Pain is the most common symptom of advanced cancer. For most cancer patients, pain can be controlled with
ABSTRACT: Pain is the most common symptom of advanced cancer. For most cancer patients, pain can be controlled with systemic analgesic and coanalgesic therapy in concert with treatment of their underlying cancer. Analgesic therapy for pain involves choosing the right drug and giving it at the proper dose and interval via the best route of administration. The goal of pain prevention requires around-the-clock dosing and aggressive titration of long-acting opioids with as-needed supplements of short-acting opioids for breakthrough pain. Sequential trials of alternative opioids plus the early use of pain-specific coanalgesics can further optimize patient comfort and function. Most clinicians should be able to control most of the pain in most of their cancer patients. Collaboration with pain and palliative care experts can help the rest. No cancer patient should live or die with unrelieved pain. [ONCOLOGY 13(Suppl 2):9-14, 1999]
Pain is the most common symptom of patients with advanced cancer.[1-4] The importance of pain is magnified by the interaction of pain and its therapies with other common cancer symptoms such as fatigue, weakness, dyspnea, nausea, constipation, and delirium.[2,5] A patient with unrelieved pain cannot sleep well and may become fatigued. If more pain medication is taken than is needed, sedation occurs. If nausea occurs, then oral therapy is difficult. Pain medicines can add to confusion or cause constipation and nausea. Alternatively, opioids for pain can help relieve dyspnea and cough.
The fear of pain continues to be one of the greatest concerns of patients with advanced cancer and has led to such desperate acts as physician-assisted suicide. This desperation is a real tragedy because we have the tools and techniques to effectively relieve cancer pain.[7-11] Cancer pain can be controlled with good comfort and function in 85% to 95% of patients with an integrated program of palliative anticancer therapies combined with an individualized regimen of systemic analgesics and coanalgesics. The appropriate use of invasive procedures can help most of the remaining patients.[12-14] In the final days of life, pain not controlled by therapies aimed at both comfort and function can be relieved by intentional sedation.[15,16] Based on current knowledge, no cancer patient needs to live or die with unrelieved pain.
There are three basic approaches to the control of any pain: 1) modify the source of the pain; 2) alter the central perception of pain; and 3) block the transmission of the pain to the central nervous system. For example, dental pain from a severely decayed tooth may warrant an extraction or a root canal, and treatment with a regional nerve block using a local anesthetic, a fixed-combination preparation of an opioid and a nonopioid analgesic. Coanalgesic therapy for these pains consists of antibiotics and nonsteroidal anti-inflammatory drugs. Therefore, the basic approach for dental pain might be a dental procedure, a regional anesthetic block, and penicillin, ibuprofen, and hydrocodone plus acetaminophen.
The vast majority of cancer patients can have their pain relieved through direct and indirect modification of the source of their pain combined with pharmacologic and nonpharmacologic alteration of their perception of pain.[7-9,18,19] The most common source of cancer pain is the cancer itself. Alternatively, cancer treatment can produce both acute pain and chronic pain,
such as mucositis and postsurgical neuropathy, that require their own specific coanalgesic therapy. Cancer patients can also experience pain from coincidental sources such as infection or degenerative arthritis. Clinicians most commonly alter central perception of pain with opioid analgesics. Perception can also be altered with psychological and behavioral interventions. Blocking pain transmission is most suited for patients who have regional pains or who have pain that is not being controlled with acceptable side effects despite aggressive pharmacologic tailoring. The most commonly used procedural interventions include regional neurolysis and spinal administration of opioids and coanalgesics.[12-14]
A clinical strategy for cancer pain relief consists of five sequential components: patient assessment, care plan development, care plan implementation, reassessment, and treatment modification. Patient assessment begins with determining the intensity, quality, location, and temporal pattern of each pain. Next, the patients cancer status, concurrent medical problems, and psychosocial status must be reviewed. It is critical to determine whether the source of the pain is progression of the cancer, residual tissue damage from the cancer and its therapy, or a coincidental problem. If the cancer is progressive, what is the likelihood that further anticancer treatment will help? What is the patients prognosis? Concurrent medical problems can cause pain and can interfere with analgesic therapy. For example, severe gastric ulcer disease, hypertension, or coronary artery disease can limit the utility of some of the coanalgesics. If the patient is infected or has a low platelet count, invasive procedures will have to be delayed. Assessment of psychosocial status must include the patients precancer psychological history as well as any current problems he or she has coping with pain or cancer.
