SUPPLEMENT

Choice of Opioids and the WHO Ladder

Paul Glare, MBBS, FRACP, FACP

Summary: Physicians in developing countries who start to develop new, palliative care services face real barriers because of ophiophobia in their countries. These physicians need to convince their colleagues in their own institutions about the need to adopt clear policies concerning pain management and palliative care in general. Moreover, these physicians need to explain the importance of such new services to their administrators and often legislators at the national level. People in the Middle East are facing cultural, traditional, and religious obstacles with regard to the introduction of opioids into regular use both in hospitals and in the community. In many countries, these drugs are believed to be drugs of addiction and in some cases, even dangerous drugs. Our goal is to enhance the establishment of pain units, being it within the framework of the Oncology Center, Palliative Care Services, or as stand-alone units. Key Words: opioids, WHO, pain management, palliative care

(J Pediatr Hematol Oncol 2011;33:S6S11)

oderate-to-severe pain is experienced by approximately one-third of the patients with advanced cancer and 70% to 90% of patients with far advanced cancer.1 Until 40 years ago, neurolytic and neurosurgical techniques were the mainstay of cancer pain management but were only rarely available, often applied haphazardly and empirically with consequent poor results and misleading reports.2 Medical management of cancer pain was restricted to postsurgical cases and patients who were actively dying. Opioids were given pro re nata and usually intramuscularly. Cancer pain management began to improve in the 1970s for a number of reasons.3 The diagnosis and treatment of cancer improved. Discovery of opioid receptors and other advances in opioid pharmacology occurred. Patients and families began to demand better pain management. The practice of repeated administration of Brompton cocktail pioneered in British hospices was disseminating globally. Studies showed rst that Brompton cocktail was superior to these traditional methods of pain relief,4 and then that single-agent morphine was just as eective and better tolerated than the cocktail.5 By 1980, pharmacological management became the main approach to cancer pain in North America and Britain with a resulting decline in neurosurgical procedures.6 Various bodies now have cancer pain guidelines and all recommend a trial of strong opioids for patients with moderate-to-severe pain.711 Uptake of the pharmacological approach to cancer pain management in developing countries has been much
Received for publication January 11, 2011; accepted January 24, 2011. From the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Reprints: Paul Glare, MBBS, FRACP, FACP, Memorial SloanKettering Cancer Center, Mailbox 496, 1275 York Avenue, New York, NY 10065 (e-mail: glarep@mskcc.org). Copyright r 2011 by Lippincott Williams & Wilkins

slower. Cultural, traditional, and religious obstacles continue to delay the introduction of opioids into regular use, both in hospitals and in the community.7 Opioid consumption rates remain very low.12 In many countries of the Middle East, these drugs are believed to be drugs of addiction and in some cases, even dangerous drugs. Around 1980, the World Health Organization (WHO) became concerned about the inadequacies of cancer pain management, which were attributed to physician-related barriers in developed countries and restricted access to strong opioids for cancer patients in developing countries. In many parts of the world, not a single dose of oral morphine was available. The WHO estimated that millions of people worldwide were suering needlessly, and this could easily be remedied if only strong opioids were made available. For many of these patients, there wasand still isno prospect of cure and the only realistic human approach to their illness was to oer pain relief and palliative care. The WHO brought together a group of experts in the management of cancer pain, who expressed the consensus that although the number of drugs was limited, pain relief was a realistic target for the majority of cancer patients. This resulted in the WHO Technical Report Cancer Pain Relief,13 which contained the Method for Pain Relief, a structured approach to drug selection for cancer pain management which has become known as the WHO analgesic Ladder. The method consists of 3 basic steps (Table 1). A trial of a strong opioid such as morphine should be given to all patients with pain of moderate or greater severity. Three decades later authorities continue to widely endorse the guiding principle behind the ladder that analgesic selection should be primarily determined by the severity of the pain.

