Supported by a grant from Endo Pharmaceuticals, Inc., USA

Editorial Board

Editor-in-Chief

Jane C. Ballantyne, MD, FRCA Anesthesiology, Pain MedicineUSA

Advisory Board

Michael J. Cousins, MD, DSCPain Medicine, Palliative MedicineAustralia

Maria Adele Giamberardino, MD Internal Medicine, Physiology Italy

Patricia A. McGrath, PhD Psychology, Pediatric Pain Canada

M.R. Rajagopal, MDPain Medicine, Palliative MedicineIndia

Maree T. Smith, PhD Pharmacology Australia

Claudia Sommer, MDNeurologyGermany

Harriët M. Wittink, PhD, PT Physical Therapy The Netherlands

Production

Elizabeth Endres, Associate Editor Kathleen E. Havers, Programs Coordinator

Musculoskeletal PainAnimal ModelsAIDS Neuropathy

The Clinical Problem of Persistent Cancer Pain

In 2008, in the United States, more than 1.4 million individuals were di-agnosed with cancer and more than 550,000 patients died from cancer.2 Pain is the first symptom of cancer in 20–50% of all cancer patients, and 75–90% of advanced or terminal cancer patients must cope with chronic pain syndromes related to che-motherapy, failed treatment, and/or tumor progression.3,23 Cancer patients can expe-rience pain with varying degrees of intensity and frequency at multiple anatomical locations. Cancer pain is multifaceted, with clinical descriptors including acute, chronic, nociceptive (somatic), visceral, and neuropathic.6 It consists of complex mixtures of nociceptive and neuropathic types of pain that are likely to be driven through different mechanisms.6

The most commonly diagnosed cancers—lung, prostate, and breast can-cers2—often metastasize to bone, and in advanced states, they are associated with bone remodeling and eventual bone fracture that contributes to incapacitating pain and limited or total loss of daily activity.18 Excessive bone destruction is correlated with ongoing pain in the area of the tumor and is characterized as dull in character, constant in presentation, and generally showing a time-dependent increase in inten-sity.18 As bone destruction progresses, breakthrough pain—an intermittent episode of extreme pain—may occur spontaneously or, more commonly, by weight bearing or movement of the affected bone.19,23 Breakthrough pain is very difficult to control, and it represents one of the most serious and highly debili-tating cancer-related events.19,23 Pain limits daily activity in 41% of patients reporting mild to moderate pain and in 94% of patients reporting moderate to severe pain, leading to greatly diminished quality of life in these patients.7 Ad-vances in cancer therapies have drastically improved survival times of patients with prostate cancer, including those with bone metastases. The lifespan of patients diag-nosed with metastatic prostate cancer has increased to an average of 55 months (4.5 years).10 However, these patients still experience pain from the bone metastases that can be severe and unpredictable and can greatly limit daily activities.6,10,18 This situ-ation highlights the need for effective treatment that can be given over long periods of time without the side effects associated with current treatments.

Volume XVIII, Issue 1 February 2010

Upcoming Issues

®

Opioids in Cancer Pain: New Considerations

Even with a similar type or severity

of pain, the effective opioid dose as

well as the relative toxicity ratios

may vary greatly across patients

2

Current treatment for prostate cancer patients with bone cancer pain follows the World Health Organization’s lad-der approach for relief of cancer pain.6,30 This approach recom-mends adjusting the strength and potency of the analgesic ac-cording to pain intensity, with nonsteroidal anti-inflammatory drugs (NSAIDs) primarily used to treat mild to moderate pain, and opioid drugs, with or without coanalgesics/adjuvant analgesics, used to treat moderate to severe pain. In patients with advanced cancer, pain is described as moderate to severe in approximately 40–50% and very severe or excruciating in 25–30% of cases.7

