ain continues to be undertreated in cancer patients despite the establishment of various treatment guidelines over the last 20 years. While epidemiologic data that estimate the prevalence of cancer pain are limited due to variations in methodology and patient populations, it is estimated that more than 9 million patients worldwide have pain due to cancer or its treatment.^1,2 Chronic pain occurs in approximately 30 percent to 50 percent of patients receiving active treatment for a solid tumor and 60 percent to 90 percent of cancer patients with advanced disease.³

Older guidelines have only focused on medical management strategies. This has increased acceptance of opioid therapy but has come at the cost of less effort in determining the cause of the complaint (tumor-related, treatment-related or noncancer-related, i.e., disc herniation). Too often opioid therapy is pushed to the extreme, resulting in a reduction in the quality of life due to oversedation or other side effects. Even with the addition of adjuvant medication, pain with activity is inadequately addressed.

The recognition that optimal pain control is best achieved with multimodal approaches reinforces the idea that pain relief strategies should be diagnosis-driven. The treatment of pain should be more objective and allow utilization of opioid analgesia without waiting for weaker analgesics to fail to provide relief first. In other words, it also is time to abandon the idea of a rigid, stepwise approach to pain relief that begins with over-the-counter drugs. Instead combined pharmacologic and nonpharmacologic techniques will yield better results. Understanding the pain generator(s) will allow more rational selection of analgesic options.⁴

Guiding Pain Management
Consistent with these ideas, revised guidelines for the management of cancer pain in adults and children were just issued this spring by the National Comprehensive Cancer Network.⁵ The guidelines attempt to bring pain management into the forefront of the overall care of the patient with cancer. The new algorithm begins with a requirement that all cancer patients be screened for pain and that clinicians attempt to achieve the patient’s goals for pain relief. The guidelines also emphasize continued reassessment and introduce the use of vertebroplasty/kyphoplasty and modalities such as spinal cord stimulation for neuropathic pain due to cancer treatment (X-ray therapy, chemotherapy or postsurgery). The revised guidelines also recognize the limitations of predicting life expectancy, and they have removed timelines with regard to the use of intrathecal therapy.

Drugs and Methods
With respect to pharmacologic therapies, COX-2 inhibitors had been used widely, especially to improve control of bone-related pain. Now that the recent Food and Drug Administration warning of increased cardiovascular risk is assigned to all nonsteroidal anti-inflammatory drugs, there has been a decrease in their use, but this concern associated with chronic use may not be relevant in a terminally ill population. Tricyclic antidepressants (TCAs) and anticonvulsants are still valued for their role in treating neuropathic symptoms. The recently developed selective serotonin reuptake inhibitors have the potential to provide benefits similar to the TCAs, but hopefully with fewer side effects. Options for sustained-release opioids include formulations of morphine, oxycodone and fentanyl. An oral once-per-day version of hydromorphone has been added recently to our armamentarium, and a transdermal sufentanil patch that lasts for one week is currently in development.

Blocks
Appropriately selected neurolytic blocks can provide significant relief and opioid-sparing benefits. The time-tested celiac plexus and splanchnic nerve blocks can be effective tools to manage pain and to minimize the total dose of medication required, thereby reducing side effects. The ganglion impar block has been used to treat radiation-induced rectal burning. In the hands of the experienced clinician, intrathecal neurolysis has the potential of relieving pain in the extremities while preserving motor function.

Infusion Therapy
Intrathecal infusion therapy has provided significant flexibility in treating pain from various sites with minimal risk. Targeted drug delivery has allowed patients to experience relief with fewer side effects compared to systemic therapy. Advances in technology have allowed pump components to be reduced in size, resulting in a doubling of pump reservoir capacity and allowing patients to go longer between refills and also reducing costs. Both somatic and neuropathic components and sometimes visceral components of pain can be reduced and even alleviated at rest and with movement. The freedom from external devices also is a great benefit.