EVIDENCE FOR THE EFFICACY OF THE LADDER AS A METHOD FOR CANCER PAIN TREATMENT
After the publication of the ladder in 1986, 8 studies showing its eectiveness in more than 70% patients across in a variety of clinical settings and countries were

TABLE 1. WHO Method of Cancer Pain Relief Patients with mild cancer-related pain should be treated with a nonopioid analgesic, which should be combined with adjuvant drugs if a specic indication for this exists Patients who are relatively nontolerant and present with moderate pain, or fail to achieve adequate relief after a trial of nonopioid, should be treated with an opioid conventionally used for mild-to-moderate pain (formerly known as weak opioids) Patients who present with severe pain, or who fail to achieve adequate relief after appropriate administration of drugs on the second step of the analgesic ladder, should receive an opioid conventionally used for moderate-to-severe pain (formerly known as a strong opioid)

S6 | www.jpho-online.com

J Pediatr Hematol Oncol

Volume 33, Supplement 1, April 2011

J Pediatr Hematol Oncol

Volume 33, Supplement 1, April 2011

Choice of Opioids and the WHO Ladder

published.1421 A systematic review criticized the evidence these studies provide for the ecacy of the ladder, citing various methodological shortcomings.22 All studies were case series with no control groups. Two were retrospective studies. Other problems included failure to provide information on the conditions in which the pain was assessed, short or variable follow-up periods and/or high withdrawal rates. These methodological deciencies precluded performing a meta-analysis to enable an estimation of the ecacy of the ladder compared with other approaches.

LIMITATIONS OF THE LADDER IN THE CLINIC

Although the WHO ladder has been very important as a global public health tool, it is really too simplistic to be useful for managing cancer pain in individual patients in a more sophisticated center. There are 3 conceptual problems with the WHO ladder in its basic 1986 format.

The Ladder Ignores the Importance of Identifying the Noxious Stimulus

Not all pain experienced by people with cancer is because of progressive disease. Pain may be a side eect of treatment, because of debilitation status posttreatment or totally unrelated to the cancer or its treatment. Many of these other nondisease-related pains have specic treatments that need to be considered, and all patients with cancer who are in pain should have a comprehensive, multidimensional assessment. This means taking a careful pain history followed by a focused physical examination, supplemented by investigations such as magnetic resonance imagings or computed tomography scans, if clinically appropriate. A psychosocial and spiritual evaluation should also be included.

The Ladder Focuses too Much on the Pharmacological Management of Cancer Pain, Especially With Opioids
The reason for a multidimensional assessment is to plan multimodal treatment. The ladder ignores the importance of psychosocial assessment and support, physiotherapy and occupational therapy, antineoplastic therapies, and invasive procedures such as spinal opioids, nerve blocks, and neurosurgical techniques.

The Ladder Implies a 1-way Escalation of Opioids

The ladder implies a 1-way inexorable increase in opioid potency, with patients ending up on morphine until they die. Although this may be the case in far advanced cancer, many patients with newly diagnosed cancer present with severe pain that requires a strong opioid from the outset, which can be stopped once eective anticancer treatment has been initiated.

MORE COMPREHENSIVE APPROACHES TO CANCER PAIN MANAGEMENT THAN THE WHO LADDER
Two variations on the WHO ladder have been posited, which have opioids analgesics as their cornerstone but go beyond merely escalating the pain medicine to obtain control of cancer pain. The best known is the pyramid plus ribbon approach advocated by the United States Department of Health and Human Services Agency for Health Care Policy and Research in its 1994 cancer pain guideline.8
r

