The Oncologist, Vol. 8, No. 6, 567–575,
December 2003
© 2003 AlphaMed Press
ORIGINAL PAPER
Symptom Management and Supportive Care |
Chronic Pain Following Treatment for Cancer: The Role of Opioids
Jane C. Ballantyne
MGH Pain Center, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
Correspondence:
Jane C. Ballantyne, M.D., F.R.C.A., Massachusetts General Hospital Pain Center, 15 Parkman Street, WACC 333, Boston, Massachusetts 02114, USA. Telephone: 617-724-2113; Fax: 617-724-2719; e-mail: jballantyne{at}partners.org
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LEARNING OBJECTIVES
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After completing this course, the reader will be able to:
- Explain the principles of chronic pain management in cancer patients.
- Discuss the principles of opioid use in patients with chronic pain.
- Recognize and prevent substance-related disorders in cancer patients treated with opioids.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
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ABSTRACT
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Opioids are the most effective analgesics for severe pain and the mainstay of acute and terminal cancer pain treatments. In those settings, opioids are used over a limited time period so that opioid tolerance, if it develops, is relatively easy to overcome, and other problems of opioid use, including substance abuse, are unlikely to be problematic. As cancer treatments improve and increasing numbers of cancer patients experience long remissions, chronic pain due to cancer, or to cancer treatment, becomes a clinical problem that oncologists will encounter. Chronic pain differs from acute and terminal pain in several fundamental respects. In the case of chronic pain, functional restoration is a predominant goal of treatment. Because it is often due to neuronal damage, the pain may be particularly sensitive to nonopioid medications, and opioids can be reserved for refractory pain. If opioids are chosen, tolerance, dependence, and addiction can interfere, and safeguards designed to minimize these must be built into the treatment plan. This article reviews the principles of chronic opioid therapy for non-cancer pain and how these principles may be adapted for patients with chronic pain due to cancer.
Key Words. Narcotics • Pain • Neoplasms • Opioid-related disorders
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INTRODUCTION
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The World Health Organization (WHO) stepladder (Fig. 1
) depicts a standardized approach to the treatment of cancer pain using nonopioid analgesics, adjuvants, and finally opioids [1]. Opioids are reserved for moderate to severe pain, while nonopioid analgesics and adjuvants are used throughout for mild, moderate, and severe pain. While the validity of the WHO approach has been questioned [2–4], the stepladder has been an invaluable tool for guiding nonspecialists in the logical use of opioids for cancer pain. The basic principles of reserving opioids for pain that cannot be treated by other means, and of continuing nonopioid treatments whenever possible, remain important. Dosing of opioids has also been guided by a simple principle: provided the source of pain cannot be treated, higher pain levels require higher opioid doses, the chief limitation on dose being unacceptable side effects. For as long as cancer pain treatment has meant pain management during painful cancer treatments (acute pain management), or pain management for disease that is progressing rapidly to death (pain management during terminal illness), the fundamental principles outlined above have been helpful and effective. However, as cancer survival improves, the number of cancer patients with chronic pain, as distinct from acute or terminal pain, increases. There are a number of reasons that patients with cancer experience chronic pain, either related to the disease itself or to its treatment [5–7]. These are summarized in Table 1. Chronic pain following cancer is a distinct disease entity, and the patients present a unique challenge in terms of their pain management. Because of their cancer diagnosis, there has been a long tradition of treating them as patients in whom opioid use and dose escalation are always justifiable, yet they have long-term survivals and can be susceptible to all the pitfalls of long-term opioid treatment. This article reviews the principles of chronic opioid treatment and their relevance to the treatment of chronic pain following cancer.
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Figure 1. The WHO Three-Step Analgesic Stepladder. In 1986, the WHO published guidelines for cancer pain management based on a three-step analgesic ladder [1]. The first step uses nonsteroidal anti-inflammatory drugs and adjuvants for mild pain. For moderate pain (step 2), opioids conventionally used for moderate pain (e.g., oxycodone) are added. Potent opioids (e.g., morphine) are reserved for the third step and the treatment of severe pain.
