescribing regulations in Washington State, where two of the authors are located (Ballantyne and Sullivan). New rules set a ceiling threshold on daily morphine-equivalent opioid dosing for chronic pain that would require consultation with a pain specialist, unless the patient is already functioning well at a stable or tapering dose.
As the rules came into effect, the authors recall that clinicians started to taper high-dose opioid therapy in their patients. “In some cases, this tapering has occurred because the rule has been misunderstood, leading prescribers to taper doses in patients who have been stable for years, resulting in the reemergence of severe pain and extreme anhedonia, both of which are likely to be withdrawal effects,” the authors state.
The lesson learned from this is that withdrawing patients from well-established, long-term opioid therapy can destabilize them, incurring craving and “aberrant behavior.” The authors claim that, “The opioid dependence that we once believed to be short-lived or easily reversed is sometimes seen to persist as complex persistent dependence for months after a taper” [emphasis added].
Ballantyne et al. observe that the persistent opioid dependence is both physical and psychological, and is not easily reversible. They say that many patients treated long-term with high-dose opioids are unwilling to taper the medication despite “continuing pain and known risks.” For such “recalcitrant cases,” understanding dependence and accepting that it may require therapy similar to addiction maintenance treatment — including a structured environment, ongoing counseling, and monitoring — “will go a long way toward being able to treat the patients without removing a class of medications on which they have become dependent,” they state.
However, at the same time they assert, “In light of new evidence that is revealing the limitations and dangers of high-dose long-term opioid therapy, we can and must question the wisdom of providing such therapy in the first place.” They do accept that patients who are already dependent on opioid therapy should not be abandoned; but, “The question is whether to maintain these patients on a regimen of opioids with the usual precautions or to try to taper their doses at least to a safer level.”
COMMENTARY: Unclear Distinctions
The title of this paper by Ballantyne and colleagues — “Opioid Dependence vs Addiction: A Distinction Without a Difference?” — is beguiling, but confusing. They actually do not clearly define distinctions between dependence and fully manifested opioid addiction; instead, the authors seem to conflate addiction in patients treated for pain with their concept of a persistent dependence syndrome and suspected aberrant behaviors.
They acknowledge that the usual criteria for diagnosing opioid addiction are not appropriate in patients treated for pain and conclude, “Whether or not it is called addiction, complex persistent opioid dependence is a serious consequence of long-term pain treatment that requires consideration when deciding whether to embark on long-term opioid pain therapy as well as during the course of such therapy” [emphasis added]. Certainly, this interpretation of addiction is intended to question the prudence of starting or continuing opioid therapy for chronic pain.
It should be noted that all 3 authors were cosigners of a recent petition to the FDA requesting opioid analgesic labeling changes that would restrict prescribing dose and time limits, and confine use to only severe pain in the case of noncancer conditions [discussed in UPDATE here]; so, there may be some biases reflected in this journal article. It is disappointing that they do not provide any research-based data on the incidence and severity of “complex persistent opioid dependence,” so the reader is left to wonder if this occurs in all patients and to the same degree.
Based on the receptor-based pharmacology of opioids, it has long been understood that during continuous administration, there is a potential for physiologic dependence to develop over time, namely tolerance and adverse withdrawal effects. However, in principle, is this sort of dependence so vastly different than occurs with other medications for chronic conditions, such as certain antidepressants or cardiac agents and many other long-term pharmacotherapies?
With any of these, patients need to be informed at the outset that taking the medication may incur certain adverse effects and become a lifelong therapy, and that discontinuing the regimen may be difficult, uncomfortable, and/or result in exacerbation of their medical condition. In balance, however, the medication may allow patients to live more functionally normal and productive lives.
A question not asked by Ballantyne and colleagues is: Would a fully informed patient with chronic pain, knowing the risks of dependence, still consent to long-term opioid therapy? Without the prospect of better, more effective alternative therapies, it might be surmised that a great many patients would likely answer “yes.”
Of course, a key difference is that persons with depression or heart conditions typically do not have to worry about receiving ongoing and adequate prescriptions for their medications; whereas, the continuation of adequate opioid therapy for chronic pain is much less certain in today’s climate of opioid regulation, plus concerns about nonmedical use or diversion with attendant overdose and death.
While Ballantyne et al. dismiss pseudoaddiction as a valid concept, it still seems understandable that, faced with uncertainties about a continuing and adequate supply of medication, bona fide patients who are physiologically dependent on opioid analgesics might exhibit what some consider “aberrant drug-seeking behaviors.” For example, although it is not to be condoned, some patients might “doctor shop” to assure alternate sources of vital analgesics.
