Opioid Rotation in Cancer Patients: Pros and Cons

Opioid rotation involves changing from one opioid to another using correct equianalgesic conversion techniques to achieve better analgesia and/or fewer side effects. The strategy appears to work because of significant interindividual variations in response to both analgesic activity and toxicity. Although there are many retrospective studies, few prospective controlled trials of opioid rotation have been published. The practical and theoretical advantages of opioid rotation include improved analgesia, reduced side effects, cost reduction, and improved compliance. Disadvantages include problems related to inaccurate conversion tables, limited availability of certain opioid formulations, drug interactions, and the possibility of increased expense. Weighing the advantages and disadvantages is essential prior to making a decision about opioid rotation selection.

More than 80% of people with advanced cancer experience pain as a major symptom,[1] and 60% of this group have moderate to severe pain. The World Health Organization (WHO) recommends opioids for treatment of moderate to severe pain.[2] Morphine has been the preferred drug historically, given the available studies, relative cost, and diverse routes of administration. Unfortunately morphine is not always successful in managing pain mainly from side effects or pain that is relatively resistant to opioid pharmacotherapy. In these circumstances opioid rotation is one solution. Another important strategy prior to rotation is to manage the side effects by (1) readjusting opioid dosing, (2) adding adjuvant analgesics and thus sparing opioids, or (3) giving specific treatment for the side effects.[3] Opioid rotation involves changing from one opioid to another using correct equianalgesic conversion techniques to achieve better analgesia and/ or fewer side effects.[4] It is also known as opioid changing, substitution, or switching.[3] Opioid rotation appears to work because of significant interindividual variations in response to both analgesic activity and toxicity.[5] These variable responses may, in part, be explained by the presence of different opioid receptor subtypes.[6] Although there are multiple retrospective studies, few prospective controlled trials on opioid rotation have been published. Both Pereira et al[7] and Anderson et al[4] reviewed these studies. The incidence of opioid rotation in these reports has ranged from 10% to 40%.[1,8] Despite the paucity of controlled trials, rotation is a commonly practiced intervention for managing opioid toxicity or resistant pain. A study in 273 cancer patients documented the reasons for rotation to be (1) insufficient analgesia in 43%, (2) side effects in 20%, (3) both of these conditions in 15%, and (4) patient choice in 18%.[9] In this article, we will discuss the practical and/or theoretical advantages (Table 1) and disadvantages (Table 2) associated with opioid rotation.

AdvantagesImproved Analgesia
All currently available opioids target the mu receptors in the peripheral and central nervous system. Methadone has affinity at multiple receptors (including N-methyl-D-aspartate, or NMDA) that may also play a role in analgesia.[10] Other opioid receptors (eg, kappa receptors) may be important in the future of analgesia. Animal studies in rats, for instance, suggest that oxycodone has a higher affinity for kappa receptors than morphine, and that this plays a role in analgesia.[ 11] This has not been confirmed in humans. Each opioid has a different binding- affinity profile and intrinsic efficacy for receptors and their subcategories. Intrinsic efficacy is a mathematic relationship between receptor occupancy and tissue response, and reflects opioid ability to activate a receptor. Opioid rotation may exploit these differences in receptor profile and intrinsic efficacy. Coupled with the individual variation in receptor profiles (suggested by pharmacogenomic studies), this may explain partial analgesic cross-tolerance, different side-effect profiles, and favorable clinical response following rotation. Reduced Side Effects