It is the interface of these four spherespain, cancer, other medical problems, and psychosocial statusthat guides therapy. It is critical to use this comprehensive assessment to formulate an individualized care plan for each patient. What is thought to be causing this pain? What kind of initial pharmacological therapy is preferred? What are our second- and third-line therapeutic considerations? What kind of psychosocial support does the patient need? What studies are needed to make or confirm a diagnosis of the source of the pain or the status of concurrent medical conditions? What kind of procedural interventions could help this patient and when should the anesthesiologist be consulted? A patient with deep boring abdominal pain from pancreatic cancer will often benefit from a celiac plexus block. We try to offer this block to patients before it becomes infeasible due to depression of the patients platelet or white blood counts from their anticancer therapy.
Comprehensive assessment facilitates the differential diagnosis of the source of the pain. To illustrate, a woman was recently referred for treatment of peripheral neuropathy from her paclitaxel (Taxol) and platinum chemotherapy for ovarian cancer. She was in such severe pain that she could not get out of bed for her next appointment. When assessed, she was found to have both peripheral neuropathy and severe sciatica. Specifically, she had pain that radiated down into her buttocks, and the back of her right thigh, which is not consistent with the usual stocking-glove distribution of peripheral neuropathy. Her peripheral neuropathy was treated with a tricyclic antidepressant and low-dose opioids, and initiated a trial of dexamethasone for her acute sciatic radiculopathy. Her pain and mobility improved dramatically and her lumbosacral MRI showed lateral spinal stenosis from degenerative disk disease. Her pain from peripheral neuropathy improved on nortriptyline, but her sciatic pain returned when the dexamethasone was lowered. She received an epidural steroid injection, which reestablished her comfort and function without the risk of systemic steroid toxicity. The net result of this interactive process of reassessment and care plan modification was a marked improvement in the womans quality of life.
Systemic pharmacologic therapy is the mainstay of cancer pain managment, but oncologists must undertand the potential of neuraxial application of pharmacologic agents or neurolytic nerve blocks. Systemic therapy must be optimized by selecting the right analgesic right dose, right route, and right interval (Table 1). This analgesic is given around-the-clock to prevent chronic pain and offered as-needed to relieve breakthrough pain. Analgesic doses must be aggressively titrated and common side effects must be anticipated, prevented, and treated. Comfort and function can be further optimized through sequential opioid rotation and appropriate use of pain-specific coanalgesics.
Pharmacologic management must be individualized for each patient with the initial aim of keeping things as simple and noninvasive as possible. Patients with advanced cancer are often overwhelmed by the progression of their disease and the toxicity of their anticancer therapy. The easier they find it to gain control of their pain, the better. Since patients vary in their response to different opioid analgesics, it is important to have a working knowledge of equianalgesic tables to be able to switch from one opioid to another.[7,10,11] It is even more critical to have the time and skill to talk with patients and their families to assure them that addiction and tolerance are not real issues in the management of advanced cancer pain.[7,11]
Selection of the appropriate analgesic depends upon the patients pain intensity and their current analgesic therapy.[7,10,11] Pain can be measured with simple unidimensional instruments, like a numeric scale or visual analogue scale, or more comprehensive scales, like the Brief Pain Inventory. By correlating pain intensity scores from the latter instrument with the impact of the pain on aspects of their quality of life, it has been shown that patients with a score of 1 to 3 can be considered to have mild pain, 4 to 6, moderate pain, and 7 to 10, severe pain.
Before selecting an analgesic to treat a patients severe pain, one has to know what pain medications he or she is already taking. A pain rated 6 by someone whos not taking any analgesic might go away with a simple nonsteroidal anti-inflammatory agent. Patients with a pain of 6 out of 10 who are already taking 300 mg of controlled-release morphine will most likely need 450 or 600 mg of controlled-release morphine for relief.
