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Pain Report #9: Update on the Pharmacologic Management of Cancer Pain

UPDATE ON THE PHARMACOLOGIC MANAGEMENT OF CANCER PAIN

Cancer research has developed and progressed at a rapid and quickening pace in recent years. This progress has taken place in a number of different domains, including clarification of the mechanisms by which the numerous types of cancer grow, metastasize, and die. Knowledge of basic cellular mechanisms of cancer has tremendously assisted in the development of agents for ameliorating, controlling and curing cancer. Despite the impressive achievements of oncology researchers, however, morbidity and mortality due to cancer continue to rise.¹ With the rising cancer rates comes an increasing demand to address cancer pain. Just as strides have been made in developing anticancer agents, so too has progress been made in the development of agents to address cancer pain.

Barriers to Appropriate Treatment
Recent development of agents to treat cancer related pain, and new, sophisticated methods of delivery of these agents, have supplemented those already available. As a result, the vast majority of patients experiencing pain related to cancer or its therapies can be effectively managed with relatively easy to use interventions. Cancer patients should be reassured that they need not live with, or in fear of, uncontrolled pain. Nevertheless, a number of barriers to appropriate implementation and use of pain therapies continue to exist. A lack of appropriate knowledge on the part of some healthcare providers, as well as patient and caregiver misconceptions about pain or opioid analgesics, and limitations of healthcare resources, may all contribute to suboptimal pain therapy.

Opioid therapy is the cornerstone of cancer pain management. Yet, resistance to opioid use, while gradually diminishing, remains a significant barrier to effective therapy. Such resistance takes multiple forms. One such form of resistance is reflected in cultural and religious beliefs regarding the experience of pain. Some patients may regard pain as inevitable or even deserved and resent or resist treatment aimed at minimizing pain. Other patients may regard the use of opioids as a last resort, signifying lost hope of recovery, and may reject medication on these grounds.²

More commonly, concern among patients and some healthcare providers about the perceived addictive properties of opioids cause these medications to be underutilized or avoided entirely. This concern is significantly exacerbated by legal and regulatory barriers. Intractable pain treatment acts, enacted by numerous state legislatures have been passed in order to assure patient comfort and appropriate opioid use. The intent of these laws was to also lessen legal concerns by health care providers when appropriately prescribing opioids for pain management. Much of this misdirected concern is based on a confusion between tolerance, physical dependence, and addiction.

Tolerance describes a systemic adaptation to an agent in which the effectiveness of the agent decreases over time when there is no increase in the pain source. This pharmacologic property is not unique to opioids. Tolerance is common with long-term opioid use and is not a sign of dysfunction or drug failure. Tolerance generally occurs in days to weeks after initiation of opioid therapy. A continued need to increase the opioid dosage more likely indicates progression of the disease or source of the pain stimulus rather than tolerance.

Physical dependence is revealed when the agent is abruptly discontinued, when there is a rapid dose reduction, or when an antagonist is administered (such as naloxone, in the case of opioids). The patient, who has almost always used opioids for at least several weeks, manifests a syndrome of withdrawal symptoms. Such symptoms include nausea, vomiting, abdominal cramping, insomnia, diarrhea, diaphoresis, hot flashes, and autonomic dysfunction. Physical dependence on opioids is normal and by no means analogous to addiction. Patients with addiction will also be dependent, but the reverse is not necessarily true. When opioids are no longer needed, many of the symptoms associated with withdrawal may be avoided by a gradual, tapering reduction in analgesic dosage and the judicious use of opioid antagonists.

Addiction to opioids is a distinct neurobiological disorder, comprised of a variety of potentially contributing factors including those of social, genetic, and environmental origin. Addiction behaviors may include a lack of control over use of an opioid, craving for or obsessive preoccupation with an opioid, and compulsive use of the opioid even after the point at which it is doing harm. While addiction to opioids is of significant concern, addiction in chronic pain patients – either cancer or noncancer – occurs relatively infrequently when there are no previous risk factors for addiction.³ In comparison, patient addiction to opioids decreases function while patient usage of opioids to adequately control pain results in enhanced function even if dependence occurs.