The pyramid represents a hierarchy of pain management strategies from least invasive (at base) to most invasive (at apex). The WHO ladder forms the base of the pyramid. Therapies depicted on the ribbon complement the somatic pain therapies provided on the pyramid. The multidisciplinary approach to assessment and treatment implicit in the pyramid and ribbon approach is based on eliciting the pain mechanism (or, more precisely, mechanisms in many patients).23 This approach is particularly helpful when opioid analgesics alone are not fully eective and other options need to be considered. A well-designed clinical trial of the pyramid and ribbon approach compared usage of a multilevel treatment algorithm based on the Agency for Health Care Policy and Research guideline with standard practice pain management strategies used by community oncologists.24 Patients randomized to the pain algorithm group achieved a statistically signicant reduction in pain intensity when compared with standard community practice. Concurrent chemotherapy and patient adherence to treatment were signicant mediators of worst pain. There were no signicant dierences in other symptoms or quality of life between the 2 treatment groups. The results of this study support the pyramid and ribbon approach operationalized by use of algorithmic decision-making in the management of cancer pain. Subsequently, a tailored cost-eectiveness analysis compared 3 approaches to cancer pain: guidelinebased care, oncology-based care, and usual care. After a month of treatment, a much higher percentage of patients treated according to guideline-based care had eective pain management (80% vs. 30% to 55%), achieved with modest (25% to 66%) increases in resource use.25 The other alternative to the WHO ladder is the 4-step Sydney Stickman approach.26 In addition, using a simple, easy-to-teach cartoon, the Sydney Stickman puts more emphasis on the comprehensive, multidimensional assessment of the patient than does the pyramid and ribbon approach. The physician should take a careful pain history followed by a focused physical examination and then order appropriate investigations. As the author states, the pain diagnosis may be made in 5 minutes or may evolve over several days. Treatment includes peripherally acting agents such as acetaminophen or a nonsteroidal anti-inammatory drug (NSAID), and possibly further antitumor therapy. The Stickman approach emphasizes communication with patientthe patient telling the self. Encouraging the patient to tell the story of themselves in relation to the cancer and their pain has the potential for self-healing and reducing some distress. This assessment lays the platform for an individualized application of various treatment modalities. Unlike the AHPCR, the Stickman approach has not been formally evaluated. Despite the acceptance of the eectiveness of medical management for treating cancer pain and widespread medical education facilitated by promulgation of the ladder and its variants, the use of opioids for cancer pain is controversial and many patients continue to have their pain undertreated.27 The controversies surrounding opioids have evolved over 40 years.3,28,29 Although many of these have been largely resolved (method of drug administration, route of drug administration, development of tolerance), 2 remain at issue, namely choice of best opioid analgesic and the risk of substance abuse and addiction. In the United States, the abuse of prescription opioids has grown rapidly since the mid-1980s and is now as frequent as the www.jpho-online.com |

2011 Lippincott Williams & Wilkins

S7

Glare

J Pediatr Hematol Oncol

Volume 33, Supplement 1, April 2011

abuse of cocaine.30 Recent high-prole cases such as Michael Jackson, Heath Ledger, and Rush Limbaugh have exacerbated societal concerns about abuse and misuse of pain medicines.31

Choice of Best Opioid

Step 1 of the ladder recommends prescribing NSAID or acetaminophen to patients with mild pain. A systematic review of the safety and ecacy of NSAIDs in cancer pain found NSAIDs to be approximately equivalent to 5 to 10 mg intramuscular morphine.32 Although there was some evidence of a dose response to these agents, there is a ceiling eect to analgesia. There is increased concern about acetaminophen-induced hepatotoxicity,33 and doses not exceeding 4 g/d are now recommended. Even at safe doses, NSAIDs or acetaminophen may be problematic in cancer patients on chemotherapy who may have thrombocytopenia or in whom it is undesirable to mask a fever. Step 2 of the ladder recommends a weak opioid such as codeine or tramadol for moderate cancer pain, and weak opioid such as in combination with acetaminophen is marginally more eective for mild-to-moderate pain than acetaminophen alone.34 At therapeutic doses there is no evidence of superiority of 1 weak opioid over another for mild-to-moderate pain.35 Physicians have traditionally been reluctant to prescribe anything stronger than codeine, but the extent to which the dose can be titrated is limited due to a ceiling eect (codeine) or toxicity (tramadol). It is now understood that codeine and hydrocodone are prodrugs (for morphine and hydromorphone, respectively) and that non-White patients frequently lack the enzyme (cytochrome P450 2D6) required to activate them.36,37 There has been concern about the abuse potential of hydrocodone, although the estimate of the extent of this problem is aected by how the abuse data are calculated.38 In November 2010, propoxyphene-containing analgesics were withdrawn by the Food and Drug Administration because of concerns about cardiotoxicity.39 Low-dose formulations of strong opioids have been shown to be safe and eective for the rst-line management of mild-to-moderate pain.40 Consequently, many experts now advocate skipping the second step of the ladder and using strong opioids for all cancer pain of moderate or greater intensity. Step 3 advocates strong opioids for severe cancer pain and these are eective in the majority of patients when the principles of correct prescribing are followed.9,41 Since the 1980s the opioid of choice for oral use has been and continues to be morphine.9,42,43 There are multiple reasons why morphine remains the rst choice strong opioid for moderate-to-severe cancer pain: The majority of patients tolerate morphine well. There are fewer long-term safety data on the alternative strong opioids. It undergoes phase II metabolism and has few important drug interactions.36 It is usually eective, and dose titration to a suitable level of analgesia is usually achievable. It is eective when given orally. A wide variety of oral formulations are available, allowing exibility of dosing intervals. It is generally inexpensive. A systematic review concluded that oral morphine is eective for cancer pain,44 although the pool of well-designed