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UNDERSTANDING OPIOID ACTIONS
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Anyone who has prescribed opioids frequently will have observed some apparently inexplicable opioid effects. For example: the patient on high-dose opioids who does not appear to suffer withdrawal, or a decrease in analgesia, when the dose is accidentally reduced; the patient on a long-term opioid who suffers acute pain that cannot be controlled no matter how high an opioid dose is used; the absence of respiratory depression and sedation in most but not all opioid-tolerant patients given high-dose opioids; the different opioid side-effect profiles exhibited by different patients; pain that improves when opioids are discontinued; the propensity to addiction in some, but not all, patients. Some opioid effects cannot be explained by our present understanding of opioid mechanisms, while recent basic science research does help us to understand some of the curiosities of opioid actions.
Definitions
Since pain and addiction medicine terminology is often confusing, it will be helpful to highlight some areas of ambiguity. Perhaps the source of greatest confusion is the use of the word addiction, which is not well defined. As generally understood, addiction is a state of dependence caused by habitual use of drugs, alcohol, or other substances. The terminology used in pain practice deliberately separates dependence from addiction, since physical dependence is an inevitable consequence of continuous opioid use that is rarely associated with aberrant behavior when opioids are used for the treatment of pain. A current consensus statement from U.S. pain and addiction societies provides definitions for addiction, physical dependence, and tolerance related to the use of opioids for the treatment of pain (Fig. 2) [8]. Substance dependence, as defined in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM IV), may include tolerance, physical dependence, and/or various aberrant drug-seeking behaviors, while substance abuse does not include tolerance, physical dependence, or compulsive use, but is a term used to describe harmful drug-seeking behaviors specifically [9]. Aberrant opioid-seeking behaviors that are not harmful may meet the criteria for substance dependence, and represent one end of a spectrum of addiction, as described in Figure 2, while aberrant opioid-seeking behaviors that are harmful constitute substance abuse, and represent the other end of the spectrum of addiction.
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Figure 2. Definitions related to the use of opioids for the treatment of pain. A consensus document from the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine [8]. Reproduced with permission.
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Opioid Tolerance and Opioid-Induced Abnormal Pain Sensitivity
Opioid tolerance is a pharmacological phenomenon that develops after repeated opioid use and necessitates an increase in dose to maintain equipotent analgesia. Pharmacological tolerance is largely a cellular adaptive process that involves downregulation (reduced number) and/or desensitization (reduced sensitivity) of opioid receptors [10, 11]. Several mechanisms contribute to opioid receptor desensitization, but the N-methyl-D-aspartate (NMDA) receptor cascade seems to be a common and important link [12]. As basic scientists elucidate mechanisms of pharmacological tolerance, it becomes clearer that an increased opioid requirement, assuming there has been no disease progression, does not always indicate simple pharmacological tolerance. Repeated opioid administration results in the development of tolerance (a desensitization process), but may also lead to a pronociceptive process (a sensitization process). Abnormal pain sensitivity has been observed in association with opioid administration in both animals and humans [13–15]. Opioid-induced abnormal pain sensitivity shares the characteristics of neuropathic pain, defined as pain due to nerve injury or disease or to the involvement of nerves in other disease processes. NMDA receptor mechanisms are again involved, and it is becoming clear that there are several interactions between neural mechanisms of opioid tolerance and neuropathic pain [12, 13, 16]. Opioid-induced abnormal pain sensitivity could have important clinical implications, particularly with regard to observed opioid tolerance and some of the curiosities of high-dose opioid treatment, and the phenomenon has been under intense scrutiny in the laboratory.
Opioid-induced abnormal pain sensitivity may exacerbate and confound pharmacological tolerance, although the relative contribution of these two processes remains unclear. Thus, apparent opioid tolerance may be the result of pharmacological opioid tolerance, opioid-induced abnormal pain sensitivity, and/or disease progression. At present, it is not clear whether opioid-induced abnormal pain sensitivity is related to dose, individual opioid, route of administration, length of administration, or other factors. Nevertheless, the phenomenon may, at least in part, explain the failure to relieve pain in some patients, despite upward titration. Thus, in some instances, pursuing increasing pain with increasing opioid doses might be counterproductive.