While all opioids have common side effects, the severity of toxicity and tolerance to side effects vary among individuals. Rapid tolerance to most common side effects such as nausea, respiratory depression, and initial sedation usually develops. Unfortunately, some individuals develop unacceptable toxicity that fails to resolve or becomes dose-limiting with subsequent titration.[5] In treating chronic cancer pain, opioid dose escalation is expected with disease progression. Although there is no ceiling dose for opioids, side effects may occur before pain relief, limiting further dose titration. Individual differences in side effects experienced with different opioids have been in part explained by a narrowed therapeutic index in organ failure (especially in the elderly).[12] Genetic polymorphism in opioid receptors may also explain variations in side-effect development. In a recent case report, a genetic analysis was done in two patients with renal failure receiving similar amounts of morphine. Pain control was adequate in both, but the second subject developed severe neurotoxicity. The former was a homozygous carrier of a mu receptor gene polymorphism that the authors hypothesized provided protection from morphine-6-glucuronide (M6G) toxicity.[13] In addition to patient variables, small studies have suggested that certain opioids may have varying potential for specific toxicities. In a study of 45 patients randomized to either morphine or oxycodone, more vomiting was noticed with the former agent but more constipation with the latter.[ 14] Methadone and fentanyl have been reported to cause less constipation.[ 15,16] Fentanyl does not cause histamine release and therefore may cause less pruritus.[17] Practical Concerns
Dosing or route convenience of different opioids can become an appropriate reason for rotation. A large number of tablets needed per dose can be problematic. In this situation, rotation to a more potent opioid or parenteral administration may be warranted. Similarly, rotation can be used when large numbers of fentanyl patches (Duragesic) are inconvenient. Cost Reduction
Expense can be a major barrier to pain control. Individuals with chronic pain but no health insurance or limited drug benefits may be faced with significant expenses. Even those with medication coverage but numerous prescriptions may find the total cost amount unmanageable. As a result, inadequate pain control follows failure to acquire prescribed analgesics. More expensive opioid products, such as sustained-release oxycodone and transdermal fentanyl currently dominate the market.[18,19] It is not unusual for these to be started as the first-line analgesic before trying less expensive, probably equally effective and welltolerated alternatives. Since hospice care has a capitated reimbursement structure with limited dollars to manage the needs of the dying (in whom pain is common), cost-effective prescribing habits are most important. Patients may be embarrassed to acknowledge their economic limitations. Physicians should not only know the relative costs of different opioids, but also ask their patients about any financial constraints, particularly when pain remains uncontrolled. Pharmaceutical company indigent programs are useful alternatives that would not require a change in medication. When cost is prohibitive, methadone becomes the most cost-effective alternative. This is an appropriate indication for rotating to methadone. Better Compliance
A key to successful pain control is patient compliance with the prescribed opioid regimen. A detailed exploration of how medications are taken by patients is fundamental in all cases of poor pain control and should be done prior to abandoning the current opioid. In a survey of 93 health-care professionals, 71% indicated that poor compliance was a problem in at least 15% of patients with cancer pain.[20] Frequent dosing schedules, side effects, cognitive impairment, fear of addiction, cost, and other factors can have a negative impact on good pain control.[21] At the time of this writing, there is no sustained-release preparation of hydromorphone available in the United States, and the drug must be given every 4 hours around-the-clock, whereas transdermal fentanyl can be applied every 3 days to achieve similar control of chronic pain. Methadone is both a short- and long-acting analgesic, with the advantage that it can be taken as needed if the patient does not like to take scheduled medications. Organ Failure
Opioid clearance and metabolism change with organ failure. Morphine and its metabolites are excreted through the kidneys and accumulate in kidney failure, but morphine is one of the safer opioids in patients with moderate liver failure.[22] In severe liver failure, clearance will be decreased and oral availablilty increased, requiring dose adjustments.[23] The half-life of oxycodone increases with kidney and liver failure. Hydromorphone is reportedly safe in modest kidney failure, but increased side effects occur with severe failure.[24] On the other hand, methadone can be used safely in kidney failure due to its low renal excretion; methadone can also be used in mild to moderate liver failure.[25] Rotation in the presence of organ failure gives physicians more flexibility in titrating opioids with less fear of increased side effects. In our practice, we frequently favor using methadone or fentanyl in renal failure. However, in cases of severe end organ failure or dysfunction, caution should be entertained with any opioid use. DisadvantagesInaccurate Conversion Tables