primary studies was small. Some authorities have challenged the primacy of morphine among the opioids,3 and there is no doubt it is far from being the ideal analgesic. Its oral bioavailability is highly variable, resulting in a broad spectrum of response and wide dosing requirements.45 It has pharmacologically active metabolites, notably morphine-6-glucuronide, which can accumulate particularly in the presence of renal dysfunction.46 Some types of pain (eg, neuropathic pain, muscle spasm) do not always respond well to morphine. For many patients, morphine is stigmatized.47 Many alternatives to morphine such as oxycodone, hydromorphone, and fentanyl have become more widely available in recent years and there has been resurgence in the use of methadone as an analgesic, raising new clinical questions and options. There is little evidence, however, to indicate the superiority of any one of these alternative opioids over morphine, or each other.48 The standard study design for comparing opioids has been that of the equivalence study using a crossover paradigm. Most studies have a lead-in phase and only patients with good pain control on stable doses of morphine go on to be randomized to switch to the alternative agent or remain on morphine.44 There are few head-to-head studies of morphine versus other agents in patients with uncontrolled pain.49 Consequently, the choice of strong opioid is currently not evidence based but on a complex mix of clinical considerations including severity of pain, response (ecacy and toxicity) to earlier opioids, the half-life and other pharmacokinetic parameters of the dierent agents, comorbidities, available formulations, physician preference, and cost/insurance restrictions. In future, pharmacogenomics may play a role in opioid choice.5052 A trial of an alternative opioid to morphine should denitely be considered for moderate-to-severe pain where dose titration is limited by the side eects. As opioids can be categorized by their analog class (phenanthrene, phenyl piperidine, diphenyl heptane), it may make sense to choose an opioid from a dierent class if adverse eects were a problem with earlier opioid exposure.53 Comorbidities, especially renal and hepatic impairment or hemodynamic compromise will aect opioid choice.54 Fentanyl and methadone are the safest in patients with marked renal dysfunction. Absorption is variable from the patches, especially in patients who are cachectic.55 Methadone has complex pharmacology, and physicians should be knowledgeable of this before prescribing it.37 There is increasing awareness of the clinical importance of drug interactions when using opioids, especially those metabolized by CYP450 such as oxycodone, fentanyl, and methadone.5658 The need for caution when coadministering opioids with other agents causing prolongation of the QT interval is also being increasingly recognized, especially for methadone.59 Formulation availability, physician preferences, and cost also inuence drug selection. There are a number of strong opioids, which are widely available but not recommended for the treatment of moderate-to-severe pain in patients with cancer. Meperidine is on the WHO Essential Drug List, but short acting and has poor oral bioavailability. With repeated dosing, there is accumulation of the neurotoxic metabolite normeperidine.60 Mixed agonist-antagonist drugs such as buprenorphine are not recommended ceiling dose that prevents continuing dose titration. Pentazocine and nalbuphine may also cause psychotomimetic side eects in some patients.
r

