This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Saroyan, J.M. Articles by Granowetter, L. Search for Related Content PubMed PubMed Citation Articles by Saroyan, J.M. Articles by Granowetter, L.

Role of Intraspinal Analgesia in Terminal Pediatric Malignancy

From the Morgan Stanley Children's Hospital of New York-Presbyterian, College of Physicians and Surgeons at Columbia University, New York, NY

Address reprint requests to William S. Schechter, MD, Columbia University College of Physicians and Surgeons, Division of Pediatric Anesthesiology, Morgan Stanley Children's Hospital of New York-Presbyterian, 622 W 168th St BHN4-440, New York, NY 10032; e-mail: ws5{at}columbia.edu

HERE'S THE CASE

A 15-year-old girl from the Caribbean presented with high-grade pleomorphic osteogenic sarcoma of her distal right femur and multiple bilateral pulmonary nodules. After two courses of high-dose methotrexate, cisplatin, and doxorubicin, a limb-sparing procedure was performed. The margins were negative for tumor, and the tumor necrosis was approximately 75%. Chemotherapy continued, bilateral thoracotomies were performed, and ifosfamide and etoposide were added to the patient's regimen. Imaging studies showed no evidence of disease, and therapy was continued in her home country.

She returned with a left-sided foot drop and intractable aching pain in her left buttock 3 months later. The pain consisted of frequent jolts of shooting electric shock–like pain, which radiated down her leg in a posterolateral distribution. There was no bowel or bladder incontinence. Physical examination revealed a bed-bound patient unable to lie supine or walk because of pain, decreased strength and tone in all muscle groups of the left lower extremity, a diminished left patellar reflex, and a generalized decrease in sensation to both pinprick and light touch in the affected extremity. Computed tomography showed multiple recurrent pulmonary nodules, local recurrence in the soft tissues around the right knee, and a large left-sided pelvic mass arising from the left iliac wing. The mass extended into the left sacral ala and deep into the pelvis involving the obturator region and sciatic notch. The patient and her parents requested further chemotherapy, and the patient was treated on an investigational trial of high-dose topotecan, ifosfamide, and carboplatin. There was no response to chemotherapy. Palliative radiation therapy to the left pelvic mass was initiated, and chemotherapy was discontinued.

Patient-controlled analgesia with hydromorphone was initiated and titrated to analgesic requirements (20 mg/d) but caused somnolence. In addition, she was receiving methadone (60 mg/d), along with maximized doses of gabapentin, oxcarbazepine, and celecoxib. She continued to awake from sleep writhing in pain.

An epidural trial using a tunneled catheter and external pump was initiated, and the patient was administered a mixture of preservative-free morphine and clonidine. Radiation therapy was completed 10 days after the epidural infusion was started, and by this time, the pain score had decreased from a score of 8 to 9 out of 10 to 2 out of 10. The dramatic improvement in pain control led the family to express a long-felt desire to return to their country of origin. In anticipation of an implantable catheter being placed, the epidural catheter was removed. Severe pain, unrelieved by high doses of opioids, returned.

Under general anesthesia, a SynchroMed LF (Minneapolis, MN) implantable intraspinal infusion system was placed with a catheter positioned in the lumbar subarachnoid space. Morphine and clonidine at doses of 0.7 mg and 340 µg per day were started based on previous epidural dose requirements. Two days after placement of the implantable pump, her buttock pain score was 0 out of 10, and the neuropathic pain involving the lower extremity that was so distressing completely resolved. A local anesthetic (bupivacaine) was added in anticipation of weaning oxcarbazepine and methadone. An anesthesiologist in her native country was supplied with an instructional video and a refill kit of a premixed solution of morphine, clonidine, and bupivacaine. The patient, assured of our ready availability by phone and electronic communication, was discharged from the hospital and was virtually pain free.

The tumor rapidly progressed. Areas of necrosis and fungating tumor mass were noted at the right knee and pulmonary involvement increased. The patient survived for almost 2 months, essentially pain free; systemic opioids and benzodiazepines were used for the treatment of dyspnea during her last week of life.