Opioid rotation is accomplished through calculated equianalgesic doses, usually coupled with reducing calculated doses to account for incomplete cross-tolerance, especially when used to reduce side effects. Conversion tables are available both commercially and in the literature. The variation in published conversion ratios is problematic when trying to rotate (especially for oxycodone, fentanyl, and methadone).[4,7] Small variations in conversion ratios can lead to large differences in calculated equianalgesic doses, especially at higher doses. For example, reported morphine- to-oxycodone conversion ratios have ranged from 1:1 to 2:1. The calculated dose for a person on 400 mg of morphine daily would be 400 or 200 mg of daily oxycodone, respectively. Furthermore, conversion may need to be calculated using daily morphine equivalents when direct ratios do not exist, creating a potential for inaccuracy. For instance, there are no data that directly address the conversion ratio from fentanyl or oxycodone to hydromorphone. Most conversion ratios are based on studies in which opioid-naive individuals were given single low-dose opioids, without attention to side effects, organ failure, polypharmacy, complications, or the reason for rotation. These studies also failed to take into account the interindividual variations that play a prominent role in determining the real ratio for each individual.[4,7] Therefore, the reliability of such tables is questionable and can poses a risk for significant overor underdosing.

Codeine by itself is inactive and requires metabolism to the active form morphine via CYP2D6; genetic variations involving this enzyme can render codeine ineffective. Rotation from codeine-if its dose was increased with poor pain control-using equianalgesic conversion tables can thus lead to overdosing in poor metabolizers. Opioid rotation without reducing the calculated dose to account for incomplete analgesic cross-tolerance may cause increased side effects such as hallucinations, respiratory depression, or sedation. On the other hand, recommendations that call for decreasing the calculated dose by 50% or more may lead to underdosing when poor pain control is the reason for rotation. Dose adjustment is also warranted in kidney and liver failure, as well as with concomitant use of other medications that may interfere with opioid pharmacodynamics. Such factors are not accounted for in available equianalgesic conversion tables. These problems can be avoided by better knowledge of conversion techniques[ 26] and careful clinical observation. One example of the difficulty with conversion tables is illustrated by the use of methadone. Conversion to methadone is listed in many tables at a fixed ratio, although a footnote may comment on the dose-dependent nature of the ratio.[27] Inexperienced practioners might use the ratio without fully understanding the inherent problems. Limited Access
Certain opioid formulations, such as sustained-release hydromorphone and intravenous oxycodone, are currently unavailable in the United States. If a patient on oxycodone requires parenteral medication, rotation will be necessary. Similarly, the absence of sustained-release hydromorphone limits utility particularly with large doses. The limited number of available opioids in some countries also impacts the utility of rotation and the choice of opioids. Drug Interactions
Drug interactions are not necessarily contraindications to using or rotating opioids but require attention to avoid inappropriate dosing. Morphine and hydromorphone are metabolized via glucuronidation. Methadone is metabolized via CYP3A4, CYP2D6, and CYP1A2. Oxycodone is also metabolized through CYP2D6. Although drugs that interfere with CYP2D6 function do not affect oxycodone analgesia, they may influence clearance. Concomitant use of medications that compete for, induce, or suppress these enzymes can potentially affect analgesia and/or side effects, thereby affecting equianalgesia. Methadone has the greatest potential for drug interactions. For instance, concomitant use of methadone and rifampin, a CYP3A4 promoter, can cause acute exacerbation of pain or withdrawal.[28] Fluconazole, a CYP3A4 inhibitor, may induce methadone toxicity if both agents are used together. Choosing opioids for rotation should take into consideration current medications to avoid or anticipate possible drug interactions. Expense