S8 | www.jpho-online.com

2011 Lippincott Williams & Wilkins

J Pediatr Hematol Oncol

Volume 33, Supplement 1, April 2011

Choice of Opioids and the WHO Ladder

Substance Abuse and Cancer Pain Relief

Fear of addiction and the risk of substance abuse have been enduring concerns of physicians over the centuries, and continue today. Experts in cancer pain management wishing to establish a cancer program must be knowledgeable about the basics of addiction medicine.61 They need to be clear on the dierences between tolerance, physical dependence, and addiction (Table 2), and be able to explain to others that tolerance and physical dependence are to be predictable and expected with repeated use of opioids, but are not precursors of addiction. Addiction is impaired control over drug use, which is compulsive and continues despite harm, and with craving.62 They must also know how to take a substance abuse history and how to develop a therapeutic strategy that addresses drug-taking behavior while implementing other therapies. Substance abuse and addiction are important to diagnose in cancer patients because compliance with treatments for the underlying disease may be so poor among cancer patients who are actively abusing drugs that the substance abuse actually shortens life expectancy by preventing the eective administration of primary therapy. Prognosis may also be altered by the use of drugs in a manner that negatively interacts with therapy or predisposes the patient to other serious morbidity.

TABLE 3. Aberrant Drug Taking Behaviors Less problematic and likely to be due to unrelieved pain or other distress Borrowing another patients drugs Obtaining prescription drugs from nonmedical sources Unsanctioned dosage escalations Aggressive complaining about need for higher doses Drug hoarding during periods of reduced symptoms Requesting specic drugs Acquisition of similar drugs from medical sources More problematic and suggestive of substance abuse or addiction Prescription forgery Stealing another patients drugs Recurrent prescription losses Injection of substances prescribed for oral use Concurrent use of related illegal drugs Selling prescription drugs

high risk for theft, they should be advised to buy a lockbox, keep limited supplies, and notify the police of any suspicious activities.

Cancer Patients Who Have a History of Substance Abuse

Nearly one-third of the population of the United States has used illicit drugs, and as many as one-quarter are estimated to have a substance abuse problem of some type.65 Therefore, many American patients with cancer will have a history of drug abuse or live among those who do drug abuse. These patients have special needs which are often underappreciated because this problem is overlooked.66 Patients who are actively abusing alcohol, illicit drugs, or prescription drugs present problems distinct from those experienced by patients in drug-free recovery or patients in methadone maintenance programs. Appropriate diagnosis of substance abuse may also be challenging because of the variability in abuse behaviors over time, the changes in comorbid physical and psychosocial factors that inuence drug abuse, and the problems inherent in the nomenclature of drug abuse in the physically ill.61 Management of these patients is complex as they present many clinical problems. Clinicians must control and monitor drug use in all patients with substance abuse histories. Strategies include prescribing limited amounts (eg, 1 week supply), rotation to methadone or tamper-proof formulations such as morphine/naltrexone,67 more frequent follow-up visits, urine toxicology screening. Strategies are also needed for managing patients who are addicted or diverting their pain medicines, including tapering of doses for discontinuation of prescribing, and referral to psychiatry or addiction medicine services.

Cancer Patients who do not Have Histories of Substance Abuse

Most patients do not have a history of substance abuse, and de novo development of substance abuse/addiction in cancer patients who do not have histories of substance abuse are exceptionally rare. Opioids and other controlled substances can be prescribed judiciously for symptom management without concern about misuse.61 In practice, many of these low-risk patients do not always adhere to the physicians directions for the correct use of their pain medicines. These nonadherent behaviors have been referred to as aberrant drug taking,63 and can range from borrowing anothers pain medicines to unauthorized escalation of the dose to forging prescriptions or selling the medicine on the street (Table 3). It is important for cancer pain experts to know that these conditions will be encountered, and to recognize which ones are likely to represent undertreatment of pain and other distress which should be addressed, and which ones are suggestive of abuse of the medications because of addiction or for nancial gain.64 All patients are at risk for diversion of opioids due to stealing by a third party ( family member, friend, or thief ). All patients need to be educated about safe storage of their medicine. If they are concerned they are at
TABLE 2. Definitions of Tolerance, Physical Dependence, and Addiction Tolerance: repeated administration of a drug leads to development of resistance to its pharmacological eects. The dose-response curve is shifted to the right and more drug is needed to produce the same pharmacological eects Physical dependence: when a patient develops physical dependence to a drug, they will experience a withdrawal syndrome. The term physical addiction should not be used as a synonym for physical dependence Addiction: this condition is now narrowly dened as an uncontrollable compulsion to continue taking a drug despite causing harm