INTRASPINAL ANALGESIA EXPERIENCE IN PEDIATRIC ONCOLOGY

Intraspinal analgesia, which includes either spinal (subarachnoid) or epidural drug delivery, has been used only sporadically to control pain in terminal pediatric malignancies. Traditionally, these forms of regional anesthesia have been used for intraoperative and postoperative pain management.¹ More recently, they are being recommended as a possible strategy for the treatment of cancer pain in the final stages of disease. Collins et al^2,3 have categorized the following three groups of pediatric patients in whom this approach may be beneficial: (1) children who have dose-limiting side effects from systemic opioid infusions despite adjunctive treatment; (2) children whose pain was poorly responsive to massive opioid infusion; and (3) children whose mental status was depressed by systemic opioids when sedation was not considered desirable. The report of the subcommittee on disease-related pain in childhood cancer of the American Academy of Pediatrics includes this modality of treatment.⁴ Other reports have demonstrated the efficacy of epidural, spinal, and perineural analgesia in selected patients with intractable cancer pain.^2,3,5,6 Additionally, the use of combined mixtures of opioid, local anesthetic, and alpha-2 adrenergic agonists has been advocated by an expert panel in their step-by-step approach to intraspinal infusions for adult patients.⁷

SELECTION OF SPINAL ANALGESIC DRUG: OPIOID, LOCAL ANESTHETIC, AND ALPHA-2 ADRENERGIC AGONIST

Morphine remains the primary drug of choice for intraspinal analgesia and is the only drug approved by the Food and Drug Administration. Ratios for conversion from total systemic daily dose of opioid to the epidural and subarachnoid route have been published.⁸ Oral morphine is first converted to the parenteral equivalent dose of morphine. The initial epidural morphine dose is equal to 10% of the 24-hour parenteral equivalent morphine dose. The initial subarachnoid morphine dose is 10% of the epidural dose. The calculated subarachnoid morphine dose should fall within the range of the corresponding published starting value of subarachnoid morphine per day (0.1 to 20 mg).⁷ If opioids other than morphine (eg, oxycodone or hydromorphone) are converted to parenteral morphine, the calculated dose should be reduced to account for incomplete cross tolerance.

Alternative pharmacologic strategies are considered when the required morphine dose reaches 20 mg/d without adequate relief of somatic or visceral pain or when neuropathic pain is present. A combination of morphine and the local anesthetic bupivacaine or an alpha-2 adrenergic agonist can be used for refractory neuropathic pain.⁹ Titration of the rate of infusion of the mixture should be based on response to pain as well as side effects; it should be adjusted approximately every 48 hours as needed. Once a stable mixture is achieved, the infusion pump may only need to be refilled as infrequently as every 1 to 3 months.

In a prospective enrollment of 53 adult cancer patients, combining morphine and bupivacaine decreased total opioid consumption.¹⁰ Total daily infusion volume was decreased by 40%, and reservoir refills were less frequent. In addition, potential side effects of intrathecal morphine, such as seizures, clonus, allodynia, hyperesthesia, respiratory depression, urinary retention, pruritus, and granuloma formation, were reduced.¹¹

The efficacy of epidural clonidine in controlling neuropathic cancer pain was suggested in a prospective, randomized, double-blind, placebo-controlled study.⁹ Successful analgesia for neuropathic pain was more commonly achieved when morphine and clonidine were combined versus morphine with placebo.

RISKS AND COMPLICATIONS OF INTRASPINAL DRUG DELIVERY

The incidence of infection in long-term pediatric epidural catheter usage has been reported to be 2.4%.¹² Of the four patients suspected of having epidural abscesses in this long-term epidural cohort, only one had radiologic evidence of an epidural abscess. Culture of the epidural catheter tip grew Candida tropicalis. The authors state that a similarly low complication rate may be replicable if there is careful monitoring of the catheters. Other risks include postdural puncture headache, backache, and nerve injury. Clinically significant bleeding is rare once the catheter is in situ. However, it may occur during placement or removal of the catheter.