Cost has been discussed in more detail in the advantages section, but we mention it here because it can play either role. Rotating to more expensive opioids may be necessary to achieve good pain control, but this may pose a financial burden. It is important to explore less expensive opioids first. For the uninsured, as mentioned, pharmaceutical company programs should be pursued. Pharmacy Availability
Some pharmacies have limited their stocking of opioids especially in the inner city.[29] This can affect pain control when a prescribed opioid is hard to find locally, or when a pharmacy won't dispense sufficient pills. It is therefore important to contact the pharmacy to confirm the availability of the prescribed opioid so patients will not be left without pain medications (although some pharmacies may not disclose such information, fearing robbery). This is especially important if a patient lives out of town or if changes are made just prior to a weekend, when prescribing physicians may be unavailable and covering colleagues may feel uncomfortable addressing issues related to opioids for a patient they do not know. Methadone Rotation
Methadone is a synthetic opioid with unique pharmacokinetic and pharmacodynamic characteristics. As mentioned, it targets different molecules, including mu and NMDA receptors. Methadone is a very potent opioid and is considered a good second-line analgesic; it is also the least expensive such agent.[30] The literature presents complex methods of conversion to methadone, but data on reverse conversion are lacking. In a recent report, 12 out of 13 patients with uncontrolled pain on methadone failed rotation to another opioid and had to be switched back.[31] More studies are needed to determine correct and safe conversion ratios from methadone to other opioids. Regulation
In rare cases, when frequent opioid rotations are needed to achieve good pain control, there is a potential risk of attracting dispensing pharmacists' attention, especially in the case of opioids that have become popular drugs of abuse. They may suspect irregular prescribing behavior by the physician, possibly subjecting them to being investigated by regulatory authorities. Discussion Chronic pain is a major health issue in cancer patients. Opioid rotation is commonly practiced in managing chronic pain and can be, if used correctly, a useful tool in achieving the best analgesia with the fewest side effects. Weighing the advantages and disadvantages is essential prior to making a decision about opioid rotation selection. The potential for inappropriate opioid rotation is real and needs to be addressed. Improving physician education about opioids and opioid rotation can help avoid errors (Table 3). Understanding the pitfalls of currently available conversion tables is important for effective and safe rotation. Anticipating and managing side effects, appropriate use of opioid-sparing agents, and careful dose titration (both up and down) are techniques that can be implemented to avoid abandoning a potentially effective/tolerated medication prematurely. Physicians inexperienced with the use of methadone should first undertake a careful study of the pharmacokinetics, recommended conversion methods, and drug interactions before using this medication. When in doubt, physicians should not hesitate to seek expert opinion about opioid usage and rotation. Local resources should be identified for consultation when needed.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Foley K: Pain assessment and cancer pain syndromes, in Doyle D, Hanks G, McDonald N (eds): Oxford Textbook of Palliative Medicine, pp 310-331. Oxford, Oxford University Press, 1998.
2. World Health Organization: Cancer Pain Relief, Geneva, WHO, 1996.
3. Cherny N, Ripamonti C, Pereira J, et al, for the Expert Working Group of the European Association of Palliative Care Network: Strategies to manage the adverse effects of oral morphine: An evidence-based report. J Clin Oncol 19:2542-2554, 2001.
4. Anderson R, Saiers J, Abram S, et al: Accuracy in equianalgesic dosing: Conversion dilemmas. J Pain Symptom Manage 21:397-406, 2001.
5. Mercadante S: Opioid rotation for cancer pain. Cancer 86:1856-1866, 1999.
6. Pasternak GW: The pharmacology of mu analgesics: From patients to genes. Neuroscientist 7:220-231, 2001.
7. Pereira J, Lawlor P, Vigano A, et al: Equianalgesic dose ratios for opioids. A critical review and proposals for long-term dosing. J Pain Symptom Manage 22:672-687, 2001.
8. de Stoutz ND, Bruera E, Suarez-Almazor M: Opioid rotation for toxicity reduction in terminal cancer patients. J Pain Symptom Manage 10:378-384, 1995.
9. Kloke M, Rapp M, Bosse B, et al: Toxicity and/or insufficient analgesia by opioid therapy: Risk factors and the impact of changing the opioid. A retrospective analysis of 273 patients observed at a single center. Support Care Cancer 8:479-486, 2000.