CONCLUSIONS
The method of using of opioids of increasing potency for escalating cancer pain developed by the WHO in the 1980sknown commonly as the WHO Laddercontinues to be the cornerstone of contemporary cancer pain management. Even if the ladder provides an incomplete management approach for individualized cancer pain treatment, more comprehensive approaches continue to have opioids as fundamental components of their plan. Morphine is the preferred strong opioid for initiating treatment but there are several other medicines to choose from and physicians need to be familiar with their clinical www.jpho-online.com |

2011 Lippincott Williams & Wilkins

S9

Glare

J Pediatr Hematol Oncol

Volume 33, Supplement 1, April 2011

pharmacology and the factors to take into account when selecting an opioid. The ladder has also been a successful tool for overcoming institutional and societal barriers in many jurisdictions, but cultural, traditional, and religious obstacles continue to be barriers to access and need to be overcome. In the past 10 years, there has been a resurgence of concern about substance abuse with cancer pain medicines in the United States. Although these concerns may not be generalizable to other societies, physicians managing cancer pain in other countries should understand the issues, learn from how they are being dealt within the United States, and decide how to apply these lessons to their own community. REFERENCES
1. Foley KM. The treatment of cancer pain. N Engl J Med. 1985; 313:8495. 2. Bonica JJ. Cancer Pain. In: Bonica JJ. ed. The Management of Pain. Philadelphia: Lea and Feabiger; 1990:437. 3. Foley KM. Controversies in cancer pain: medical perspectives. Cancer. 1989;63:22572265. 4. Melzack R, Oesh JG, Mount BM. The Brompton mixture: eects on pain in cancer patients. Can Med Assoc J. 1976;115: 125129. 5. Melzack R, Mount BM, Gordon JM. The Brompton mixture versus morphine solution given orally: eects on pain. Can Med Assoc J. 1979;120:435438. 6. Black P. Management of cancer pain: an overview. Neurosurgery. 1979;5:507518. 7. Cancer Pain Relief and Palliative Care. Geneva: World Health Organization; 1990. Report No.: Technical Report Series 804. 8. Jacox AK, Carr DB, Payne R. Clinical Practice Guideline Number 9: Management of Cancer Pain. Dept of Health and Human Services AfHCPaR. Rockville. MD: 1994. 9. Hanks GW, Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer. 2001;84:587593. 10. Morphine in cancer pain: modes of administration. Expert Working Group of the European Association for Palliative Care. BMJ. 1996;312:823826. 11. Swarm R, Abernethy AP, Anghelescu DL, et al. Adult cancer pain. J Natl Compr Canc Netw. 2010;8:10461086. 12. Shamieh O, Jazieh A-R. Modication and implementation of NCCN guidelines on palliative care in the Middle East and North Africa region. JNCCN. 2010;8:s41-ss47. 13. Cancer Pain Relief. Geneva: World Health Organization; 1986. 14. Ventafridda V, Tamburini M, Caraceni A, et al. A validation study of the WHO method for cancer pain relief. Cancer. 1987;59:850856. 15. Walker VA, Hoskin PJ, Hanks GW, et al. Evaluation of WHO analgesic guidelines for cancer pain in a hospital-based palliative care unit. J Pain Symptom Manage. 1988;3:145149. 16. Goisis A, Gorini M, Ratti R, et al. Application of a WHO protocol on medical therapy for oncologic pain in an internal medicine hospital. Tumori. 1989;75:470472. 17. Ventafridda V, Caraceni A, Gamba A. Field-testing of the WHO guidelines for cancer pain relief. In: Foley KM, Bonica JJ, Ventafridda V, et al. eds. Second International Congress on Cancer Pain. New York: Raven Press; 1990:451464. 18. Takeda F. Japans WHO cancer pain relief program. In: Foley KM, Bonica JJ, Ventafridda V, et al. eds. Second International Congress on Cancer Pain. New York: Raven Press; 1990: 475483. 19. Wenk R, Diaz C, Echeverria M, et al. Argentinas WHO Cancer Pain Relief Program: a patient care model. J Pain Symptom Manage. 1991;6:4043. 20. Siguan SS, Damole AA, Mejarito AG. Results of cancer pain treatment at Southern Islands Medical Center, Cebu, Philippines. Philipp J Surg Spec. 1992;47:173176.

