Correspondence

Treatment of Pain in Sickle-Cell Crisis

N Engl J Med 1994; 331:334-335August 4, 1994

Article

To the Editor:

Griffin et al. (March 17 issue)1 report decreased duration of severe pain in children and adolescents with sickle cell disease after treatment with high-dose methylprednisolone. There are serious deficiencies in the methods used in this clinical study that arouse both scientific and ethical concern. Simply stated, the authors confuse the duration of analgesic use with analgesia. They describe the main analgesic outcome measures as the number of morphine doses used, the need for continuous morphine infusions, and the duration of opioid therapy. Only the data on duration were statistically significant. Despite an abundant literature on pain measurement in children,2 pain relief, or analgesia, was not evaluated with either validated self-report scales or observer-related scales. All the study's outcome variables depend on the assessments of clinicians, but the criteria for dose escalation by intermittent bolus or continuous infusion are not mentioned. Given the well-known underestimation and undermedication of pain by both nurses and physicians,2,3 the duration of analgesic use in these patients cannot be considered to be equivalent to analgesia and may indeed have little clinical relevance.

Equally important, the study raises an important ethical question. Ten patients had painful episodes requiring a continuous infusion of morphine. According to the protocol, these patients could potentially remain in severe pain for 24 hours (part of the time at the starting dose and part of the time at 1 1/2 times the starting dose) before a substantive change in the dose and timing was made. Severe pain should be treated as an emergency, with aggressive dose titration and careful monitoring and treatment of side effects4. The study protocol appeared to preclude standard pain therapy of this type. Studies of pain in children require scientifically validated methods of assessment and treatment protocols that incorporate titration of the opioid dose according to the analgesic effect and either “rescue” medications or clearly defined rules for dropping out should standard dosing fail. Unlike Platt,5 we believe this study should not be replicated. The methods used may confound science and lead to substandard pain management.

Kathleen M. Foley, M.D.
Russell K. Portenoy, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021

5 References

1
Griffin TC, McIntire D, Buchanan GR. High-dose intravenous methylprednisolone therapy for pain in children and adolescents with sickle cell disease. N Engl J Med 1994;330:733-737
Full Text | Web of Science | Medline

2
McGrath P. The measurement and assessment of pain. In: McGrath P, Unruh AM, eds. Pain in children and adolescents. Pain research and clinical management. Vol. 1. Amsterdam: Elsevier Science, 1987.

3
Schechter NL, Allen DA, Hanson K. Status of pediatric pain control: a comparison of hospital analgesic usage in children and adults. Pediatrics 1986;77:11-15
Web of Science | Medline

4
Agency for Health Care Policy and Research, Acute Pain Management Guideline Panel. Acute pain management. In: Infants, children, and adolescents: operative and medical procedures. Quick reference guide for clinicians. Rockville, Md.: Department of Health and Human Services, 1994. (AHCPR publication no. 92-0020.)

5
Platt OS. Easing the suffering caused by sickle cell disease. N Engl J Med 1994;330:783-784
Full Text | Web of Science | Medline

To the Editor:

Griffin et al. suggest that an analgesic and mood-elevating effect of steroids, as well as their well-known antiinflammatory activity, may have a role in sickle cell disease. Another possible mechanism is corticosteroid deficiency. We studied the function of the pituitary-adrenal axis in adult patients with sickle cell disease1 and showed that the adrenal response to administered corticotropin was blunted and that metyrapone inhibition of 11-hydroxylation failed to raise levels of 11-deoxycortisol as expected. We concluded that there may be an impaired pituitary-hypothalamic-adrenal axis in sickle cell disease.

Our findings may offer an additional explanation for the apparent effectiveness of high-dose methylprednisolone in ameliorating sickle-cell pain.

Barry E. Rosenbloom, M.D.
Cedars-Sinai Medical Center, Los Angeles, CA 90048

Kouichi R. Tanaka, M.D.
Harbor-UCLA Medical Center, Torrance, CA 90509

1 References

1
Rosenbloom BE, Odell WD, Tanaka KR. Pituitary-adrenal axis function in sickle cell anemia and its relationship to leukocyte alkaline phosphatase. Am J Hematol 1980;9:373-379
Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We thank Drs. Foley and Portenoy for their constructive criticism. We agree that our study did not conclusively demonstrate a reduction in pain during the period when the children were receiving methylprednisolone and parenteral opioids. However, we believe the shortening of the severe painful event by approximately one day did have clinical relevance as well as statistical significance. We attempted to use several pain-assessment scores (and are also doing so in the continuation of our study), but we have had great difficulty with their use in children with sickle cell disease at times of painful crisis.

Foley and Portenoy raise the ethical concern that our study design allowed these children to suffer severe pain. Our center has a long tradition of delivering aggressive pain treatment to children with severe sickle-cell crisis. We were to our knowledge the first to report the use of continuous opioid analgesia to achieve effective pain control in these patients1. Moreover, during the 24 hours before the 10 children were switched to a continuous infusion of morphine, they did not remain in constant severe pain but received intravenous bolus injections of morphine as often as every 2 hours, an approach considered standard in many centers.

We believe that our method of assessing the effects of methylprednisolone was valid, and we agree with Platt that further studies should use a similar design2. The time has come to implement carefully controlled trials to manage sickle-cell crisis with more than just the time-honored regimen of “fluids and analgesia.”

George R. Buchanan, M.D.
University of Texas Southwestern Medical Center, Dallas, TX 75235

Timothy C. Griffin, M.D.
Cook-Fort Worth Children's Medical Center, Fort Worth, TX 76104

2 References

1
Cole TB, Sprinkle RH, Smith SJ, Buchanan GR. Intravenous narcotic therapy for children and severe sickle cell pain crisis. Am J Dis Child 1986;140:1255-1259
Web of Science | Medline