Most patients with advanced cancer will need World Health Organization (WHO) step three opioids: morphine, oxycodone, hydromorphone, or fentanyl.[7,11] These single-entity opioid analgesics are free of the dose-limiting aspects (i.e., the maximal safe dose of the nonopioid component) of WHO step two fixed-combinations of opioids plus nonopioids, such as codeine plus acetaminophen or hydrocodone plus ibuprofen. It is important to use step three opioids one at a time to allow for sequential trials of alternative opioids should the patient experience unacceptable side effects from the first drug.[21-24] Patients receiving controlled-release morphine should be on immediate-release morphine for breakthrough pain. Those receiving controlled-release oxycodone should have immediate-release oxycodone available for rescue doses. Meperidine (Demerol) should be avoided because of its toxic metabolite, normeperidine.[7,10] There are new reasons to learn how to use methadone in sequential opioid trials,[22,24] it is usually not a first drug due to its prolonged metabolism and risk of delayed accumulation.[7,10,11]
When switching from one opioid to another, and from one route of opioid administration to another, the clinician must know how to utilize an opioid equianalgesic table (Table 2).[7,10,11] These tables offer relative analgesic equivalencies to guide dose conversions. Most cancer patients will need more than one opioid and more than one route of opioid administration over the course of their disease.[7,19] The parenteral route is more potent, but not more effective, than the oral route.[7,11] When switching from the oral route to the parenteral route or vice versa, dose adjustments must be made for optimal safety and efficacy.
For most cancer pain patients, most clinicians use controlled-release morphine and immediate-release morphine,[25,26] controlled-release oxycodone and immediate-release oxycodone.[27,28] For patients who cannot swallow or be relied on to take oral medications twice a day, transdermal fentanyl (Duragesic) is an excellent alternative for control of their persistent pain.[29,30] A long-acting form of hydromorphone should be on the market sometime in the next year.
Similar to the choice of the opioid, the opioid dose is based upon the patients pain intensity and current analgesic therapy. The important message is that there is no one preset optimal dose and no one preset maximal dose.[7,9-11] The right dose is the dose that relieves pain throughout the dosing interval without causing unacceptable side effects.
The oral route is usually preferred because of its convenience and ease of administration.[7,9-11] Some patients prefer the transdermal route and this route is best suited for patients with chronic pain cannot utilize the oral route. The rectal route is sometimes used. The parenteral route is used when patients are temporarily unable to swallow or tolerate their oral medications, or when they are in a pain crisis and need rapid dose titration. The spinal or neuraxial route of opioid administration should be considered when patients do not achieve satisfactory comfort and function with systemic pharmacotherapy.[12-14]
The best opioid dosing interval is one that is short enough so the pain does not return before the next dose, but not so short that patients are taking medicines too many times a day. The dosing interval depends on the opioid selected and the route by which it is administered.[7,9-11] Immediate-release oral opioids should be given every 4 hours, controlled-release oral opioids, every 12 hours, and the transdermal fentanyl patch, every 72 hours. If pain relief from these opioids does not last the full dosing interval, their dose should be increased or the dosing interval can be shortened.