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PRINCIPLES OF CHRONIC OPIOID THERAPY
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Addiction does not appear to be a problem when treating acute or terminal pain with opioids, but can develop during chronic pain treatment, especially in patients with a history of substance abuse. The number of patients with a history of substance abuse and cancer-related chronic pain is increasing as more patients survive associated diseases such as AIDS. Estimates of the incidence of addiction in patients treated with opioids for chronic pain range from 8%–17%, differences being due to differences in definition, as well as in the populations under study, and in the reporting physicians’ approach to treatment [17–21]. Every country that uses opioids for the treatment of chronic pain has its own model guidelines for opioid use in chronic nonmalignant/noncancer pain [22–25]. These guidelines suggest means by which the development of addiction during chronic opioid treatment can be minimized. While there is little scientific evidence to support the principles outlined in these consensus documents, they have been developed by experienced experts, are remarkably consistent, and can be summarized, as in Table 2. For more detail, the reader is referred to two U.S. consensus documents [23, 24]. Even though patients with chronic pain due to cancer differ in some respects from patients with nonmalignant/noncancer pain, understanding the principles of opioid management in chronic noncancer pain can be helpful in the management of chronic cancer pain. Differences are outlined below.
In the management of chronic noncancer pain, the decision to start opioid therapy must be very carefully considered, balancing likely benefits with risks in view of the possible long-term commitment and informing patients about the liabilities of opioid use. Ideally, follow-up should include regular and formal assessments of pain, goal achievement, functional status, and quality of life, and may include toxicology screening. Patients embarking on chronic opioid therapy need to understand its likely benefits and risks and agree to all that is involved in the commitment to long-term opioid therapy, including intensive follow-up and monitoring. A written contract or consent can be a useful aid to establish agreement between the patient and physician.
The natural history of chronic pain in patients with cancer differs in that it is often one of severe pain during the initial phases of treatment, followed by chronic, less severe pain during remission. Thus, cancer patients start opioid treatment during their curative treatment, and if they develop chronic pain, the opioid treatment is continued. There may not be an obvious point at which it would seem necessary to question whether long-term opioid treatment is the right choice of treatment for the chronic pain. At the same time, there is a reluctance to emphasize the risks of opioid treatment, founded on years of needing to persuade patients and the medical community that opioid treatment is the most effective and safest available treatment for cancer pain. Many cancer patients already carry prejudices against opioids, and the focus tends to be on persuading them to accept opioid treatment, rather than on stressing the risks.
Opioids may not be the optimal treatment for chronic cancer pain, and therapy that includes only opioids is unlikely to be helpful in the long term. Nonopioid and nonmedical treatments may not have been tried, in which case their efficacies will be unknown. It is always important to establish the opioid sensitivity of pain, especially chronic cancer pain, which is often neuropathic (Table 1
), has variable opioid sensitivity, and may respond at least as well to neuropathic pain medications such as tricyclic antidepressants or anticonvulsants [5–7, 26–31]. Table 3 outlines some commonly used nonopioid and nonmedical treatments. Nonopioid and nonmedical treatments should be regarded as the mainstay of chronic pain treatment, but it is reasonable to include an opioid if pain control is unsatisfactory without it. Sometimes it is advisable to wean and discontinue opioid treatment, even if only temporarily, in order to establish the effectiveness of other approaches, especially when acute pain progresses to chronic pain.
The point at which the treating physician recognizes that pain has become chronic rather than acute, and that survival is likely to be prolonged, is also a good opportunity to explain the benefits and risks of long-term opioid therapy, and document the conversation, if this has not already been done. It is helpful to explain that there is a risk of addiction, albeit small, but that careful follow-up and frequent prescription renewals will be used precisely so that addiction does not develop. A written consent or contract may be helpful, but is rarely needed in this population. It is also helpful to establish treatment goals at this point; the established goals of therapy prove an invaluable guide for difficult and complex treatment decisions if complications emerge. In general, an important goal of therapy for chronic pain is functional improvement, whereas in terminal illness, the primary goal is symptom relief. Obviously, the exact functional goals will vary according to the patient’s degree of disability. Patients should understand that chronic stable opioid therapy does not impair cognitive function or the ability to work, drive, or operate machinery [32–34], and may even improve cognitive functioning when compared with functioning under conditions of uncontrolled pain [26].