10. Mao J: NMDA and opioid receptors: Their interactions in antinociception, tolerance and neuroplasticity. Brain Res Rev 30:289-304, 1999.
11. Ross FB, Smith MT: The intrinsic antinociceptive effects of oxycodone appear to be kappa-opioid receptor mediated. Pain 73:151- 157, 1997.
12. American Geriatrics Society: The management of chronic pain in older persons: AGS panel on chronic pain in older persons. J Am Geriatr Soc 46:635-651, 1998.
13. Lotsch J, Zimmermann M, Darimont J, et al: Does the A118G polymorphism at the muopioid receptor gene protect against morphine- 6-glucuronide toxicity? Anesthesiology 97:814- 819, 2002.
14. Heiskanen T. Kalso E: Controlled-release oxycodone and morphine in cancer related pain. Pain 73:37-45, 1997.
15. Daeninck P, Bruera E: Reduction in constipation and laxative requirements following opioid rotation to methadone: A report of four cases. J Pain Symptom Manage 18:303-309, 1999.
16. Ahmedzai M, 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.
17. Hermens JM, Ebertz JM, Hanifin JM, et al: Comparison of histamine release in human skim mast cells induced by morphine, fentanyl, and oxymorphone. Anesthesiology 62:124-129, 1985.
18. Varga J, Dickerson ED, Davis MP: United states prescribing habits: What’s going on (abstract)? Support Care Cancer 9:311, 2001.
19. Davis MP, Varga J, Dickerson D, et al: Normal-release and controlled-release oxycodone: Pharmacokinetics, pharmacodynamics, and controversy. Support Care Cancer 11:84- 92, 2003
20. Abbas SQ, Abbas Z: Is opiate compliance a problem in cancer pain? A survey of healthcare professionals’ views. Int J Palliate Nurs 9:56-63, 2003.
21. Davis M, Srivastava M: Demographics, assessment and management of pain in the elderly. Drugs Aging 20:23-57, 2003.
22. Donnelly S, Davis MP, Walsh D, et al, for the World Health Organization: Morphine in cancer pain management: a practical guide. Support Care Cancer 10:13-35, 2002.
23. Tegeder I, Lotsch J, Geisslinger G: Phar macokinetics of opioids in liver disease. Clin Pharmacokinet 37:17-40, 1999.
24. Babul N, Darke AC, Hagen N: Hydromorphone metabolite accumulation in renal failure. J Pain Symptom Manage 10:184- 186, 1995.
25. Kreek MJ, Schecter AJ, Gutjahr CL, et al: Methadone use in patients with chronic renal disease. Drug Alcohol Depend 5:197-205, 1980.
26. Kochhar R, LeGrand SB, Walsh D, et al: Opioids in cancer pain: Common dosing errors. Oncology 17:571-575, 2003.
27. Panchal SJ, Grossman SA, Benedetti C, et al: Cancer pain, in National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology, version 1.2004. Available at www.nccn.org/professionals/physician_gls/ PDF/pain.pdf. Accessed February 28, 2005.
28. Niemi M, Backman JT, Fromm MF, et al: Pharmacokinetic interactions with rifampicin: Clinical relevance. Clin Pharmacokinet 42:819-850, 2003.
29. Morrison RS, Wallenstein S, Natale DK, et al: “We don’t carry that”-failure of pharmacies in predominantly nonwhite neighborhoods to stock opioid analgesics. N Engl J Med 342:1023-1026, 2000.
30. Davis MD, Walsh D: Methadone for relief of cancer pain: A review of pharmacokinetics, pharmacodynamics, drug interactions and protocol for administration. Support Care Cancer 9:73-83, 2001.
31. Moryl N, Santiago-Palma J, Kornick C, et al: Pitfalls of opioid rotation: substituting another opioid for methadone in patients with cancer pain. Pain 96:325-328, 2002.