Opioids in Chronic Nonterminal Pain

Jane C. Ballantyne

The Angelic face of Opium is dazzlingly seductive, but if you look upon the other side of it, it will appear altogether a Devil. There is so much poison in this All-healing Medicine, that we ought not to be by any means secure or confident in the frequent and familiar use of it.

—Thomas Willis, “Medicine in Mans Body,” 1621–1673

I. INTRODUCTION

The earliest evidence of opium use by humans was the discovery of opium poppy seedpods in a 4200 Bc burial site in Spain. In fact, throughout the ages, even when medical science was virtually nonexistent, opium was one of the few remedies known to humans, and it maintained a central role in medicine because most diseases were palliated rather than cured. The explosion of medical and scientific knowledge that has occurred over the last hundred years has profoundly altered the role of opioids in our lives. We prolong life, shorten terminal illness, and expect to be pain- and disease-free. Medically, we use opioids to two distinct ends: to treat physical pain and to treat addiction. Regulatory controls, introduced during the 20th century, have given physicians a central role in determining who should and should not receive opioids. We have begun to understand the neurobiologic basis of opioid analgesia, tolerance, dependence, and addiction. We are in a better position now than ever before to understand opioid effects and to use opioids so that they help and do not harm patients. After years of caution brought about by regulatory controls, we use opioids liberally for acute and terminal pain, knowing that we can substantially reduce pain and maintain safety. But the issue of using opioids for chronic nonterminal
pain (CNTP) is vastly more complicated and is a key issue in pain management.

II. RATIONALE FOR CHOOSING OPIOID THERAPY

The student reading this book is well aware that there are many ways to control pain, some relying on psychological override, some on physical approaches, some on neural blockade, some on counterstimulation, and others on medication. The choice often depends on culture, background, habit, and fashion rather than on the superiority or the likely success of one medication over another. The link between these indicators of treatment choice and the placebo effect (see Chapter 3) is clear; treatments work better when patients believe in them. Present-day fashion, at least in the Western world, dictates that medications are the most trusted and applicable of the treatment options. Opioids are the only class of pain medication offering powerful analgesia without a ceiling effect, meaning that doses can be increased until pain is overcome. This advantage makes the opioids theoretically attractive options for the management of pain, and the reason that pain advocates believe that all patients with pain have a right to opioid therapy—it being the only therapy that can reliably and effectively relieve pain. But, of course, this is only true in a society or culture that places medications at the top of its hierarchy of effectiveness.

Nobody doubts that opioids are powerful and effective analgesics, and scientific evidence supports this assumption. However, whether analgesic efficacy is maintained with prolonged use is less clear, and other liabilities can also interfere with long-term treatment. There must be sustained and obvious benefit in order to justify continued use. When making the decision to start opioid treatment of CNTP, one can usefully consider two phases—an initial phase, in which opioid treatment is used as part of a multimodal and aggressive rehabilitative approach that aims to restore function and to reduce reliance on medications, followed by a chronic phase, in which opioids are utilized according to strict criteria. The desirable end point of chronic opioid treatment is much debated, but it would seem that some improvement in quality of life must be seen to justify the treatment, whether this is an improvement in function or simply a meaningful reduction in pain.

III. LIABILITIES

1. Loss of Efficacy

Many patients receiving opioid therapy for chronic pain appear to obtain satisfactory and sustained pain relief without dose escalation. This seems counter to our belief that the development of tolerance, a pharmacologic phenomenon, is an inevitable consequence of prolonged opioid use. It is evident, nevertheless, that in many patients, tolerance “levels off,” not only in the case of side effects but also in the case of analgesia, and that these patients can derive adequate analgesia at a stable dose.