The goal of pharmacologic therapy for cancer pain is not simply pain relief but pain prevention.[7,9-11] Pain prevention is best achieved by using around-the-clock dosing of the right dose of the right drug given at the right interval. Supplements for breakthrough pain must always be available on an as-needed basis. In general, the supplement dose should be correlated with the around-the-clock dose. Typically, the breakthrough dose available during any given time period should be equal to the pain prevention dose given in that period.[7,9-11] If a patient is taking 120 mg of controlled-release oxycodone every 12 hours, 40 mg of immediate-release oxycodone should be available every 4 hours as-needed for breakthrough pain. Should that patient regularly need their immediate-release oxycodone throughout the day, the dose of controlled-release oxycodone should be increased for better pain prevention. Increasing the dose of the around-the-clock, pain-preventing opioid may cause unacceptable sedation in patients who have predominantly incident or episodic breakthrough pain. In these patients, continued use of as-needed immediate release opioid supplements is the best way to optimize their comfort and function. Oral transmucosal fentanyl citrate, which has recently become available, could be the ideal agent for these patients. This buccally administered fentanyl works quicker and has a shorter duration than oral immediate-release opioids, allowing it to more closely mimic the temporal pattern of these brief flares of spontaneous or incident breakthrough pain.[33,34]
When titrating opioid doses, an increment of 33% to 100% is usually needed. It is not uncommon to double the opioid dose if pain is severe and there are no serious opioid side effects. Dose intensity is an important conceptual approach today in anticancer therapy. Dose intensity is also important in pain management.[7,9-11] Because morphine, oxycodone, and hydromorphone have half-lives of approximately 4 hours, their plasma levels reach steady-state in 12 to 24 hours. These pharmacokinetics allow aggressive upward dose titration on a daily basis until pain is relieved. For most patients, if you administer a high enough dose of their opioid, you can control their pain. The issue is whether you can control their pain without unacceptable side effects.
To achieve the desired goal of optimal comfort and function, side effects must be prevented or managed. [7,9-11] The most common side effect that needs intensive therapy and continuous reassessment is constipation. Virtually all patients on around-the-clock opioids need to be on around-the-clock laxatives with as-needed supplements and upward dose titration. Unrelieved constipation is one of the most common causes of opioid-related nausea. Opioids also cause nausea trough a central action. Antiemetics such as prochlorperazine (Compasine), haloperidol (Haldol), or metaclopramide may be needed. It is important to identify other common causes of nausea in these patients, such as their chemotherapy, hypercalcemia, brain or meningeal metastases, or bowel obstruction, so as not to unfairly blame their opioids and to initiate inappropriate cause-specific therapy. Patients may experience sedation, confusion, and hallucinations just after initiation or upward dose titration of their opioid analgesia. For most patients, these side effects wear off within days.[36,37] Patients with residual nausea, sedation, or confusion might benefit from opioid rotation, addition of coanalgesic agents, or consideration of neuraxial procedures.
Switching from one opioid to another can reduce side effects from the initial opioid.[21-24] Typical side effects that might improve are sedation, nausea, and myoclonus. In patients with a rare, true allergy to morphine or morphine congeners, switching to fentanyl or methadone may be best. Patients with severe toxicity from high doses of morphine often do particularly well when switched to methadone. Because of the unique pharmacology of this drug, it should be started at only 25% of the equianalgesic dose of the previous drug; a switch to another drug.[22-24,38]
Another way of reducing opioid-related side effects is to add coanalgesic agents, which allows the dose of the patients opioid to be reduced.[7,9-11] Coanalgesics can indirectly modify the source of the patients pain or modulate its neurophysiology. The early use of coanalgesic agents can forestall or avoid opioid-induced side effects. Fortunately, the most common cancer pain syndromesbone metastasis, nerve compression, visceral distention, and nerve damageare the most amenable to coanalgesic therapy.
The pain from bone metastases may respond well to the addition of a nonsteroidal anti-inflammatory drug, or a bisphosphonate, such as pamidronate (Aredia). The inflammatory component of pain from nerve compression or visceral distention responds well to high-dose corticosteroids. Nerve damage from tumor compression or infiltration, herpetic infection, surgical trauma, radiation therapy, or chemotherapy can result in neuropathic pain that is one of the most challenging types of pain. Neuropathic pain is often described in vivid terms such as burning, electric, or shooting, and sometimes cannot be controlled by opioids alone. The most effective coanalgesic agents for neuropathic pain are tricyclic antidepressants and anticonvulsants. A typical coanalgesic combination is either nortriptyline or desipramine and gabapentin (Neurontin).[44,45] Optimal relief with these agents requires chronic use of scheduled dosing and aggressive, individualized dose titration.
The pharmacologic management of cancer pain requires choosing the right drug and administering it at the right dose, by the best route, and in the most effective dosing interval. The goal is pain prevention with as-needed relief of breakthrough pain. Comfort and function are maximized with aggressive opioid titration, management of side effects, consideration of alternative opioids, and addition of appropriate coanalgesics. Following these principles, most clinicians should be able to control most of the pain experienced by most of their cancer patients throughout the course of their illness (Table 3).