Breakthrough pain is very difficult to

control, and it represents one of the most

serious and highly debilitating cancer-

related events

Although opioids are recommended for treatment of moderate to severe cancer pain, several barriers can limit the effective treatment of such pain.6 Many of these barriers hinge on opioid-related concerns held by physicians, patients, and patients’ families.6 Adding to concerns related to fear of ad-diction, opioid administration can be associated with severe, sometimes debilitating side effects including somnolence, men-tal confusion, and constipation.5 Moreover, some patients de-velop analgesic tolerance to opioids, in which greater doses of opioids are required to produce effective pain management.6,25 In addition, some patients report opioid-induced abnormal pain (opioid-induced hyperalgesia) that occurs at sites unassociated with the original pain complaint.20,25

Successful opioid treatment of any duration depends on achieving a favorable balance between analgesia and ad-verse effects.3,26 Importantly, there is great interindividual vari-ability in opioid effects; even with a similar type or severity of pain, the effective opioid dose as well as the relative toxicity ratios may vary greatly across patients.3,26 Critical for effec-tive management of cancer pain is appropriate knowledge of analgesic (primarily opioid) pharmacology with respect to dos-ing, timing, alternative routes of administration (such as rectal, subcutaneous, epidural, and intrathecal), and converting from intravenous to oral therapies.3,26 The American Pain Society proposes several important considerations for appropriate pain management, including: (1) the source of the patient’s pain; (2) the patient’s age, general health, and comorbidities; (3) the potential for medication-related adverse effects; (4) potential drug interactions; (5) comorbidities that may be relieved by nonanalgesic effects of the medications (e.g., sleep distur-bances, depression, or anxiety); (6) comorbidities that may be exacerbated by the nonanalgesic effects of the medications (e.g., hypertension, ulceration, renal impairment, or cognitive impairment); (7) costs associated with therapy; (8) potential risks for medication abuse; and (9) risks of overdose.3 It is ar-gued that although no single opioid is optimal for all patients, an optimal opioid can generally be found for each patient.26

Long-Term Opioid Administration

Opioids are recommended for treatment of moderate to severe cancer pain, with morphine being used most frequent-ly.19 Although opioids have good efficacy with acute treatment, it has been argued that analgesic efficacy for chronic pain con-ditions, although initially good, is not always sustained during continuous and long-term treatment (months to years).4,26 Im-portantly, the chronic nature of cancer pain often requires pro-longed opioid administration through controlled-release tablets, repeated bolus injections, or transdermal patches.1,11,29 Another potential problem with the use of opioids in treating cancer pain is decreased analgesic efficacy, which can potentially arise from multiple mechanisms, including the development of re-ceptor desensitization, opioid-induced hyperalgesia, subtle and intermittent withdrawal, and psychological factors.4,25 In ad-dition, increased doses of opioids may be required because of advancement of the disease, resulting in greater pain.21 Clinical studies have reported that opioids administered by different routes of administration (transdermal, oral, intrathecal, and intravenous) can unexpectedly produce hyperalgesia and allo-dynia, particularly during rapid dose escalation.20

Preclinical studies have demonstrated that opioids can paradoxically enhance pain.22 Structurally distinct opioids, including nonpeptidic agonists (e.g., morphine, oxymorphone, and fentanyl) as well as peptides acting at mu-opioid receptors (e.g., DAMGO), have been shown to produce hyperalgesia in preclinical models.22 Recent research has demonstrated that sustained morphine administration for several days induces neuroplastic adaptations in rodents that paradoxically enhance pain.22 In rodents, sustained morphine administration has been demonstrated to: (1) upregulate excitatory neurotransmit-ters, such as substance P and calcitonin gene-related peptide (CGRP) in primary afferent fibers and the spinal cord; (2) increase evoked release of excitatory neurotransmitters within the spinal cord; (3) upregulate spinal dynorphin levels, promot-ing enhanced input from afferent nociceptors; and (4) activate descending pain facilitation from the rostral ventromedial me-dulla.22