21. Zech DF, Grond S, Lynch J, et al. Validation of World Health Organization Guidelines for cancer pain relief: a 10-year prospective study. Pain. 1995;63:6576. 22. Jadad AR, Browman GP. The WHO analgesic ladder for cancer pain management: stepping up the quality of its evaluation. JAMA. 1995;274:18701873. 23. Ashby MA, Fleming BG, Brooksbank M, et al. Description of a mechanistic approach to pain management in advanced cancer: preliminary report. Pain. 1992;51:153161. 24. Du Pen SL, Du Pen AR, Polissar N, et al. Implementing guidelines for cancer pain management: results of a randomized controlled clinical trial. J Clin Oncol. 1999;17:361370. 25. Abernethy AP, Samsa GP, Matchar DB. A clinical decision and economic analysis model of cancer pain management. Am J Manag Care. 2003;9:651664. 26. Lickiss JN. Approaching cancer pain relief. Eur J Pain. 2001; 5(suppl A):514. 27. Deandrea S, Montanari M, Moja L, et al. Prevalence of undertreatment in cancer pain: a review of published literature. Ann Oncol. 2008;19:19851991. 28. Glare P, Aggarwal G, Clark K. Ongoing controversies in the pharmacological management of cancer pain. Intern Med J. 2004;34:4549. 29. Davis MP, Walsh D, Lagman R, et al. Controversies in pharmacotherapy of pain management. Lancet Oncol. 2005;6: 696704. 30. SAMHSA. Results From the 2001 National Household Survey on Drug Abuse: Volume I. Summary of National Findings. Studies SAaMHSAOoA. Rockville, Md: DHHS; 2002. 31. Clines FX, Meier B. Cancer Painkillers Pose New Abuse Threat. NY Times; 2001. 32. Eisenberg E, Berkey CS, Carr DB, et al. Ecacy and safety of nonsteroidal antiinammatory drugs for cancer pain: a metaanalysis. J Clin Oncol. 1994;12:27562765. 33. Organ-Specic Warnings; Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use; Final Monograph. In: HHS FaDA, ed.; 2009:25. 34. Moore A, Collins S, Carroll D, et al. Paracetamol with and without codeine in acute pain: a quantitative systematic review. Pain. 1997;70:193201. 35. De Conno F, Ripamonti C, Sbanotto A, et al. A clinical study on the use of codeine, oxycodone, dextropropoxyphene, buprenorphine, and pentazocine in cancer pain. J Pain Symptom Manage. 1991;6:423427. 36. Smith HS. Opioid metabolism. Mayo Clin Proc. 2009;84: 613624. 37. Trescot AM. Review of the role of opioids in cancer pain. J Natl Compr Canc Netw. 2010;8:10871094. 38. Cicero TJ, Surratt H, Inciardi JA, et al. Relationship between therapeutic use and abuse of opioid analgesics in rural, suburban, and urban locations in the United States. Pharmacoepidemiol Drug Saf. 2007;16:827840. 39. Xanodyne agrees to withdraw propoxyphene from the U.S. market. In: FDA NEWS RELEASE; 2010. 40. Marinangeli F, Ciccozzi A, Leonardis M, et al. Use of strong opioids in advanced cancer pain: a randomized trial. J Pain Symptom Manage. 2004;27:409416. 41. Krakowski I, Theobald S, Balp L, et al. Summary version of the Standards, Options and Recommendations for the use of analgesia for the treatment of nociceptive pain in adults with cancer (update 2002). Br J Cancer. 2003;89(suppl 1):S6772. 42. Hardy JR, Nauck F. Opioids for cancer pain. In: Walsh D. ed. Palliative Medicine. Philadelphia: Elsevier; 2008:140411. 43. Davis MP. Cancer pain. In: Olver IN. ed. The MASCC textbook of cancer supportive care and survivorship. New York: Springer; 2010:1122. 44. Wien PJ, McQuay HJ. Oral morphine for cancer pain. Cochrane Database Syst Rev. 2007;CD003868. 45. Andersen G, Christrup L, Sjogren P. Relationships among morphine metabolism, pain and side eects during long-term treatment: an update. J Pain Symptom Manage. 2003;25:7491.
r