SEQUENCE AND TIMING OF INTRASPINAL CATHETER PLACEMENT

Patients at risk for chemotherapy-induced thrombocytopenia require special attention to the timing of the procedure and the need for platelet transfusion. Intercurrent coagulopathy or sepsis with seeding of the catheter are also serious concerns. Therefore, the decision to place such a device must be made in the context of life expectancy, the presence of severe terminal pain, a desire for alertness, and the risk of rare but potentially significant complications.

Once a decision is made to use this technique, an intraspinal catheter is usually placed for a 48- to 72-hour trial. This allows the clinician to determine efficacy and to decide on a drug or drug mixture, on doses of the drug or drug mixture, and on the rate of infusion. The temporary catheter is then removed, and if it was successful, an intraspinal catheter is placed and subcutaneously tunneled to a self-contained, totally implantable reservoir and pump containing an internal battery. The system is inserted under sterile conditions in the operating room.

SUBARACHNOID VERSUS EPIDURAL DRUG DELIVERY: ADVANTAGES AND DISADVANTAGES

Advantages of a subarachnoid delivery system include small medication dosages and infusate rates because the drug is widely distributed by bulk CSF flow. Pump refill is infrequent. Disadvantages of an epidural delivery system include the need for higher drug volume to obtain adequate spread over several dermatomal segments. More frequent refilling of the system is needed, which theoretically makes infectious risk greater. Long-term epidural catheter drug delivery, however, may lead to impaired drug diffusion or transport across the dura mater and inadequate spread of analgesic.¹³ Clinical data demonstrate that, for adult cancer patients whose life expectancies exceed 3 months, the overall costs of intrathecal pain therapy may be less than those of tunneled epidural catheters or external infusion devices.¹⁴

The initial intent for the patient described in this article was to discharge her to a residential facility near the medical center. A tunneled epidural catheter connected to an external pump seemed most appropriate. Tunneled catheters have been used for this purpose in Europe¹⁵; children have also been discharged to home with such systems, with visiting nurse follow-up, or to hospice care. Because of the degree of pain control achieved, the family decided to return to their native country in the Caribbean. It would not have been possible for us to discharge this patient with a tunneled catheter accessed by an external port because of narcotic restrictions and frequent electrical outages in her home country and her long distance from any medical support. Therefore, the tunneled epidural catheter was converted directly to a totally implantable intraspinal delivery system.

REGIONAL VERSUS SYSTEMIC ANALGESIA

In the only randomized comparison of aggressive comprehensive medical management to implantable intraspinal drug administration, clinical success was better with intraspinal treatment. The group that had implantable drug delivery systems had a 52% reduction in pain scores. An anticipated 20% improvement of pain at 30 days was not achieved, likely because of the unexpected effectiveness of comprehensive medical management.¹⁶ However, there was a significant (P < .05) reduction in the frequency of opioid side effects, such as fatigue and depression of level of consciousness, in the group receiving intraspinal therapy compared with comprehensive medical management.

Eighty-nine percent of children dying of cancer have been reported to suffer significantly from fatigue.¹⁷ Intraspinal analgesia was of benefit to our patient because it was the only technique that could satisfactorily control the neuropathic component of her pain without significant sedation. It maximized her wakefulness by decreasing her oral opioid dose by 75%, and it allowed one neuropathic agent, gabapentin, to be eliminated completely.

The potential for interventional pain medicine techniques to prolong life by decreasing or eliminating the need for high doses of systemic medication deserves further investigation. There is evidence, but not proof, of improved immune competence once the stress of severe pain is relieved.¹⁸ The short- and long-term psychological benefits to the families of patients who have had their child's pain optimally controlled by intraspinal analgesia is worthy of future investigation.

DISCUSSION

It is appreciated that intraspinal analgesia is not readily available in all centers caring for children with cancer. Initially, placement of the catheter and titration of the opioid, local anesthetic, and alpha-2 adrenergic agonist is labor intensive and requires expertise. Implantable devices may also be considered quite invasive. The experience with this patient demonstrates the potential benefits of intraspinal analgesia, including relief of intractable pain, minimal sedation, and simplification of home care. Providing optimized pain management strategy is essential to providing the best end-of-life treatment. Centers that do not have expertise in pediatric intraspinal analgesia may be able to refer their patients to centers that are able to provide this management and then continue to care for the patient in cooperation with the consultants.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

Acknowledgment

We thank the Christopher Colangelo Home Care Fund for their generous support in the care of this patient.