Despite the appropriate use of these pharmacologic guidelines, there will still be a subset of patients whose comfort and function is not acceptable. For these patients, the primary clinician, whether the family physician or the oncologist, should consult and collaborate with a pain or palliative care specialist. Beyond the benefits of their expertise in pharmacologic and psychological/behavioral control of cancer pain, these specialists may be able to offer interventional procedures that may be the most direct, if not the only, way to provide these patients with their desired quality of life.
If clinicians work together, no cancer patient needs to live or die with unrelieved pain. Although the focus of this Desk Reference is cancer pain, even more patients suffer from pain from noncancerous conditions such as low back pain, degenerative arthritis, interstitial cystitis, sickle cell anemia, and fibromyalgia. The comprehensive, interdisciplinary approach that we have developed to control cancer pain without addiction, without tolerance, and without uncontrolled side effects can and should be applied to these patients as well.[46-48]
Elliot Krames, MD: Methadone is one of the drugs that we use quite routinely because its inexpensive and an excellent analgesic. With expertise in how to titrate long half-live drugs, both levorphanol and methadone are excellent drugs to use.
Russell K. Portenoy, MD: Could you put your comments into the perspective of overall palliative care and how that is now evolving in the United States?
Dr. Levy: I think that pain management has been one of the cracks in the wall through which the broader field of palliative medicine has been able to enter. There are a lot of studies of pain and we can measure it better than most other symptoms. If you look at the past decades of advancements in pain management, hospice was imported as an effective method of treating pain in patients with terminal cancer. Early on, we showed that we could control their pain without addiction, without tolerance, without too many side effects. Then people asked why we should wait until the last month of life to control pain. It really opened the door to combining cancer management with broader management of palliative care needs. So now we try to integrate palliative care earlier in the course of the patients disease.
Good pain management facilitates good cancer management. If patients are in too much pain, they cant lie on the radiation therapy table. They wont come in for their appointment to get their chemotherapy. So, we really brought pain control to the time of diagnosis. You have to control the pain if you want to hope to control the cancer and get the best quality and longevity of life. There are a significant number of patients who are cancer survivors who have chronic treatment-related pain. Instead of blaming them or telling them they have to live with it, were now bringing pain management into survivorship as something that really is a mandate for the oncologist.
Dr. Portenoy: So you would endorse the idea that pain management throughout the course of the disease is sort of the door opener to good palliative carequality-of-life-oriented care, function-oriented care--throughout the disease?
Dr. Levy: Yes. I think that pain management really is the beginning of palliative care. In fact, palliative care can precede the diagnosis. We have to be aggressive in treating symptoms even before we know their exact etiology. Palliation of those symptoms might involve treating the disease, aggressive medical management, local or regional therapy, and then followup throughout the continuum of disease. As the disease progresses and further disease-oriented therapy is considered ineffective, inappropriate, or not desired, we intesify the palliative care. We then bring in the other aspects of end-of-life and hospice care to help the patient die well with the same commitment that we had when we helped them live well. We also help their family grieve well with bereavement follow-up support.
Peter S. Staats, MD: I thought that you did a wonderful job in sketching out that theres more than the World Health Organization Three-Step Analgesic Ladder. The World Health Organization and its ladder has done a wonderful service in improving the availability of opioids both in the United States and abroad, but it really leaves a lot to be desired in terms of the coanalgesics that you discussed. It does not provide a framework for when to consider interventional therapiesthe celiac plexus blocks that you discussedor when to intervene with neuraxial delivery systems. I think in the next millennium were going to concentrate on integrating these various therapies into something that we know works pretty well, which is the World Health Organization Ladder, to decrease side effects and improve pain relief.
Dr. Levy: I agree. We need to look at where oncology care is right now. We use combination chemotherapyand in pain control thats analgesics and coanalgesicsdose intensity, and combined modalities. Most of the cancers that were curing today are curable because we know when to use surgery, radiation, local radiation, implantsworking it all together in sequence. Pain control must be slipped right into that same model.