S10 | www.jpho-online.com

2011 Lippincott Williams & Wilkins

J Pediatr Hematol Oncol

Volume 33, Supplement 1, April 2011

Choice of Opioids and the WHO Ladder

46. McQuay H. Opioids in pain management. Lancet. 1999;353: 22292232. 47. Reid CM, Gooberman-Hill R, Hanks GW. Opioid analgesics for cancer pain: symptom control for the living or comfort for the dying? A qualitative study to investigate the factors inuencing the decision to accept morphine for pain caused by cancer. Ann Oncol. 2008;19:4448. 48. Bell RF, Wislo T, Eccleston C, et al. Controlled clinical trials in cancer pain: How controlled should they be? A qualitative systematic review. Br J Cancer. 2006;94:15591567. 49. Bruera E, Palmer JL, Bosnjak S, et al. Methadone versus morphine as a rst-line strong opioid for cancer pain: a randomized, double-blind study. J Clin Oncol. 2004;22: 185192. 50. Ross JR, Rutter D, Welsh K, et al. Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics J. 2005;5:324336. 51. Reyes-Gibby CC, Shete S, Rakvag T, et al. Exploring joint eects of genes and the clinical ecacy of morphine for cancer pain: OPRM1 and COMT gene. Pain. 2007;130:2530. 52. Mercadante S. Opioid titration in cancer pain: a critical review. Eur J Pain. 2007;11:823830. 53. Amabile CM, Bowman BJ. Overview of oral modied-release opioid products for the management of chronic pain. Ann Pharmacother. 2006;40:13271335. 54. Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage. 2004;28:497504. 55. Heiskanen T, Matzke S, Haakana S, et al. Transdermal fentanyl in cachectic cancer patients. Pain. 2009;144:218222. 56. Mercadante S, Villari P, Ferrera P. Itraconazole-fentanyl interaction in a cancer patient. J Pain Symptom Manage. 2002; 24:284286. 57. Horton R, Barber C. Opioid-induced respiratory depression resulting from transdermal fentanyl-clarithromycin drug

58.

59. 60.

61. 62.

63.

64. 65. 66. 67.

interaction in a patient with advanced COPD. J Pain Symptom Manage. 2009;37:e2e5. Essandoh S, Sakae M, Miller J, et al. A cautionary tale from critical care: resolution of myoclonus after fentanyl rotation to hydromorphone. J Pain Symptom Manage. 2010;40:e4e6. Krantz MJ, Martin J, Stimmel B, et al. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150:387395. Szeto HH, Inturrisi CE, Houde R, et al. Accumulation of normeperidine, an active metabolite of meperidine, in patients with renal failure of cancer. Ann Intern Med. 1977;86:738741. Substance Abuse Issues In Cancer (PDQ) In: National Cancer Institute; 2008. Fainsinger RL, Thai V, Frank G, et al. Whats in a word? Addiction versus dependence in DSM-V. Am J Psychiatry. 2006;163:2014. Passik SD, Messina J, Golsorkhi A, et al. Aberrant DrugRelated Behavior Observed During Clinical Studies Involving Patients Taking Chronic Opioid Therapy for Persistent Pain and Fentanyl Buccal Tablet for Breakthrough Pain. J Pain Symptom Manage. 2010. [Epub ahead of print]. Fisher FB. Interpretation of Aberrant Drug-Related Behaviors. J Am Phys Surg. 2004;9:2528. Gfroerer J, Brodsky M. The incidence of illicit drug use in the United States, 1962-1989. Br J Addict. 1992;87:13451351. Weissman DE, Haddox JD. Opioid pseudoaddictionan iatrogenic syndrome. Pain. 1989;36:363366. Stauer J, Setnik B, Sokolowska M, et al. Subjective eects and safety of whole and tampered morphine sulfate and naltrexone hydrochloride (ALO-01) extended-release capsules versus morphine solution and placebo in experienced nondependent opioid users: a randomized, double-blind, placebocontrolled, crossover study. Clin Drug Investig. 2009;29: 777790.

2011 Lippincott Williams & Wilkins

www.jpho-online.com |

S11