Stable Pain Treatment
Ideal chronic opioid therapy, assuming the pain and disease are stable, uses a stable dose of opioid medication. The simplest route, that is, oral or transdermal, is always preferred. Opioid injections should be avoided in the treatment of chronic pain. Often, chronic pain is constant and unremitting, and in that case, long-acting drugs and formulations given round the clock are useful. Round-the-clock dosing allows many patients to achieve maximum functionality, without the need to focus on the next dose of drug and without the swings in analgesic level associated with as-required dosing. The steady state produced by long-acting drugs and formulations may have some advantages in terms of the likelihood of developing addiction. Some patients prefer not to receive round-the-clock opioid medication and need opioids only occasionally, and in that case, it is reasonable to prescribe the drugs to be used as needed. In general, the choice of drug and dosing regimen should be based on the patient’s pain pattern, lifestyle, and preference. It is usually preferable to encourage patients with chronic pain to treat breakthrough pain by means other than supplementary opioid doses, again, in order to remove their focus from obtaining the next dose of opioid. Some of the commonly used opioids in chronic pain management are listed in Table 4. Opioids are best prescribed by a single physician and supplied by a single pharmacy. Whenever possible, patients should pick up prescriptions in person, and brief assessments of pain and side effects should be made at each pick up, with referral for comprehensive follow-up if necessary. Comprehensive assessments of pain and functionality should occur at least every year, and more frequently if indicated, and should include formal assessments of pain relief, the effects of pain on well-being, goal achievement, functional status, and quality of life. Quality-of-life questionnaires can be helpful. Some pain clinics are willing to take on the role of monitoring chronic opioid therapy.
Dose Escalation
There are several reasons why it is preferable when treating chronic stable disease to avoid dose escalation whenever possible, and these are related to both efficacy and harm. In the case of stable disease, dose increases are needed to overcome tolerance or apparent tolerance, and responses are variable. Differences in opioid handling mean that some patients maintain stable pain levels using a stable and moderate opioid dose, while in others, opioid efficacy diminishes over time and dose escalation may or may not be effective [30, 35–37]. When there is no improvement, pursuing increasing pain with increasing opioid doses can be counterproductive. For example, opioid-induced abnormal pain sensitivity may, at least theoretically, contribute to the clinical picture of apparent tolerance, in which case dose increases will worsen the pain and the apparent tolerance. While such mechanisms are poorly understood at present, as more patients are treated with long-term high-dose opioids, we encounter increasing numbers of patients whose pain is extremely difficult to control when they present for surgery, or with new or recurrent disease. To make matters worse, high doses may have toxic effects, including neuronal, hormonal, and immune effects, that are potentially important when high doses of opioids are used over a prolonged period and are relevant if the patient has a normal life expectancy [38–44]. Toxic effects may be acceptable if the gain in quality of life produced by good analgesia is significant, but if dose escalation does not achieve this, possible toxicity should be taken into account. Loss of efficacy and toxicity may only arise in a small minority of cancer patients but is worth considering when dose escalation fails to produce the desired improvement in pain relief.
If a dose escalation seems necessary, the increase in dose should be introduced with extreme caution. Some experts recommend hospital admission for dose escalation [22]. First, disease escalation should be identified or excluded. The dose should be titrated upward as rapidly as possible to achieve a new stable level. The upward titration should not take more than 8 weeks. When treating chronic pain, whether related to cancer or not, very high doses should be avoided because they are rarely helpful.