Furthermore, in an interesting article on the subject, Alford et al.  describe a condition of “therapeutic dependence” whereby patients exhibit what is considered drug-seeking because they fear the reemergence of pain and/or withdrawal symptoms from lack of adequate medication; their ongoing quest for more analgesics is in hopes of insuring an acceptable level of comfort. These authors also propose “pseudo-opioid resistance” as describing patients with adequate pain control who continue to report pain or exaggerate its presence, as if their opioid analgesics are not working, to prevent reductions in their currently effective doses of medication.
Clearly, these situations pose dilemmas for both patients and prescribers. Ballantyne et al.  caution that embarking on long-term opioid therapy must be cautiously considered at the outset, with well-informed patient consent. And, once this therapy is started, they allow, these patients should not be abandoned and opioid analgesia should be viewed as other ongoing therapy for a chronic condition that may last a lifetime, including a supportive and structured clinical environment with patient monitoring and counseling as appropriate. That sounds like good old-fashioned sound medical practice.
Backstory Sheds More Light
A great deal more can be written on this subject of opioid addiction versus dependence in patients with pain, and the true distinctions. But, to limit the discussion, we should note that some aspects of the present article by Ballantyne et al.  may be unclear because, in many respects, it appears to be a shorthand version of an earlier, longer, and much more enlightening review article by the lead author, Jane Ballantyne (along with Steven LaForge) [Ballantyne and LaForge 2007].
In this earlier article, Ballantyne and LaForge point out that drug-seeking behaviors associated with opioid analgesic withdrawal “must be distinguished from long-term drug craving and the compulsive drug-seeking of addiction.” They explain at great length how true addiction is a quite complex multistage syndrome with neurobiological, psychosocial, and genetic components that manifest as an enduring pattern of deviant behaviors.
They also stress that inconsistencies in addiction terminology have greatly confused attempts to define and measure iatrogenic opioid addiction resulting from its use during pain treatment. Psychological and physical dependence may arise independently of addiction in persons with pain, and problematic opioid use and other aberrant behaviors once thought to be cardinal symptoms of addiction or substance abuse are inapplicable in the pain management setting.
Ballantyne and LaForge further assert that physiological dependence is a common and natural consequence of long-term opioid administration, and it might start to develop after as few as 3 days of continuous opioid use. However, in some cases, tolerance may relate more to disease progression or a change in pain status requiring added medication and can be mistaken for analgesic tolerance. The picture is further complicated by psychiatric comorbidities in persons with chronic pain, which can distort the presentation of physical and psychological symptoms of dependence as well as problematic opioid use.
Very importantly, Ballantyne and LaForge also state the following…
“When patients are maintained on opioids for the treatment of pain, there is currently no satisfactory means of distinguishing true addiction from problematic behaviors caused by a variety of factors other than addiction. Unfortunately, advances in understanding the neurobiological foundation of addiction have not been matched by any improvement in physicians’ ability to recognize and diagnose the condition. There is no single diagnostic marker of addiction, no definitive change on brain imaging and as yet no genetic markers to provide a reliable prognosis of risk. When it comes to iatrogenic opioid addiction, the clinician is faced with even greater difficulty: the behaviors encountered do not resemble those outlined in the criteria for addiction to illicit drugs.”
“One of the great difficulties of quantifying, recognizing, and treating iatrogenic opioid addiction is the subjective nature of the judgment on whether behaviors have crossed an ill-defined boundary between problematic opioid use and addiction. This judgment then becomes dependent on the reporting person’s experience, prejudices, and knowledge.”
Given the difficulties of definition, observation, and measurement — and potential influences of bias and prejudice — it is not surprising that estimated risks, prevalence (which includes pre-existing substance-use disorders), and incidence rates of de novo iatrogenic opioid addiction in persons treated for chronic pain have varied widely. Ballantyne and LaForge describe in some detail (with references) how reported addiction rates during opioid analgesic treatment have ranged from 0.03% to 50%, with discrepancies being clearly dependent on criteria used by investigators to define alleged addiction. Much of the data also have been discussed in a Pain-Topics e-Briefing report [2008, PDF here].
An often-cited systematic review of 67 studies by Fishbain et al.  found opioid abuse/addiction incidents rates of 0% to 50% among patients in pain treatment. Of 2,507 patients studied, there were only 82 with alleged addiction for an overall incidence of 3.27%. However, none of the investigators used validated criteria of addiction and most cases represented signs of physiological dependence, problematic opioid use, and/or drug-seeking behaviors rather than observations of what might be construed as true addiction in patients with pain.
