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Randomized Clinical Trial of an Implantable Drug Delivery System

The Harry R. Horvitz Center for Palliative Medicine, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH

To the Editor: The article by Dr Thomas Smith and colleagues¹ about an implantable drug delivery system compared with comprehensive medical management for refractory pain is a well-written, well-conducted, and well-analyzed industry-sponsored study. However, we have several concerns. The authors did not clearly define refractory cancer pain. The need for 200 mg or more of oral morphine per day is not unusual in advanced cancer and is not and should not be used as a definition of refractory cancer pain.

There were two populations of patients in this study: those with side effects limiting dose escalation and those who reached the arbitrary 200 mg of oral morphine per day limit without opioid toxicity. These two distinctive subsets are usually managed differently in clinical practice. The first group is managed with opioid rotation, opioid conversion, or the addition of an adjuvant along with opioid dose reduction (opioid sparing). The second group is managed by oral opioid dose titration. It is difficult to justify the risks (including infections and catheter displacement) of invasive (spinal) catheters in the second group of patients.

The median age of the patients within the study was 10 years younger than the mean age of cancer patients, so it is unlikely that this study represents the cancer population at risk. Age also has a significant effect on morphine dosing (higher doses are required in younger age groups), which also invalidates the 200-mg definition.

The two groups (comprehensive medical management [CMM] and spinal group) had significantly different morphine oral equivalent doses. The authors’ claim within the study that side effects are reduced by spinal opioids compared with conventional routes, and that opioids have the same or greater analgesic effect, is problematic. Other investigators did not find an advantage to spinal analgesia when controlled for calculated relative milligram potency morphine equivalents.² Comparisons need to be made to equianalgesic doses of parenteral opioids before spinal opioids are recommended on the basis of improved analgesia. Patients were allowed to receive radiation therapy, chemotherapy, and bisphosphonates, all of which may also reduce pain and may have influenced the study results. These factors were not controlled in the design.

Another interpretation of the study is that prescribing physicians knew how to use spinal opioid pumps but were less comfortable with and less knowledgeable about prescribing nonspinal analgesic. Were the physicians trained in CMM before the study? We do not know the patient or physician compliance to CMM guidelines or the proportion of patients whose pain was not controlled with treatment that adhered to the CMM guidelines. Cancer will continue to grow postrandomization with some expectation of increasing pain. Thirty-two percent of the CMM group were crossed over to spinal therapy because of "uncontrolled pain," which was assumed to be the same as unrelieved pain (> 5 on a 0 to 10 scale). Parenteral dose-conversion escalation or rotation might be more appropriate than spinal therapy in this setting, particularly with short expected survival. Were these patients switched from CMM to spinal therapy because of pain plus opioid side effects? We do not know what intrathecal or peroral opioid relative milligram dose guidelines were used. What was the percentage of opioid rotation on potency spinal therapy because analgesics other than morphine were allowed?

Survival is a precarious outcome measure unless planned within a study. Patients received chemotherapy for their underlying malignancy. Performance-status data were not mentioned. Performance score is as significant a variable in predicting survival in cancer as is stage of disease (which also was not mentioned). Cross-over between groups occurred. The greater symptom burden in the CMM arm (such as fatigue, anorexia, or nausea) could be disease related (short expected survival with greater symptom burden) and not opioid related. Selection bias also played a role, given that only half of those randomly assigned to spinal opioids received therapy.

Finally, pharmacoeconomic data are not provided. Many of these patients will eventually enter hospice programs, which have limited and capitated reimbursement. Expensive therapies, such as implantable pumps, are not affordable for most American hospices.

Consideration of opioid rotation or conversion in the management of cancer pain naturally leads to the concept of opioid responsiveness. The most common reasons for switching opioids or altering routes of administration (opioid conversion) are poorly controlled pain and unacceptable adverse effects (or both). Opioid unresponsiveness should not be based on one opioid trial but should be determined after at least one additional alternative opioid rotation.³ There is incomplete cross-tolerance between opioids and between adjuvants even among the same class. Usual practice suggests opioid rotation or parenteral conversion for uncontrolled pain when faced with dose-limiting side effects (Fig 1).^4–7 A third alternative in the presence of side effects is to reduce the opioid dose and add an adjuvant. Opioid equianalgesic conversion to subcutaneous infusion is as effective as spinal opioid therapy, is less technically involved, and perhaps has the same improved therapeutic index.^2,7 Parenteral opioid conversion before spinal infusion is preferred for this reason.

View larger version (11K): [in this window] [in a new window]   Fig 1. Clinical practice. The opioid closing strategy for patients with uncontrolled pain and opioid side effects.

View larger version (12K): [in this window] [in a new window]   Fig 2. Present study. Opioid closing strategy utilized by the Implantable Drug Delivery Systems Study Group.

REFERENCES

1. Smith TJ, Staats PS, Deer T, et al: Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory pain: Impact on pain, drug related toxicity, and survival. J Clin Oncol 20:4040–4049, 2002[Abstract/Free Full Text]

2. Mercadante S: Controversies over spinal treatment in advanced cancer patients. Support Care Cancer 6:495–502, 1998[CrossRef][Medline]

3. Fallon M: Opioid rotation: Does it have a role? Palliat Med 11:177–178, 1997[Free Full Text]

4. Mercadante S: Opioid rotation for cancer pain: Rationale and clinical aspects. Cancer 86:1856–1866, 1999[CrossRef][Medline]

5. McQuay HJ: Opioid clinical pharmacology and routes of administration. Br Med Bull 47:703–717, 1991[Abstract/Free Full Text]

6. Walsh D: Pharmacological management of cancer pain. Semin Oncol 27:45–63, 2000[Medline]

7. Hanks GW, DeConno F, Cherny N, et al: Expert Working Group of the Research Network of the European Association for Palliative Care: Morphine and alternative opioids in cancer pain—the EAPC recommendations. Br J Cancer 84:587–593, 2001[CrossRef][Medline]

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