The ongoing efforts to contain healthcare costs constitute a further challenge to the appropriate treatment of pain. Many pain specialists have procedure-oriented practices, with resultant increased pain management delegation to primary care providers. If a primary care provider lacks the time, resources, and knowledge to treat pain appropriately, the risk of patients being undertreated for pain increases. Indeed, despite clarification in medical literature of the appropriateness and utility of opioids for chronic pain, inadequate analgesia continues to be a serious problem across the spectrum of demographic groups.⁴

Pharmacologic Options

Opioid therapy constitutes the primary means of treating persistent cancer pain. For most cancer patients, pain can be treated with an oral opioid alone or in combination with coanalgesics.⁵ Apart from opioids, several other drug classes have been applied more specifically to cancer pain, including NSAIDs and bisphosphonates. There are circumstances where these drugs will be more effective analgesics or less toxic than opioids. Addressing the entire pharmacologic armamentarium for the treatment of cancer pain in detail is beyond the scope of this article. The focus will instead be confined to a brief description of available cancer pain agents and a more detailed review of several recent advances in analgesic therapy. Of primary importance is the fact that effective anticancer therapy can be extremely beneficial in reducing or eliminating pain secondary to a cancer. This should not preclude analgesic use for the patient in pain, possibly for a short time, even if anticipated effective therapies are to be used.

NSAIDs

Non-steroidal anti-inflammatory drugs (NSAIDs) are primarily used as analgesics for patients with mild to moderate pain. NSAIDs have relatively limited use for the patient with cancer and severe pain. NSAIDs can cause end organ toxicity which may be exacerbated in the patient with a malignancy who can have metastasis to these organs or suboptimal organ function secondary to co-morbid medical conditions. Chemotherapy or radiation therapy-induced organ toxicities also necessitate caution in the use of NSAIDs. NSAIDs are further limited in their application for more severe cancer pain by their fixed dose ceiling.

Adverse effects of NSAIDs include GI toxicities (e.g. dyspepsia and ulcer formation), liver dysfunction, bleeding resulting from inhibition of platelet aggregation, renal insufficiency, and in rare cases, acute renal failure.⁶ Not all NSAIDs confer equal risk of adverse effects. Since NSAIDs tend to be relatively similar in analgesic efficacy, selection of an NSAID is usually based upon the cost, convenience in administration, route of administration needed and possible toxicity profile. Opioid analgesics usually do not have a ceiling dose or histopathologic associated organ toxicities and in many cases will be the safer and more effective analgesic.

Clinical trials have suggested that combining an NSAID with an opioid may provide improved analgesia and may also be dose-sparing of the opioid. Most of these studies compare opioid monotherapy versus an opioid with an NSAID. In general, the studies report that an opioid combined with an NSAID is either more effective or equally effective as an opioid alone.⁷ Such studies are notable for their short duration, however, most of them lasting for only 1 to 7 days.

One study, performed by Mercadante et al, employed a sophisticated study design in order to provide more pragmatic data.⁸ Forty-seven patients with advanced cancer who were experiencing pain progression after one week of morphine stabilization were randomized into two groups: Group O and Group OK. Group O received continued morphine escalation based on their analgesic needs, while Group OK received the NSAID, ketorolac, in a daily oral dose of 60 mg and also continued morphine dose escalation as needed. The OK group experienced superior analgesia after 1 week (P = 0.005), and from the 1-week point on, morphine escalation occurred at a slower place. Maximum morphine doses were also lower in the OK group. Gastric discomfort occurred at higher rate in the OK group and constipation was higher in the morphine only group. A pharmacoeconomic analysis found that cost differential in the OK compared to morphine-only were negligible.

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