In other patients, the outcome is less favorable. Satisfactory analgesia is not sustained, and the patients request increasing doses. Tolerance develops to the analgesic and euphoric effects of
opioids, as well as to their side effects (except direct bowel effects). Tolerance to opioids can be learned (associative), involving psychological factors and linked to environmental clues; or adaptive (nonassociative), involving down-regulation and/or desensitization of opioid receptors. Mechanisms of pharmacologic tolerance to opioids have not been fully elucidated, but many mechanisms appear to be linked to the N-methyl-D-aspartate (NMDA)-receptor cascade. Alternatively, “apparent” tolerance could arise as a consequence of opioid-induced hyperalgesia, a phenomenon that has been largely forgotten for years but one that has been amply described and could sometimes explain resistance to opioid treatment. Recently, the mechanism of opioid-induced hyperalgesia has been elucidated, and, interestingly, it is also linked to the NMDA-receptor cascade. This process may represent a form of neurotoxicity, considering that the NMDA-receptor is also implicated in the hyperalgesia associated with neuropathic pain (see Chapter 25). We are now presented with a quandary when a patient presents with escalating pain unresponsive to opioid therapy: Do we, having eliminated the possibility of a change in disease state, assume that the cause is pharmacologic tolerance and will be overcome by dose increase; or would dose increase make matters worse?

2. Unacceptable Side Effects

The side effects of opioids include sedation, respiratory depression, nausea and vomiting, slowing of bowel activity, pruritus, and dysphoria. These side effects are described in more detail in Chapter 9. As mentioned in the preceding text, it is common for tolerance to develop to all these side effects except the bowel effects, which are peripherally mediated and to which tolerance does not develop. Patients starting opioid therapy who experience side effects can be reassured that the side effects will likely subside in time. Patients taking opioids for a long term should always receive bowel prophylaxis to prevent constipation because this is an almost inevitable consequence of chronic opioid therapy. Despite the development of tolerance to side effects, a significant number of patients—one estimate is 50%—will stop taking opioids because of intolerable side effects or because of lack of efficacy.

3. Hormonal Effects

Opioids influence at least two major hormonal systems, the hypothalamic–pituitary–adrenal axis and the hypothalamic pituitary–gonadal axis. The resultant increase in levels of prolactin and decreases in levels of plasma cortisol, follicular stimulating hormone, luteinizing hormone, testosterone, and estrogen may have deleterious clinical effects including male and female infertility, decreased libido and aggression, menstrual disorders, and galactorrhea. These opioid effects were observed long before they were chemically confirmed in heroin addicts. Later, testosterone depletion was demonstrated in male patients in methadone programs. Testosterone levels can be particularly low in patients receiving intrathecal opioids, to the extent that these patients often feel better and regain energy when they are treated with testosterone. The extent of hormonal changes in patients with
CNTP treated with opioids, and the clinical significance of the change is unknown, but one recent study did find decrements in testosterone and cortisol in these patients. Whether hormonal replacement would improve the well-being of patients with CNTP who are treated with opioids remains uncertain.

4. Immune Effects

Animal and human studies demonstrate the presence of opioid receptors on a wide range of immune cells, and the ability of opioids to alter the development, differentiation, and function of immune cells. Prolonged exposure to opioids appears more likely to suppress immune function than short-term exposure, whereas the abrupt withdrawal of opioids also seems to cause immunosuppression. Few studies have been conducted assessing immune function in patients with CNTP receiving opioids, but the direct evidence that opioids impair immune function does give rise to concern in these patients. Pain itself can produce immunosuppression, so the greatest concern is likely to pertain to patients who receive high doses of opioids and yet do not experience good pain relief.

5. Problematic Opioid Use

Problematic opioid use, comprising addiction, diversion, and other less serious problem behaviors, is an inescapable aspect of opioid treatment of CNTP. To deny these problems is to sweep aside the most challenging aspect of treating long-term pain with opioids, which in turn compromises care, and denies patients appropriate treatment when problematic behavior does arise. Most problematic behaviors are manifestations or harbingers of addiction. Problematic behaviors arise in a substantial proportion of chronic pain patients who are treated with opioids, albeit a minority. Published reports suggest a rate of 3% to 19%.

Typical problematic behaviors for patients with pain who are treated with opioids are listed in Chapter 35, Table 1.

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