Moderate-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 first that Brompton cocktail was superior to these traditional methods of pain relief,4 and then that single-agent morphine was just as effective 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.7–11
Uptake of the pharmacological approach to cancer pain management in developing countries has been much 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 suffering needlessly, and this could easily be remedied if only strong opioids were made available. For many of these patients, there was—and still is—no prospect of cure and the only realistic human approach to their illness was to offer 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 effectiveness in more than 70% patients across in a variety of clinical settings and countries were published.14–21 A systematic review criticized the evidence these studies provide for the efficacy 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 deficiencies precluded performing a meta-analysis to enable an estimation of the efficacy 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 effect of treatment, because of debilitation status posttreatment or totally unrelated to the cancer or its treatment. Many of these other nondisease-related pains have specific 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 effective 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 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 effective 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 significant reduction in pain intensity when compared with standard community practice. Concurrent chemotherapy and patient adherence to treatment were significant mediators of worst pain. There were no significant differences 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-effectiveness analysis compared 3 approaches to cancer pain: guideline-based 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 effective 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-inflammatory drug (NSAID), and possibly further antitumor therapy. The Stickman approach emphasizes communication with patient—the 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 effectiveness 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 abuse of cocaine.30 Recent high-profile 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 efficacy 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 effect 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 effective 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 effect (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 affected 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 effective for the first-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 effective 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 first 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 effective, and dose titration to a suitable level of analgesia is usually achievable.
It is effective when given orally.
A wide variety of oral formulations are available, allowing flexibility of dosing intervals.
It is generally inexpensive.
A systematic review concluded that oral morphine is effective 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 (efficacy and toxicity) to earlier opioids, the half-life and other pharmacokinetic parameters of the different agents, comorbidities, available formulations, physician preference, and cost/insurance restrictions. In future, pharmacogenomics may play a role in opioid choice.50–52
A trial of an alternative opioid to morphine should definitely be considered for moderate-to-severe pain where dose titration is limited by the side effects. As opioids can be categorized by their analog class (phenanthrene, phenyl piperidine, diphenyl heptane), it may make sense to choose an opioid from a different class if adverse effects were a problem with earlier opioid exposure.53 Comorbidities, especially renal and hepatic impairment or hemodynamic compromise will affect 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.56–58 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 influence 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 effects in some patients.
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 differences 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 effective 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.
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 physician's 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 another's 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 financial 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 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 influence 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.
The method of using of opioids of increasing potency for escalating cancer pain developed by the WHO in the 1980s—known commonly as the WHO Ladder—continues 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 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.
1. Foley KM. The treatment of cancer pain N Engl J Med.. 1985;313:84–95
2. Bonica JJBonica JJ. Cancer Pain The Management of Pain.. 1990 Philadelphia Lea and Feabiger:437
3. Foley KM. Controversies in cancer pain:: medical perspectives Cancer.. 1989;63:2257–2265
4. Melzack R, Ofiesh JG, Mount BM. The Brompton mixture: effects on pain in cancer patients Can Med Assoc J.. 1976;115:125–129
5. Melzack R, Mount BM, Gordon JM. The Brompton mixture versus morphine solution given orally: effects on pain Can Med Assoc J. 1979;120:435–438
6. Black P. Management of cancer pain: an overview Neurosurgery.. 1979;5:507–518
7. Cancer Pain Relief and Palliative Care. 1990 Geneva World Health Organization . 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.. 1994 Rockville. MD
9. Hanks GW, Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations Br J Cancer.. 2001;84:587–593
10. . Morphine in cancer pain: modes of administration. Expert Working Group of the European Association for Palliative Care. BMJ.. 1996;312:823–826
11. Swarm R, Abernethy AP, Anghelescu DL, et al. Adult cancer pain J Natl Compr Canc Netw.. 2010;8:1046–1086
12. Shamieh O, Jazieh A-R. Modification and implementation of NCCN guidelines on palliative care in the Middle East and North Africa region. JNCCN
13. Cancer Pain Relief. 1986 Geneva World Health Organization
14. Ventafridda V, Tamburini M, Caraceni A, et al. A validation study of the WHO method for cancer pain relief Cancer.. 1987;59:850–856
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;3:145–149
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;75:470–472
17. Ventafridda V, Caraceni A, Gamba A, et al.Foley KM, Bonica JJ, Ventafridda V Field-testing of the WHO guidelines for cancer pain relief eds. Second International Congress on Cancer Pain.. 1990 New York Raven Press:451–464
18. Takeda F, et al.Foley KM, Bonica JJ, Ventafridda V Japan's WHO cancer pain relief program Second International Congress on Cancer Pain.. 1990 New York Raven Press:475–483
19. Wenk R, Diaz C, Echeverria M, et al. Argentina's WHO Cancer Pain Relief Program: a patient care model J Pain Symptom Manage. 1991;6:40–43
20. Siguan SS, Damole AA, Mejarito AG. Results of cancer pain treatment at Southern Islands Medical Center, Cebu, Philippines Philipp J Surg Spec.. 1992;47:173–176
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;63:65–76
22. Jadad AR, Browman GP. The WHO analgesic ladder for cancer pain management:: stepping up the quality of its evaluation JAMA.. 1995;274:1870–1873
23. Ashby MA, Fleming BG, Brooksbank M, et al. Description of a mechanistic approach to pain management in advanced cancer:: preliminary report Pain.. 1992;51:153–161
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;17:361–370
25. Abernethy AP, Samsa GP, Matchar DB. A clinical decision and economic analysis model of cancer pain management Am J Manag Care.. 2003;9:651–664
26. Lickiss JN. Approaching cancer pain relief Eur J Pain.. 2001;5(suppl A):5–14
27. Deandrea S, Montanari M, Moja L, et al. Prevalence of undertreatment in cancer pain:: a review of published literature Ann Oncol.. 2008;19:1985–1991
28. Glare P, Aggarwal G, Clark K. Ongoing controversies in the pharmacological management of cancer pain Intern Med J.. 2004;34:45–49
29. Davis MP, Walsh D, Lagman R, et al. Controversies in pharmacotherapy of pain management Lancet Oncol. 2005;6:696–704
30. SAMHSA. . Results From the 2001 National Household Survey on Drug Abuse: Volume I. Summary of National Findings. Studies SAaMHSAOoA.. 2002 Rockville, Md DHHS