The above studies exploring preclinical mechanisms of opioid-induced hyperalgesia have focused on opioid-in-duced pronociceptive changes in uninjured animals. However, the effects of prolonged, sustained opioid administration in the presence of a persistent pain state, such as cancer-induced bone pain, have only recently begun to be examined. Single bolus injections of morphine were shown to effectively block behav-ioral measures of cancer-induced bone pain in mice.15 Similar efficacy was observed with daily bolus morphine injections, with no tolerance to morphine’s antinociceptive effects.28 In contrast, sustained delivery of morphine through osmotic mi-nipumps, designed to maintain stable blood plasma levels for several days, enhanced cancer-induced pain in a murine model of sarcoma-induced bone pain.12 Moreover, sustained morphine infusion increased the expression of excitatory neurotransmit-ters (substance P and CGRP) in primary afferent fibers, sug-gesting the potential for enhanced nociceptive signaling in the

3

morphine-treated animals.12 In addition, sustained morphine administration surprisingly enhanced sarcoma-induced bone loss and fracture, as well as expression of activating transcrip-tion factor 3 (ATF3, a marker of neuronal damage) in cell

bodies of primary afferent fibers.12 These data indicate that sustained morphine infusion may result in “add-on” mecha-nisms of pain beyond those engaged by the sarcoma alone.12 In addition, both the enhanced cancer-induced bone pain and bone loss were dose dependent and were reversed by coadministra-tion of naloxone, suggesting that these effects are dependent on the mu-opioid receptor.12

Sustained morphine exposure has also been suggested to alter cancer growth in vitro and in vivo. However, results are conflicting as to whether morphine enhances or inhibits tumor cell proliferation.27 Several studies have shown that morphine inhibits tumor cell proliferation.27 However, others have found that morphine promotes tumor cell proliferation as well as metastasis and mortality.8,9 The discrepancies between these results may be due to a number of factors, including the use of different cell lines, different doses of morphine, and dif-ferent durations of morphine exposure across experiments.9,27

While it is unknown whether these effects will generalize to other cancers or opioids, it is clear that there is a need for in-creased understanding of the neurobiological consequences of prolonged opioid exposure in chronic pain conditions. Such an understanding may allow improvements in the use of opioids and enhance the effective management of patients with chronic cancer pain. The debilitating side effects of opioids and chronic opioid treatment required in most patients with bone metas-tases, together with the increase in survival time of prostate cancer patients with bone metastases, call for better pain man-agement options.

Opioid Switching and Rotation

Responses to opioids vary significantly among pa-tients and even in an individual patient at different stages of treatment, leading to difficulties in finding long-term analgesia with minimum side effects.25,26 Moreover, after selection of the initial opioid, it is probable that a change in opioid will become necessary at some point.26 Changes in opioids are likely (1) when the selected opioid has failed to provide adequate anal-gesia at doses below those that produce adverse side effects (opioid switching); or (2) following a period of chronic treat-ment with the selected opioid when it appears that the analge-sic benefits are diminishing (opioid rotation).26 For both opioid switching and opioid rotation, sequential trials may be required to find the optimal opioid for effective pain management.26 No single mechanism adequately explains the intraindividual or

interindividual variability observed with opioids. Available evidence suggests that a constellation of neurobiological, demographic, medical, and patient-specific factors all con-tribute to determining a patient’s response to a particular opioid.3,4,25,26 Moreover, several factors may contribute to the diminished analgesic efficacy of opioids given in chronic pain conditions, including pharmacological tolerance, pos-sible development of opioid-induced hyperalgesia, and progression of the disease.3,4,25,26 The recommended practice for opioid switching and rotation is to use an “equianalgesic table” to estimate the dosing equivalence for the new opioid relative to the previous opioid.3 Given that the potency and bioavailability of opioids vary dramatically and are depen-dent on route of administration, the conversion ratios must be carefully considered during opioid switching or rotation.26 Effective pain management with opioids is dependent on understanding of opioid pharmacology, including different formulations, the impact of route of administration, and the potential for interactions with concurrent medications. These concepts are important for selection of the initial opioid, as well as for opioid switching and rotation, to maintain effec-tive pain management.