Two fairly recent and frequently-cited studies by Boscarino and colleagues [2010, 2011; also discussed by Twillman in an UPDATE here] used validated DSM-IV and DSM-5 criteria of addiction to assess patients receiving long-term opioid therapy for chronic noncancer pain. They reported that 26% of subjects met criteria for current opioid addiction and 35% to 36% for lifetime addiction; although, it is not known what percentage was de novo iatrogenic addiction. Furthermore, as conceded above by Ballantyne et al.  and Ballantyne and LaForge , without significant adjustments, DSM criteria are inapplicable or misleading in persons with chronic pain; so, the findings of Boscarino et al. are most likely distorted and invalid.
The most convincing evidence of this misrepresentation had been presented in a study by Elander et al. . Using standard DSM-IV criteria they found that 31% of a sample of patients with sickle cell disease taking opioids for pain met criteria for substance dependence (ie, addiction) — remarkably similar to the results of Boscarino et al. However, when the assessment was limited to only non-pain-related symptoms, the addiction incidence rate fell to merely 2%. In other words, if symptoms that could be related to seeking pain relief are discounted, radically fewer patients meet criteria for addiction. (This study also was acknowledged by Ballantyne and LaForge  in their paper, but was not referenced by Boscarino et al.)
If nothing else, the extreme range of alleged “addiction” reported in the various studies to date suggests that little is known about the true risks and occurrence rates of this disorder in persons with chronic pain maintained on long-term opioid therapy. As Ballantyne and LaForge state, “Overall, there remains considerable uncertainty about rates of iatrogenic opioid addiction, and this uncertainty is largely related to lack of consensus on definition and on the distinction between problematic opioid use and true addiction.”
However, it should be recognized that, even though de novo iatrogenic opioid addiction rates among pain-treated patients are largely unknown, it still might be expected that substance abuse or addiction could be present in the population of persons with chronic pain to an extent worthy of concern. This is accepting that the prevalence of abuse/addiction in persons with pain might match that of the general population, which some authorities estimate to be 13% [in Jones et al. 2012]. This takes into account that a certain percentage of persons coming into pain treatment may have current or past substance-use disorders, whether abuse or addiction and related to opioids or to other drugs including alcohol.
Opioid-treated patients with pain who develop addiction during treatment undergo the same initial physiological adaptations as illicit opioid users, Ballantyne and LaForge  observe. “Yet in pain patients,” they state, “the clinical picture of progression from use to problematic use to addiction differs markedly from that in illicit users. Continued use in an illicit setting often progresses rapidly to addiction, to the extent that dependence and addiction are indistinguishable, and this rapid progression is likely accounted for by the circumstances and motivations associated with illicit use.”
However, in patients with pain the picture is different. If the progression from simple dependence through problematic use to addiction occurs, it is more subtle and insidious. While, addiction may emerge as a separate syndrome, it is less obvious and much more difficult to identify in pain treatment settings, but it is distinct from physiologic dependence.
Ballantyne and LaForge acknowledge that the most difficult question is whether certain patients should be excluded from opioid pain treatment altogether, which raises thorny ethical dilemmas. While it might be assumed that patients with known substance-use disorders carry inordinate risks of problematic use or addiction during opioid therapy for pain, the authors claim that “evidence to date suggests that even these high-risk patients do not necessarily present an increased risk during pain treatment.”
In part, this may relate to the fact that the opioid itself is only one component of much more complex circumstances involving psychosocial, genetic, and other factors that foster addiction. Thus, Ballantyne and LaForge propose, “provided the treatment is ‘medicalized,’ and the circumstances associated with abuse are avoided, it is possible that the drug itself will not reinstate addiction.”
These authors emphasize that more research is needed to find ways of better identifying risk and deterioration factors leading to iatrogenic substance abuse or addiction. Also, it would seem that better protocols are needed for comfortably tapering patients off of opioids if that becomes necessary, along with safe and effective options for replacing analgesia in these patients so they are not left to suffer without hope of pain relief.
Concluding Notes on Addiction — Distinctions Do Make a Difference
A great deal has been written about addiction — what it is, who develops it, how it destroys lives. Yet, relatively few healthcare professionals really understand the true and vicious nature of the disease. Even persons who once became lost in the dark labyrinth of addiction, and later found their way out through an ongoing program of recovery, can at best describe the “green-eyed monster” that prowled the passageways as cunning, baffling, and powerful.
In an interesting essay on “The Role of Addictions in Human Culture” [here], Vikas Shah observes that various psychoactive drugs have been used and abused by humans for thousands of years, but only toward the end of the 19th century did “addiction” begin to be used in describing a preoccupation with drugs. Opium and its opiate derivatives were openly and legally used in the U.S. and many other countries until the beginning of the 20th century, and alcohol was thought to cause far more health damage — in fact, opium or morphine was used as an alcohol substitute to treat alcoholics.
