Opioids for cancer pain: the challenge of optimizing treatment
Introduction
Cancer pain is heterogeneous. Its nature depends on many factors, including the type of cancer, the disease location, the stage of the disease, and the patient's pain tolerance. In their classic book, The Challenge of Pain, Melzack and Wall [1] have pointed out that, compared with other kinds of pain, cancer pain is a special case.
“… cancer does not induce the immune reactions which reject grafts. Furthermore, it does not even produce inflammation as a primary reaction.… A lung cancer may grow silently to the size of a grapefruit before any disorder is noticed.… What then, is the cause of pain if this silent enemy can infiltrate without disturbance? The answer is very largely mechanical.… In abdominal cancer pains, by far the commonest cause is mechanical obstruction of one or another of the viscera followed by dilation above the block … producing intense (painful) muscle contractions. On occasion, the tumor may have directly painful effects by expanding and increasing the pressure on sensitive structures—such as a bone tumor.…”
Cancer-induced pain is usually described under 3 headings: acute pain, chronic pain, and breakthrough pain (BTP). Acute pain, for example, may result from the pathologic fractures that occur when tumors invade bone. Although some of these fractures are initially painless, others may give rise to acute painful inflammation. One form of chronic pain may occur when cancers directly invade nerves causing severe neuropathic pain. Among patients with chronic, persistent cancer pain controlled by around-the-clock analgesics, there is a high prevalence of superimposed BTP—often precipitated by physical activity. It has been reported that more than 80% of patients with advanced, metastatic cancer experience BTP [2]. Breakthrough pain characteristically reaches peak intensity within a matter of minutes, requiring treatment with a rapidly acting, potent opioid.
When treating cancer pain, physicians have to select the analgesic best suited to the patient's particular clinical problem. What is needed is a medication—usually an opioid—that is sufficiently potent and prolonged in action to relieve the pain and keep it at bay for an appropriate period. To minimize the occurrence of damaging adverse effects, it is extremely important to assess the drug's safety profile in light of the patient's age, ethnic background, and overall medical condition. To enhance individualization of treatment, the physician needs answers to a number of questions; for example: How severe is the pain and how is the patient reacting to it? Are there preexisting medical or surgical problems that may be differentially exacerbated by certain opioids? Is the patient depressed or anxious? What other medications is the patient taking—antidepressants, sedatives, or tranquilizers? Does the patient have a history of seizure disorder or mental illness? Can the patient profit from certain ancillary or adjunctive treatments that may reduce the pain burden? Is there any reason to select a particular route (eg, oral, subcutaneous, transdermal, transmucosal, intrathecal) for administration of the analgesic?
Because of the complexities involved in treating severe cancer pain, the attending physician will often find it helpful to consult with a pain specialist, if one is available. The proliferation of clinics in pain control attests to the increased use of specialist-run pain services in both in- and outpatient settings.
Section snippets
Prevalence of pain in cancer patients
The onset of cancer is usually not heralded by pain. This is one reason why so many cancers are well advanced at the time of diagnosis. Not surprisingly, prevalence of pain increases as the disease progresses. The presence or development of comorbidities may complicate the pain picture. Moreover, pain prevalence is affected by type of neoplasm. For example, in their early stages, lymphomas and leukemias are less likely to be associated with pain than bone cancer or pancreatic cancer. After a
Opioids for treatment of cancer pain
At present, opioids are the most effective analgesics available for treatment of moderate and severe cancer pain. Over the years, a veritable arsenal of opioid compounds with a wide range of chemical, physiologic, and pharmacokinetic properties has become available for use in different pain situations. Certain attributes of 6 of the most commonly used opioid analgesics are listed in Table 1, together with the different routes of administration that have been used for the delivery of these
Nonpharmacologic treatment of cancer pain
It is increasingly recognized that the perception of pain undergoes substantial modulation by a number of cortical mechanisms. There is evidence that the brain network for chronic pain perception may be, to some extent, distinct from that for acute pain. Chronic pain engages and interacts with brain regions that also process cognitive and emotional responses, suggesting that the eliciting of such responses may be among the features that distinguish chronic from acute pain [8]. According to
The 3-step approach to cancer pain management
With respect to analgesics, the World Health Organization has developed a 3-step “analgesic ladder” [16] to guide management of cancer pain, based on the pain's severity, estimated by use of a 1 to 10 numeric rating scale (Table 2). If the pain falls within the 1 to 4 range, it is considered “mild.” The WHO recommends that, when possible, acetaminophen and nonsteroidal anti-inflammatory agents (NSAIDs) may be used initially to control mild cancer pain. Contrary to popular belief, these agents
Some considerations governing selection of an opioid for analgesic use
According to a 2008 International Expert Panel consensus statement on opioids and management of chronic severe pain in the elderly [18], the 6 most commonly used WHO step 3 opioids are morphine, oxycodone, buprenorphine, fentanyl, hydromorphone, and methadone (Table 1). In the Consensus Statement, the criteria set forth for selecting analgesics for the treatment of pain in older patients included (1) overall efficacy, (2) overall adverse effect profile, (3) onset of action, (4) drug
Treatment of BTP
There is a need for a rapidly acting, powerful “rescue” analgesic for treatment of BTP. Intravenously given morphine has been used for this purpose with reported success [21]. However, fentanyl has features that appear to make it preferable for treatment of BTP. Fentanyl's potency is about 100 times that of morphine, and its analgesic activity is of relatively short duration after it is administered intravenously or subcutaneously. It is less constipating than morphine. Because of its low
Opioid receptors and the search for the ideal analgesic
Research conducted in many laboratories since the 1960s has established that there are (at present) 4 important G-protein–coupled opioid receptors, known as μ, δ, κ, and nociceptin receptor, respectively. Many other receptors and putative receptors are under active investigation. The μ, κ, and δ receptors are composed of 3, 3, and 2 subtypes, respectively (μ1, μ2, and μ3; κ1, κ2, and κ.3; and δ1 and δ2). These receptors are located in various parts of the brain, in the spinal cord, and also (in
Endogenous opioids
Endogenous opioid peptides are opioids produced naturally in the body. They include endorphins, enkephalins, dynorphins, and endomorphins. β-Endorphin is expressed in cells in the arcuate nucleus of the hypothalamus and in the brainstem. It acts via μ-opioid receptors and influences appetite and sexual behavior. Enkephalin is widely distributed throughout the brain and acts through μ- and δ-opioid receptors. Dynorphin acts via κ-opioid receptors and is found in the spinal cord and in many parts
Acknowledgment
The authors thank Jonas Goldstone, MD, for helpful and perceptive editorial suggestions based on his many years of clinical and teaching experience with the treatment of cancer pain. Thanks are also due Robert P. Lombardo, MD, for his critical review of the article and valuable comments.
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Publication of this article was supported by the Collège International de Recherche Servier (CIRS).
STATEMENT OF CONFLICT OF INTEREST: The authors have nothing to disclose.