If pain cannot be adequately controlled after a careful dose escalation, it may be helpful to switch to a different opioid as a means of restoring analgesic efficacy and reducing side effects when one drug is not working [45–48]. The rationale for opioid rotation is that there is incomplete crosstolerance among different opioids acting at different opioid receptors [47]. The second opioid can be started at half the dose equivalence of the first opioid, because tolerance to the second opioid will be less. For reasons that are not fully elucidated, methadone works particularly well in opioid rotations and can be started at less than half the dose equivalence of the first opioid [49]. Table 4 outlines dose equivalencies for some commonly used opioids. The second opioid can be titrated upward if necessary. Methadone can be a difficult drug to use in rotations because of its prolonged and unpredictable half-life, and detailed dosing schedules should be used [46, 48, 50, 51]. Sometimes, several different rotations are needed before a satisfactory regimen can be found [52].
If neither dose escalation nor opioid rotation is successful, it is reasonable to question whether opioids are effective at all. Sometimes the only way to make this determination is to wean the patient off opioids and reassess. Two to three months off opioids may be needed in order to make the assessment. Nonopioid and nonmedical treatments can be intensified during the period of opioid detoxification, if necessary. Some patients will actually experience an improvement in pain [14, 15]. Patients who do not improve off opioids can have their opioid therapy restarted, but at much lower doses.
Failed Opioid Treatment
If opioid treatment is not providing overall benefit, it should be discontinued. However, deciding when a patient is more harmed than helped by opioid treatment is not simple and presents one of the greatest challenges in pain management. Addiction is a potentially devastating, albeit rare, complication of long-term opioid use, which, if it develops, must be factored into the decision of whether or how to continue opioid management. Physicians who prescribe long-term opioids should be wary of persistent opioid-seeking behavior and understand the complex relationships between noncompliance, inadequate pain relief, and addiction so that they can identify aberrant behaviors. Typical features of noncompliance are summarized in Table 5.
Although noncompliance shares many of the features of addictive behavior, it may or may not indicate addiction. Occasionally, opioid-seeking behavior is a manifestation of inadequate analgesia, in which case the behavior normalizes when pain is adequately treated. The term pseudoaddiction is used to describe opioid-seeking behavior that reverses when pain is adequately treated. In other cases, habitual diversion rather than addiction drives abnormal opioid-seeking behavior. Noncompliance should always raise concern about possible addiction or diversion and is an indication for careful control and monitoring of opioid treatment, and possible discontinuation of treatment if the behavior persists.
It is clear that both efficacy and complications are dynamic, not stable, and that the prescribing physician must be able to ensure treatment benefit throughout a long course of treatment. The concept of goal-directed treatment is extremely helpful in this context because the established goals provide a basis for judging treatment efficacy. Although treatment goals may change through the course of cancer treatment, if the disease and pain are stable, a change in treatment goals is a possible marker of functional deterioration and should be interpreted as such. Even in the presence of diminished analgesic efficacy, addictive features, or other complications, it may be reasonable to continue treatment provided treatment goals are met, particularly in the case of pain due to devastating disease. The prescribing physician must decide whether to continue or wean the opioid treatment based on his or her judgment of benefit versus harm. Some addictive features (Fig. 2) may be acceptable, while harmful behaviors that constitute substance abuse always negate analgesic benefit in the case of chronic opioid therapy. If the possibility of harm, either to the patient or to others, dominates, the treatment should be weaned and discontinued, if necessary, under the direction of addiction specialists.
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CONCLUSION
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When strict regulatory controls were placed on opioid use in the 1940s, there was a backlash against opioid use, and cancer pain became woefully undertreated. It has not been easy to rebuild confidence in the use of opioids as an effective, safe, and humane treatment for cancer pain. It is not surprising, therefore, that principles of chronic pain management that incorporate constraints on opioid use are not easily adopted by oncologists who have been taught the different principles of opioid use for severe accelerating cancer pain. Now that cancer survival has improved and many cancer patients suffer chronic pain, oncologists will need to incorporate the principles of chronic opioid pain management into their practice so that patients are not harmed by unrecognized complications of long-term opioid therapy.
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Received May 29, 2003;
accepted for publication August 13, 2003.
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Learning Objectives
Abstract