NOTES

Authors' disclosures of potential conflicts of interest are found at the end of this article.

REFERENCES

1. Berde CB: Regional analgesia in the management of chronic pain in childhood. J Pain Symptom Manage 4:232-237, 1989[CrossRef][Medline]

2. Collins JJ, Grier HE, Sethna NF, et al: Regional anesthesia for pain associated with terminal pediatric malignancy. Pain 65:63-69, 1996[CrossRef][Medline]

3. Collins JJ, Grier HE, Kinney HC, et al: Control of severe pain in children with terminal malignancy. J Pediatr 126:653-657, 1995[CrossRef][Medline]

4. Berde C, Ablin A, Glazer J, et al: Report of the subcommittee on disease related pain in childhood cancer. Pediatrics 86:818-825, 1990[Abstract/Free Full Text]

5. Aram L, Krane EJ, Kozloski LJ, et al: Tunneled epidural catheters for prolonged analgesia in pediatric patients. Anesth Analg 92:1432-1438, 2001[Abstract/Free Full Text]

6. Cooper MG, Keneally JP, Kinchington D: Continuous brachial plexus neural blockade in a child with intractable cancer pain. J Pain Symptom Manage 9:277-281, 1994[CrossRef][Medline]

7. Hassenbusch SJ, Portenoy RK, Cousins M, et al: Consensus Conference 2003: An update on the management of pain by intraspinal drug delivery—Report of an expert panel. J Pain Symptom Manage 27:540-563, 2004[CrossRef][Medline]

8. Krames ES: Intrathecal infusional therapies for intractable pain: Patient management guidelines. J Pain Symptom Manage 8:36-45, 1993[CrossRef][Medline]

9. Eisenach JC, DuPen S, Dubois M, et al: The epidural clonidine study group epidural clonidine analgesia for intractable cancer pain. Pain 61:391-399, 1995[CrossRef][Medline]

10. Samuelsson H, Nordberg G, Hedner T, et al: CSF and plasma morphine concentrations in cancer patients during chronic epidural morphine therapy and its relation to pain relief. Pain 30:303-310, 1987[CrossRef][Medline]

11. Horais K, Hruby V, Rossi S, et al: Effects of chronic intrathecal infusion of a delta opioid agonist in dogs. Toxicol Sci 71:263-275, 2003[Abstract/Free Full Text]

12. Strafford MA, Wilder RT, Berde CB: The risk of infection from epidural analgesia in children: A review of 1620 cases. Anesth Analg 80:234-238, 1995[Abstract]

13. Sjoberg M, Nitescu P, Appelgren L, et al: Long-term intrathecal morphine and bupivacaine in patients with refractory cancer pain: Results from a morphine:bupivacaine dose regimen of 0.5:4.75 mg/ml. Anesthesiology 80:284-297, 1994[Medline]

14. Hassenbusch SJ, Paice JA, Patt RB, et al: Clinical realities and economic considerations: Economics of intrathecal therapy. J Pain Symptom Manage 14:S36-S47, 1997[CrossRef][Medline]

15. Gestin Y, Vainio A, Pegurier AM: Long-term intrathecal infusion of morphine in the home care of patients with advanced cancer. Acta Anaesthesiol Scand 41:12-17, 1997[Medline]

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

17. Wolfe J, Grier H, Klar N, et al: Symptoms and suffering at the end of life in children with cancer. N Engl J Med 342:326-333, 2000[Abstract/Free Full Text]

18. Page GG: The immune-suppressive effects of pain. Adv Exp Med Biol 521:117-125, 2003[Medline]

Submitted July 6, 2004; accepted November 22, 2004.

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Saroyan, J.M. Articles by Granowetter, L. Search for Related Content PubMed PubMed Citation Articles by Saroyan, J.M. Articles by Granowetter, L.