During the 20th century addiction took on new meaning; that of an uncontrollable “disease.” This disease — referred to as “dependence” by the American Psychiatric Association and World Health Organization — was characterized by the state of needing or depending on a substance “for support or to function or survive…,” which presents as “…a cluster of cognitive, behavioral and physiologic symptoms that indicate a person has impaired control of psychoactive substance use and continues use of the substance despite adverse consequences….”
At greater length, about a year ago in August 2011, the American Society of Addiction Medicine (ASAM) came out with a new Policy Statement [here] presenting their definition of the disease of addiction. The short version states:
“Addiction is a primary, chronic disease of brain reward, motivation, memory and related circuitry. Dysfunction in these circuits leads to characteristic biological, psychological, social and spiritual manifestations. This is reflected in an individual pathologically pursuing reward and/or relief by substance use and other behaviors.”
“Addiction is characterized by inability to consistently abstain, impairment in behavioral control, craving, diminished recognition of significant problems with one’s behaviors and interpersonal relationships, and a dysfunctional emotional response. Like other chronic diseases, addiction often involves cycles of relapse and remission. Without treatment or engagement in recovery activities, addiction is progressive and can result in disability or premature death.”
ASAM stresses that those descriptive features are not intended to be used as “diagnostic criteria” for determining if addiction is present or not, and each feature may not be equally prominent in every case [also discussed in an UPDATE here]. Application of their definition to persons with chronic pain is not discussed by ASAM, but they emphasize that diagnosis of addiction requires a comprehensive biological, psychological, social, and spiritual assessment by a trained and certified professional. It is significant that the organization recognizes spiritual manifestations as worthy of notice, and that addiction is a progressive and potentially deadly condition.
In The War of the Gods in Addiction [2009, here, pp 4-5], psychoanalyst David E. Schoen, LCSW, MSSW, describes rather dramatically what he believes are two essential components of addiction…
“First, the addictive substance… must ultimately take over complete and total control of the individual, psychologically. That is, it must take over control of normal ego functioning — thoughts, emotions, perceptions, motivations, judgments, decisions, actions, and behaviors.”
“And the second part of this definition is crucial: the addiction takes over control in an inherently destructive and ultimately life threatening way. It is not an addiction unless it is a death sentence… of the mind, of the emotions, of the body, and of the spirit. It is a death sentence to the addict’s career, community, marriage, family and friends. It is not an addiction unless it has the lethal capacity and potential, the power to kill the individual. It is not an addiction unless it is the most powerful, controlling, possessing, dictating, and determining agenda in the psyche. It must take precedence over everything else.”
If one accepts this definition, then addiction is a quite significantly different and distinct “beast” from the complex persistent dependence described by Ballantyne et al. . Addiction is not a term or a diagnosis to be applied casually or dispassionately; for those truly afflicted, it is of life-consuming and mortal consequence.
Of further concern, Schoen’s characterization is how many persons with unrelieved pain might describe their condition as a “death sentence” — substituting the words “chronic pain” for “addictive substance” or “addiction” in the above description. And, regarding mortality, some research has indeed demonstrated significant links between unrelieved chronic pain and premature death [UPDATE here], as well as increased suicide risk [see UPDATE here and here] in these patients.
The prospect of dire outcomes for patients without relief of chronic pain is something to consider when debating whether long-term opioid therapy, even with its attendant physiological dependence, might be suitable. Or, in deciding whether opioid analgesics should be tapered or discontinued in a patient stabilized on adequate dosing, no matter what the dose or the duration of therapy.
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- Ballantyne JC, LaForge KS. Opioid dependence and addiction during opioid treatment of chronic pain. Pain. 2007;129(3):235-255 [abstract].
- Ballantyne JC, Sullivan MD, Kolodny A. Opioid Dependence vs Addiction: A Distinction Without a Difference? Arch Intern Med. 2012(Aug 13); online ahead of print [abstract].
- Boscarino JA, Rukstalis MR, Hoffman SN, et al. Prevalence of prescription opioid-use disorder among chronic pain patients: comparison of the DSM-5 vs. DSM-4 diagnostic criteria. J Addict Dis. 2011;30:185-194.
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- Elander J, Lusher J, Bevan D, Telfer P. Pain management and symptoms of substance dependence among patients with sickle cell disease. Soc Sci & Med 2003;57:1683-1696.
- Fishbain DA, Cole B, Lewis J, Rosomoff HL, Rosomoff RS. What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/or aberrant drug-related behaviors? A structured evidence-based review. Pain Med. 2008;9(4):444-459.
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