Potential Benefits of Coanalgesics

Coanalgesics are drugs administered in conjunction with NSAIDS and opioids that may enhance the analgesic activity of the NSAIDs or opioids, have independent analge-sic activity in certain pain states, such as neuropathic pain, or may counteract some of the adverse side effects associ-ated with NSAIDS or opioids.3 Several preclinical studies indicate that combination therapies may prove beneficial in improving the analgesic efficacy of opioids as well as diminishing adverse side effects and disease progression. Coadministration of selective cyclooxygenase-2 (COX-2) inhibitors with morphine has been demonstrated to diminish tumor growth in vitro as well as in vivo. Moreover, COX-2 inhibitors were found to block morphine-induced enhanced tumor growth, angiogenesis, and metastases in preclinical studies.8,24 Other studies have shown that COX-2 inhibitors block development of opioid-induced hyperalgesia.13 More-over, coadministration of COX inhibitors with morphine provided synergistic antiallodynic effects in a rat model of neuropathic pain.14 As neuropathic pain is a recognized component of cancer-induced bone pain that is resistant to opioids,17 coadministration of COX inhibitors may prove a useful strategy for effective pain management that limits the adverse side effects of opioids.

The use of coanalgesics that target

neuropathic pain may be particularly

important because such pain is resistant

to opioids

Clinically, coanalgesics consist of a diverse range

of drug classes, including anticonvulsants (e.g., gabapentin,

Although opioids are recommended

for treatment of moderate to severe

cancer pain, several barriers can

limit effective treatment

4

pregabalin), antidepressants (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin norepi-nephrine reuptake inhibitors), N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., ketamine), corticosteroids, skeletal muscle relaxants, local anesthetics, and alpha-2 adrenergic agonists (e.g., clonidine).3 Coanalgesics are frequently admin-istered with opioids in efforts to diminish the dose required for effective pain management and reduce adverse effects.16 The American Pain Society states that the proper use of coan-algesics is critical to successful pain management, and that it depends on evaluation of risks (adverse effects and drug interactions) versus benefits (improved pain relief, sleep, and quality of life).3 Moreover, the use of coanalgesics that target neuropathic pain may be particularly important because such pain is resistant to opioids, and it occurs in 40–50% of patients with cancer pain.17

Combination therapies may prove benefi-

cial in improving the analgesic efficacy

of opioids as well as diminishing adverse

side effects and disease progression

Overall, multimodal therapy for pain management is recommended3 for two main reasons: (1) coadministration of adjuvants that block adverse effects such as nausea, constipa-tion, and opioid-induced hyperalgesia will improve pain man-agement and decrease adverse side effects, thus improving the patient’s quality of life; and (2) combination pharmacotherapy is often better than opioids alone due to multiple mechanisms of action, particularly given the multifaceted nature of cancer pain regarding neuropathic, inflammatory, and mechanical qualities.3,18 In combination with traditional analgesics, patients

also receive therapies designed to diminish tumor burden, such as radiation therapy, or bone remodeling, such as bisphospho-nates.3 As stated above, issues of potential interactions between analgesics and nonanalgesic medications must be taken into account to optimize disease treatment and pain management for these patients.3

Conclusion

Opioids are currently the most effective and most appropriate treatment for moderate to severe cancer-induced pain, and they remain the best front-line treatment for cancer pain patients. However, care must be taken to closely monitor patients for potential adverse effects of opioids. Alternatives such as co-therapies and opioid rotation must be considered and appropriately used to minimize opioid-induced adverse side effects and to maintain the analgesic efficacy of opioid treatment. Focusing on the impact of the disease as well as that of the therapeutic strategies becomes particularly important as chemotherapeutic treatments advance and extend the lifespan of patients. Important advances are increasing the therapeutic options for patients with metastatic bone pain. New drugs, such as anti-nerve growth factor antibodies, are currently undergo-ing clinical trials for cancer-induced bone pain. In addition, preclinical studies indicate that agents such as COX inhibitors, neurokinin-1 antagonists, and serotonin (5-HT3) antagonists may be considered as adjuncts in ameliorating opioid side effects such as opioid-induced induced hyperalgesia and an-algesic tolerance, thus increasing the therapeutic potential of the opioids in these patients. Further study on the effects of prolonged opioid exposure on pain processing and on disease progression will provide important insights as to potential im-provements in long-term pain management in cancer patients with chronic tumor-induced pain.

