Opioids in Cancer Pain: A Few Clarifying Thoughts

While I congratulate the authors on a very thoughtful and relevant review, I am going to respectfully challenge some of the nuances in this otherwise excellent paper.

Opioid Responsiveness and Selection

The issue of interindividual variability of opioid responsiveness is one of the most fascinating aspects of opioid pharmacology. There are few other pharmacologic agents with a 1,000-fold variability in effective clinical doses. While the pharmacogenomic studies described are interesting, it remains premature to draw definitive conclusions. Hopefully the biobank being developed by Prof. Kassa and his international colleagues from the European Palliative Care Research Collaborative will help add clarity to this picture.

The discussion on opioid selection is well presented. Despite the concerns raised by the authors, I think it is important to indicate that the development of liver failure in a patient who has been previously stable on an opioid does not necessitate changing the opioid or its dose unless the patient develops new dose-limiting adverse effects. There are important differences between liver failure caused by tumor infiltration and that caused by global hepatocellular disease. In the setting of metastases, there are usually well preserved areas of healthy hepatocytes that continue to function well until a very advanced stage of liver infiltration. Indeed, it is not uncommon to observe good preservation of synthetic and metabolic liver function in patients with relatively advanced liver metastases; this function is maintained by the residual healthy parenchyma.

Regarding the use of fentanyl, I would challenge some of the assertions made. While I deplore decisions made on the basis of a seductive technology, there is a rationale for many patients to consider fentanyl as a viable and appropriate first-line option. This is particularly true for patients with an already heavy burden of oral medications and those for whom there may be problems of compliance. In many countries, a generic form of transdermal fentanyl is now available and the cost of this therapeutic option is falling. For many insured patients, this consideration may even be irrelevant. There are no data to indicate that titration with transdermal fentanyl need be slower than the titration of controlled-release morphine. Indeed, all of the comparative studies of transdermal fentanyl and oral morphine showed no difference in level of pain control. Though the use of transdermal fentanyl is not generally recommended as first-line therapy, it is an overstatement to maintain that it is an "inappropriate" option.

The concern regarding dose selection when switching to or from transdermal fentanyl is also overstated. That equianalgesic conversion tables need to be used with caution when making these calculations as part of an opioid switch holds true for all opioids. This admonition is not specific to fentanyl.

Pain Assessment

In their discussion on the assessment of pain, the authors state that a realistic goal is a 33% to 50% reduction in pain intensity, or a 2-point decrease in the 10-point numerical rating of pain (as well as maintained or improved physical function, reduced pain interference, and minimal opioid side effects). These assertions are based on acute pain studies . Although such parameters may be meaningful in the context of chronic pain, the notion of satisfactory relief to a tolerable level remains a gold standard. Although this is variable, in practice, pain rated less than 5 on a 10-point scale is usually associated with low levels of interference with function.[1]

Adverse Effects

Some adverse effects appear to transiently and spontaneously abate after the initiation of an opioid or after dose escalation. This phenomenon has been well demonstrated in a prospective study on the effect of morphine dose escalation on cognitive performance.[2] The study demonstrated that cognitive impairment commonly improved after 7 days. This phenomenon, although often described, has not been formally studied with regard to other adverse effects. Indeed, the oft-stated assertion that nausea generally will resolve over several days is not supported by data.

Regarding persistent nausea and vomiting, which effects about 15% to 30% of patients, the authors accurately write that multiple classes of antiemetics have been used to manage opioid-induced nausea. The issue of antiemetic selection remains problematic. No studies have indicated the superiority of one antiemetic over another in the management of opioid-induced nausea. Commonly, recommendations have been made based on the inferred mechanism of opioid-induced nausea. In one of the few studies to address this issue, both metocolpramide and ondansetron were found to be no better than placebo.[3] This is a fertile subject for clinical studies.

Managing Dose-Limiting Toxicity

In the section on managing pain associated with dose-limiting side effects, the authors suggest three strategies for managing dose-limiting opioid toxicity. They write, "effective means of managing toxicity and maintaining analgesia include (1) route conversion (oral to parenteral or spinal), (2) opioid rotation to an alternative potent mu agonist, or (3) opioid dose reduction by 30% plus the addition of an adjuvant analgesic." While the principles are for the most part correct, the likelihood of benefit is overstated and other options are overlooked.

Only minimal anecdotal data support the suggestion that adverse effects observed with oral morphine will abate when the route is changed to an alternative systemic route of administration, be it subcutaneous, rectal, or intravenous. Indeed, given that the effective agent is in the same systemic compartment, this makes little pharmacologic sense and observational experience suggests that this approach rarely works.

The strategy of reducing the opioid dose and adding an adjuvant analgesic is an important one, but expectations should be modest. There is great interindividual variability in the response to all adjuvant analgesics and, for most, the likelihood of benefit is limited. This is particularly true of the agents used for neuropathic pain, where the likelihood of benefit for most agents does not exceed 20% to 30%. Furthermore, many of the adjuvant analgesics can cause side effects, which may be additive to the opioid-induced adverse effects that are already problematic. In evaluating the utility of an adjuvant agent in a particular patient setting, the clinician must consider the likelihood of benefit, the risk of adverse effects, the ease of administration, and patient convenience.