Dr. Staats: Unfortunately, many oncologists dont know that these types of therapies exist. They dont know about the appropriate role of celiac plexus neurolysis. They dont know about intercostal neurolytic blocks. Theyve forgotten about cordotomies. They are uncomfortable with implantable infusion devices.
1. Cleeland CS, Gonin R, Hatfield AK, et al: Pain and its treatment in outpatients with metastatic cancer. N Engl J Med 330:592-596, 1994.
2. Coyle N, Adelhardt J, Foley KM, et al: Character of terminal illness in the advanced cancer patient: Pain and other symptoms during last four weeks of life. J Pain Symptom Manage 5:83-93, 1990.
3. Portenoy RK, Miransky J, Thaler HT, et al: Pain in ambulatory patients with lung or colon cancer: Prevalence, characteristics, and effect. Cancer 70:1616-1624, 1992.
4. Ventafridda V, Ripamonti C, DeConno F, et al: Symptom prevalence and control during cancer patients last days of life. J Palliat Care 6:7-11, 1990.
5. Grond S, Zech D, Diefenbach C, et al: Prevalence and pattern of symptoms in patients with cancer pain: A prospective evaluation of 1635 cancer patients referred to a pain clinic. J Pain Symptom Manage 9:372-382, 1994.
6. Foley KM: Competent care for the dying instead of physician-assisted suicide. New Engl J Med 336: 54-58, 1997.
7. Jacox AK, Carr DB, Payne R, et al: Management of cancer pain. Clinical practice guideline no. 9. Rockville, Md.: Agency for Health Care Policy and Research, 1994. (AHCPR publication no. 94-0592).
8. Doyle D, Hanks GWC, MacDonald N, (eds): Oxford Textbook of Palliative Medicine. Oxford, Oxford Medical Publishing, 1997.
9. Twycross R: Pain Relief in Advanced Cancer. London, Churchill Livingstone, 1994.
10. Levy MH: Pharmacolgoic treatment of cancer pain. New Engl J Med 335:1124-1132, 1996.
11. American Pain Society (4th ed): Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. Skokie, American Pain Society, 1999.
12. Arbit E, (eds): Management of Cancer-Related Pain. Mount Kisco, Futura Publishing Co Inc, 1993.
13. Patt RB, (ed): Cancer Pain. Philadelphia. J. B. Lippincott Co, 1993.
14. Rosen SM: Procedural control of cancer pain. Semin Oncol 21:740-747, 1994.
15. Bottomley DM, Hanks GW: Subcutaneous midazolam infusion in palliative care. J Pain Symptom Manage 5:259-261, 1990.
16. Greene WR, Davis WH: Titrated intravenous barbituates in control of symptoms in patients with terminal cancer. Southern Med J 84:332-337, 1991.
17. Ferrer-Brechner T: The management of pain associated with malignancy. Semin Anesthes 4:313-322, 1985.
18. Levy MH: Integration of pain management into comprehensive cancer care. Cancer 63:2328-2335, 1989.
19. Cherny NJ, Portenoy RK: The management of cancer pain. Cancer J Clin 44:262-303, 1994.
20. Serlin RC, Mendoza TR, Nakamura Y, et al: When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function. Pain 61:277-284, 1995.
21. Galer BS, Coyle N, Pasternak GW, et al: Individual variability in the response to different opioids: Report of five cases. Pain 49:87-91, 1992.
22. Crews JC, Sweeney NJ, Denson DD: Clinical efficacy of methadone in patients refractory to other mu-opioid receptor agonist analgesics for management of terminal cancer pain: Case presentations and discussion of incomplete cross-tolerance among opioid agonist analgesics. Cancer 72:2266-2272, 1993.
23. MacDonald N, Der L, Allan S, et al: Opioid hyperexcitability: The application of alternate opioid therapy. Pain 53:353-355, 1993.
24. de Stoutz ND, Bruera E, Suarez-Almazor M: Opioid rotation for toxicity reduction in terminal patients. J Pain Symptom Manage 10:378-384, 1995.