5

16. Lussier D, Huskey AG, Portenoy RK. Adjuvant analgesics in cancer pain

management. Oncologist 2004;9:571–91.

17. Manfredi PL, Gonzales GR, Sady R, Chandler S, Payne R. Neuropathic pain

in patients with cancer. J Palliat Care 2003;19:115–8.

18. Mantyh PW, Clohisy DR, Koltzenburg M, Hunt SP. Molecular mechanisms of

cancer pain. Nat Rev Cancer 2002;2:201–9.

19. Mercadante S, Arcuri E, Ferrera P, Villari P, Mangione S. Alternative treatments

of breakthrough pain in patients receiving spinal analgesics for cancer pain. J

Pain Symptom Manage 2005;30:485–91.

20. Mercadante S, Ferrera P, Villari P, Arcuri E. Hyperalgesia: an emerging

iatrogenic syndrome. J Pain Symptom Manage 2003;26:769–75.

21. Mercadante S, Portenoy RK. Opioid poorly-responsive cancer pain. Part 1:

clinical considerations. J Pain Symptom Manage 2001;21:144–50.

22. Ossipov MH, Lai J, King T, Vanderah TW, Porreca F. Underlying mechanisms of

pronociceptive consequences of prolonged morphine exposure. Biopolymers

2005;80:319–24.

23. Portenoy RK, Lesage P. Management of cancer pain. Lancet 1999;353:1695–

700.

24. Sabino MA, Ghilardi JR, Jongen JL, Keyser CP, Luger NM, Mach DB, Peters

CM, Rogers SD, Schwei MJ, de Felipe C, Mantyh PW. Simultaneous reduction

in cancer pain, bone destruction, and tumor growth by selective inhibition of

cyclooxygenase-2. Cancer Res 2002;62:7343–9.

25. Silverman SM. Opioid induced hyperalgesia: clinical implications for the pain

practitioner. Pain Physician 2009;12:679–84.

26. Slatkin NE. Opioid switching and rotation in primary care: implementation and

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27. Tegeder I, Geisslinger G. Opioids as modulators of cell death and survival:

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Tamara King, PhD, and Frank Porreca, PhDDepartment of PharmacologyUniversity of Arizona Health Sciences CenterTucson, Arizona 85724, USAkingt@email.arizona.edu; frankp@u.arizona.edu

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Visit the IASP website for information about the Global Year Against Pain

www.iasp-pain.org/GlobalYear/MSP

Coming Soon from IASP Press

Edited by Judith A. Paice, Rae F. Bell, Eija A. Kalso, and Olaitan A. Soyannwo

This book provides an in-depth analysis of basic and clinical research on cancer pain. It describes mechanisms of cancer pain and reviews opioid treatment issues,

including tolerance. The book discusses clinical trial designs, covers the psychology of cancer pain, and describe disparities in the availability of cancer care worldwide.

CanCer PainFrom Molecules to Suffering

Timely topics in pain research and treatment have been selected for publication, but the information provided and opinions expressed have not involved any verification of the findings, conclusions, and opinions by IASP. Thus, opinions expressed in Pain: Clinical Updates do not necessarily reflect those of IASP or of the Officers or Councilors. No responsibility is assumed by IASP for any injury and/or damage to persons or property as a matter of product liability, negligence, or from any use of any methods, products, instruction, or ideas contained in the material herein. Because of the rapid advances in the medical sciences, the publisher recommends independent verification of diagnoses and drug dosages.

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