To optimize results, it is important to understand the spread characteristics of each drug that is used. Morphine is very hydrophilic and therefore spreads much farther than hydromorphone, fentanyl and sufentanil. Local anesthetics and alpha-2 agonists such as clonidine also have limited spread characteristics. This is relevant if the catheter tip is not close to the dermatomal areas involved in the patient’s nociception. Animal data suggest that the use of high concentrations of opioids may promote the development of granulomas, and periodic magnetic resonance imaging scans may be prudent if high concentrations are used to reduce the frequency of pump refills.

The Cutting Edge
Ziconotide is the newest addition to our armamentarium. Ziconotide, a peptide present in the venom of a marine snail, is a selective N-type voltage-sensitive calcium channel blocker that blocks neurotransmission from primary nociceptive afferents. The drug must be administered intrathecally to maximize antinociceptive effectiveness and minimize sympatholysis. The most common serious adverse events noted have been confusion, urinary retention, somnolence and nausea.⁶ Lower doses and slower titration of ziconotide appear to minimize side effects, and with greater experience, we will better understand where this agent fits into treatment algorithms.

Recent insights into mechanisms of bone cancer pain implicate chemical or mechanical signaling from tumor cells to nociceptors in bone or periosteum. Work has been performed investigating tumor necrosis factor alpha (TNFa) and ET-1, mediators secreted by cancer cells that have an excitatory effect on nociceptive afferents, which may contribute to the development of persistent pain.² Further understanding of these and other mediators may allow us to create novel methods to relieve pain.

Total Patient Care
Palliative care extends beyond pain treatment, as quality of life is impacted also by fatigue, sedation, nausea, air hunger and depression that accompany the cancer itself or its treatment (chemotherapy or radiation therapy). Modafinil is valuable in treating sedation, without the hemodynamic changes associated with amphetamines or methylphenidate. As patients with cancer undergo many phases of treatment, including multiple surgical procedures, physical and psychologic recovery can be difficult. Appetite loss contributes to weight and muscle loss and may worsen patient outcomes as this makes restoration of normal activities more difficult. Bed rest and immobilization can lead to loss of muscle mass and decreased strength that is debilitating in several ways. Poor body image and a sense of worthlessness can impede overall recovery and instill a sense of impending demise. Functional rehabilitation necessitates good nutritional support, aggressive physiotherapeutic involvement and sensitive psychological input. Our ability to allow the patient to rehabilitate without pain offers the patient a chance to regain strength and function and to expend physical and mental energy on recovery and restoration of life.

A multidisciplinary approach to cancer pain is crucial. One needs to look for the culprits believed to be responsible for the pain symptoms and then treat these causes with an open mind and the appropriate tools. We have a wide variety of skills to offer patients and should do so in a manner that is consistent with each individual patient’s goals.

References:
1. Rainone F. Treating adult cancer pain in primary care. J Am Board Fam Prac. 2004; 17:S48-S56.
2. Davar G. Pain Clinical Updates, IASP. June 2002; Vol X (2).
3. Goudas LC, Bloch R, Gialeli-Goudas M, et al. The epidemiology of cancer pain. Cancer Invest. 2005; 23(2):182-190. Review.
4. Panchal S. In: Susman E: Cancer Pain Management Guidelines Issued for Children. Adult Guidelines Updated. J Nat Cancer Inst. 2005; 97(1):711-712.
5. National Comprehensive Cancer Network (NCCN), Adult Cancer Pain, Clinical Practice Guidelines in Oncology; v.2. 2005.<www.nccn.org/professionals/physician_gls/PDF/pain.pdf>. Accessed on August 3, 2005.
6. Penn RD, Paice JA. Adverse effects associated with the intrathecal administration of ziconotide. Pain. 2000; 85(1-2):291-296.

Beth H. Mintzer, M.D., M.S., is Associate Clinical Professor of Anesthesiology, Columbia University, New York, New York.

Sunil J. Panchal, M.D., is Director, Interventional Pain Medicine, and Associate Professor, Departments of Oncology and Anesthesiology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, Florida.