Neglected Strategies

In cases where the opioid dose needs to be reduced, three important coanalgesic strategies are neglected.

(1) The addition of a nonopioid coanalgesic: The analgesia achieved from nonopioid coanalgesics is additive and often synergistic with that achieved by opioids. This is supported by a number of prospective studies[4,5] and from one retrospective drug utilization survey.[6]

(2) The application of a therapy targeting the cause of the pain: Specific antitumor therapies such as radiotherapy, chemotherapy, or surgery targeting the cause of cancer-related pain can provide substantial relief and thus lower the need for opioid analgesia.

Radiotherapy is of proven benefit in the treatment of painful bone metastases,[7] epidural neoplasm,[7] and headache due to cerebral metastases.[8] In other settings, well established supportive data are lacking, and the use of radiotherapy is largely anecdotal. Despite a paucity of evidence concerning the specific analgesic benefits of chemotherapy,[9,10] there is a strong clinical impression that tumor shrinkage is generally associated with relief of pain. Although some investigators have reported analgesic value even in the absence of significant tumor shrinkage,[11-13] the likelihood of a favorable effect on pain is generally related to the likelihood of tumor response. Surgery may have a role in the relief of symptoms caused by specific problems, such as obstruction of a hollow viscus, unstable bony structures, and compression of neural tissues.

(3) Anesthetic and neurosurgical techniques may reduce or eliminate the requirement for systemically administered opioids to achieve adequate analgesia. In general, regional analgesic techniques such as intraspinal opioid and local anesthetic administration or intrapleural local anesthetic administration are usually considered first because they can achieve this end without compromising neurologic integrity. Neurodestructive procedures, however, are valuable in a small subset of patients,[14] and some of these measures, such as celiac plexus blockade in patients with pancreatic cancer,[15] may have a sufficiently favorable risk:benefit ratio that early treatment is warranted.

-Nathan I. Cherny, MBBS, FRACP, FRCP

Disclosures:

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

References:

1. Serlin RC, Mendoza TR, Nakamura Y, et al: When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function. Pain 61:277-284, 1995.

2. Bruera E, Macmillan K, Hanson J, et al: The cognitive effects of the administration of narcotic analgesics in patients with cancer pain. Pain 39:13-6, 1989.

3. Hardy J, Daly S, McQuade B, et al: A double-blind, randomised, parallel group, multinational, multicentre study comparing a single dose of ondansetron 24 mg p.o. with placebo and metoclopramide 10 mg t.d.s. p.o. in the treatment of opioid-induced nausea and emesis in cancer patients. Support Care Cancer 10:231-236, 2002.

4. Axelsson B, Borup S: Is there an additive analgesic effect of paracetamol at step 3? A double-blind randomized controlled study. Palliat Med 17:724-725, 2003.

5. Stockler M, Vardy J, Pillai A, et al: Acetaminophen (paracetamol) improves pain and well-being in people with advanced cancer already receiving a strong opioid regimen: A randomized, double-blind, placebo-controlled cross-over trial. J Clin Oncol 22:3389-3394, 2004.

6. Zech DF, Grond S, Lynch J, et al: Validation of World Health Organization guidelines for cancer pain relief: A 10-year prospective study. Pain 63:65-76, 1995.

7. Chow E, Harris K, Fan G, et al: Palliative radiotherapy trials for bone metastases: A systematic review. J Clin Oncol 25:1423-1436, 2007.

8. Pease NJ, Edwards A, Moss LJ: Effectiveness of whole brain radiotherapy in the treatment of brain metastases: A systematic review. Palliat Med 19:288-299, 2005.

9. Rubens RD, Towlson KE, Ramirez AJ, et al: Appropriate chemotherapy for palliating advanced cancer. BMJ 304:35-40, 1992.

10. Queisser W: Chemotherapy for the treatment of cancer pain. Recent Results Cancer Res 89:171-177, 1984.

11. Patt YZ, Peters RE, Chuang VP, et al: Palliation of pelvic recurrence of colorectal cancer with intra-arterial 5-fluorouracil and mitomycin. Cancer 56:2175-2180, 1985.

12. Rothenberg ML: New developments in chemotherapy for patients with advanced pancreatic cancer. Oncology (Williston Park) 10(9 suppl):18-22, 1996.

13. Thatcher N, Anderson H, Betticher DC, et al: Symptomatic benefit from gemcitabine and other chemotherapy in advanced non-small cell lung cancer: Changes in performance status and tumour-related symptoms. Anticancer Drugs 6(suppl 6):39-48, 1995.

14. Kim PS: Interventional cancer pain therapies. Semin Oncol 32:194-199, 2005.

15. Yan BM, Myers RP: Neurolytic celiac plexus block for pain control in unresectable pancreatic cancer. Am J Gastroenterol 102:430-438, 2007.