25. Thirlwell MP, Sloan PA, Maroun JA, et al: Pharmacokinetics and clinical efficacy of oral morphine solution and controlled-release morphine tablets in cancer patients. Cancer 63:2275-2283, 1989.
26. Ferrell B, Wisdom C, Wenzl C, et al: Effects of controlled-release morphine on quality of life for cancer pain. Oncol Nurs Forum 16:521-526, 1989.
27. Bruera E, Belzile M, Pituskin E, et al: Randomized, double-blind, cross-over trial comparing safety and efficacy of oral controlled-release oxycodone with controlled-release morphine in patients with cancer pain. J Clin Oncol 16:3222-3229, 1998.
28. Kaplan R, Parris WCV, Citron ML, et al: Comparison of controlled-release and immediate-release oxycodone tablets in patients with cancer pain. J Clin Oncol 16: 3230-3237, 1998.
29. Payne R: Transdermal fentanyl: Suggested recommendations for clinical use. J Pain Symptom Manage 7(suppl):S40-44, 1992.
30. Ahmedzai S, Brooks D: Transdermal fentanyl versus sustained-release oral morphine in cancer pain: Preference, efficacy, and quality of life. J Pain Symptom Manage 13:254-261, 1997.
31. Hays H, Hagen N, Thirlwell M, et al: Comparitive clinical efficacy and safety of immediate release and controlled release hydromorphone for chronic severe cancer pain. Cancer 74:1808-1816, 1994.
32. Portenoy RK, Hagen NA: Breakthrough pain: Definition, prevalence and characteristics. Pain 41:273-281, 1990.
33. Christie JM, Simmonds M, Patt R, et al: Dose-titration, multicenter study of oral transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain. J Clin Oncol 16:3238-3245, 1998.
34.Portenoy RK, Payne R, Coluzzi P, et al: Oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in cancer patients: A controlled dose titration study. Pain 79:303-312, 1999.
35. Levy MH: Constipation and diarrhea in cancer patients. Cancer Bull 43:412-422,1991.
36. Bruera E, Macmillan K, Hanson J, et al: The cognitive effects of the administration of narcotic analgesics in patients with cancer pain. Pain 39:13-16, 1989.
37. Vainio A, Ollila JH, Matikainen E, et al: Driving ability in cancer patients receiving long-term morphine analgesia. Lancet 346:667-670, 1995.
38. Ripamonti C, Groff L, Brunelli C, et al: Switching from morphine to oral methadone in treating cancer pain: What is the equianalgesic dose ration? J Clin Oncol 16:3216-3221, 1998.
39. Eisenberg E, Berkey CS, Carr DB, et al: Efficacy and safety of nonsteroidal antiinflammatory drugs for cancer pain: A meta-analysis. J Clin Oncol 12:2756-2765, 1994.
40. Body JJ, Bartl R, Burckhardt P, et al: Current use of bisphosphonates in oncology. J Clin Oncol 16:3890-3899, 1998.
41. Watanabe S, Bruera E: Corticosteroids as adjuvant analgesics. J Pain Symptom Manage 9:442-445, 1994.
42. Watson CPN: Antidepressant drugs as adjuvant analgesics. J Pain Symptom Manage 9:392-405,1994.
43. McQuay H, Carrol D, Jadad AR, et al: Anticonvulsant drugs for management of pain: A systematic review. Brit Med J 311:1047-1052, 1995.
44. Backonja M, Beydoun A, Edwards KR, et al: Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus. J Amer Med Assoc 280:1831-1836, 1998.
45. Rowbotham M, Harden N, Stacey B, et al: Gabapentin for the treatment of postherpetic neuralgia. J Amer Med Assoc 280:1837-1842, 1998.
46. Portenoy RK: Chronic opioid therapy in nonmalignant pain. J Pain Symptom Manage 5(suppl):S46-62, 1990.
47. Brookoff D, Polomano R: Treating sickle cell pain like cancer pain. Ann Intern Med 116:364-368, 1992.
48. Zenz M, Strumpf M, Tryba M: Long-term oral opioid therapy in patients with chronic nonmalignant pain. J Pain Symptom Manage 7:69-77,1992.