31. Clines FX, Meier B. Cancer Painkillers Pose New Abuse Threat NY Times ; 2001.
32. Eisenberg E, Berkey CS, Carr DB, et al. Efficacy and safety of nonsteroidal antiinflammatory drugs for cancer pain: a meta-analysis J Clin Oncol.. 1994;12:2756–2765
33. Organ-Specific 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;70:193–201
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;6:423–427
36. Smith HS. Opioid metabolism Mayo Clin Proc.. 2009;84:613–624
37. Trescot AM. Review of the role of opioids in cancer pain J Natl Compr Canc Netw. 2010;8:1087–1094
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;16:827–840
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;27:409–416
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):S67–72
42. Hardy JR, Nauck FWalsh D. Opioids for cancer pain Palliative Medicine.. 2008 Philadelphia Elsevier :1404–11.
43. Davis MPOlver IN. Cancer pain The MASCC textbook of cancer supportive care and survivorship.. 2010 New York Springer:11–22
44. Wiffen 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 effects during long-term treatment: an update J Pain Symptom Manage.. 2003;25:74–91
46. McQuay H. Opioids in pain management Lancet.. 1999;353:2229–2232
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 influencing the decision to accept morphine for pain caused by cancer Ann Oncol.. 2008;19:44–48
48. Bell RF, Wisloff T, Eccleston C, et al. Controlled clinical trials in cancer pain:: How controlled should they be? A qualitative systematic review Br J Cancer.. 2006;94:1559–1567
49. Bruera E, Palmer JL, Bosnjak S, et al. Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study J Clin Oncol.. 2004;22:185–192
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;5:324–336
51. Reyes-Gibby CC, Shete S, Rakvag T, et al. Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene Pain.. 2007;130:25–30
52. Mercadante S. Opioid titration in cancer pain: a critical review Eur J Pain.. 2007;11:823–830
53. Amabile CM, Bowman BJ. Overview of oral modified-release opioid products for the management of chronic pain Ann Pharmacother. 2006;40:1327–1335
54. Dean M. Opioids in renal failure and dialysis patients J Pain Symptom Manage. 2004;28:497–504
55. Heiskanen T, Matzke S, Haakana S, et al. Transdermal fentanyl in cachectic cancer patients Pain.. 2009;144:218–222
56. Mercadante S, Villari P, Ferrera P. Itraconazole-fentanyl interaction in a cancer patient J Pain Symptom Manage. 2002;24:284–286
57. Horton R, Barber C. Opioid-induced respiratory depression resulting from transdermal fentanyl-clarithromycin drug interaction in a patient with advanced COPD J Pain Symptom Manage. 2009;37:e2–e5
58. 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:e4–e6
59. Krantz MJ, Martin J, Stimmel B, et al. QTc interval screening in methadone treatment Ann Intern Med.. 2009;150:387–395
60. 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;86:738–741
61. Substance Abuse Issues In Cancer (PDQ) In: National Cancer Institute; 2008.
62. Fainsinger RL, Thai V, Frank G, et al. What's in a word? Addiction versus dependence in DSM-V Am J Psychiatry. 2006;163:2014
63. Passik SD, Messina J, Golsorkhi A, et al. Aberrant Drug-Related 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].
64. Fisher FB. Interpretation of “Aberrant” Drug-Related Behaviors. J Am Phys Surg. 2004;9:25–28
65. Gfroerer J, Brodsky M. The incidence of illicit drug use in the United States, 1962-1989 Br J Addict.. 1992;87:1345–1351
66. Weissman DE, Haddox JD. Opioid pseudoaddiction—an iatrogenic syndrome Pain.. 1989;36:363–366
67. Stauffer J, Setnik B, Sokolowska M, et al. Subjective effects and safety of whole and tampered morphine sulfate and naltrexone hydrochloride (ALO-01) extended-release capsules versus morphine solution and placebo in experienced non-dependent opioid users: a randomized, double-blind, placebo-controlled, crossover study Clin Drug Investig.. 2009;29:777–790