Pilot study of continuous co-infusion of morphine and naloxone in children with sickle cell pain crisis

Abstract

Patients with sickle cell disease experience painful crises that often require hospitalization for a continuous infusion of morphine that may cause significant pruritus. We conducted a pilot study to determine the feasibility of simultaneous continuous co-infusion of naloxone with morphine, test novel assessment instruments for pruritus, and explore whether pruritus could be reduced while maintaining effective analgesia. Patients with sickle cell disease and painful crisis requiring continuous infusion morphine received continuous co-infusion of naloxone at 0.25 (low dose) or 1.0 mcg/kg·hr (high dose). Pain scores were obtained using the FACES scale and a 100-mm visual analog scale (VAS). Itching was quantified by a modified VAS score. Evaluable data were obtained on 16 patients. Simultaneous co-infusion of naloxone and morphine was feasible, did not seem to reduce the analgesic efficacy of morphine, and was associated with no adverse effects. The high dose group reported a lower median “VAS worst itch” score than the low dose group (4.8 vs. 7.3, P = 0.08). Simultaneous continuous infusion of naloxone with morphine in pediatric patients with sickle cell disease and pain crisis was feasible and well tolerated. A quantitative pruritus score allowed us to systematically measure pruritus. Further evaluation by randomized, placebo-controlled study of 1 mcg/kg·hr naloxone in this setting is required.

Introduction

The recurrent painful crisis is the hallmark of sickle cell disease. These events occur without warning, may necessitate hospitalization, and often require opioids for relief [1,2]. Opioids are frequently associated with unwanted side effects including nausea, vomiting, and pruritus, which may be more debilitating and distressing than the pain itself. Some patients refuse a continuous infusion of opioids, despite its potential for additional pain relief, because of “unbearable” itching that may accompany its use [3,4].

The concomitant use of an opioid antagonist to ameliorate the side effects of opioids has been studied in adults and adolescents receiving morphine for pain relief with both positive [5–11] and negative results [12–14]. A few investigators have reported improved pain control with the coadministration of naloxone because use of morphine was decreased [5,9]. These studies have been performed primarily in opioid naive, postoperative adult patients, with the exception of one study in adolescents [7] and one in the emergency department [14].

To the best of our knowledge, concomitant administration of an opioid and an opioid antagonist has not been reported in pediatric sickle cell patients during painful crisis or in patients who have previously received continuous opioid infusions. The pain experienced during sickle cell crisis is different than postoperative pain [15], and patients with sickle cell disease who may repeatedly received opioids might respond differently than postoperative, opioid naive patients. Finally, postanesthesia studies traditionally evaluate only the first 24 hr of pain relief, not the effects of continued opioid therapy for the average 2–4 day hospitalization for severe painful sickle cell crisis.

Painful crisis is a significant problem for children with sickle cell disease, and there has been little progress in its management. We, therefore, conducted a pilot study of the concomitant administration of naloxone and continuous infusion morphine in children with sickle cell disease and painful crisis to test the feasibility of its administration, its acceptability to patients, and its potential ability to reduce pruritus.

Results

Patients

Eighteen patients were enrolled (14 with SS, four with SC Disease). All received the intervention, but only 16 patients were evaluable. One 16-year-old male was removed from the study protocol on day 2 because of newly observed hypertension despite adequate pain control. He has subsequently required chronic treatment for essential hypertension. One 8-year-old female received a continuous infusion morphine and naloxone for only 90 min because she experienced excessive somnolence. Continuous morphine infusion was not restarted in this patient.

Of the 16 evaluable patients, 6 (38%) were male and all were African–American. The mean age was 14.0 years (range 8–18, median 15). Study patients had previously been admitted to the hospital a mean of 11.9 times (range 1–59, median 8), with a mean of 7.1 admissions (range 1–41, median 4) for isolated painful crises. Only two patients had never been hospitalized before for the treatment of pain with continuous infusion morphine. The median time between the study admission and previous admission for pain requiring continuous infusion of morphine was 8 months (range 0.3–37 months).

Measurements of pain and pruritus

For all evaluable subjects, medication use and symptom scoring for days 1 and 2 are summarized in Table I. The mean time to initiation of the naloxone infusion after starting the continuous morphine infusion was 164 min (range 0–690, median 60). The naloxone infusion was begun more than 2 hr after the continuous infusion morphine in 6 patients, because a parent was not immediately available earlier to provide informed consent. Subjects' perceptions of the control of their pruritus and pain during the study compared by recollection to a previous hospitalization are detailed in Table II.

TABLE 1.

Medication Use and Symptom Scoring for Days 1 and 2

	Day 1 (N = 18)		Day 2 (N = 14)
Measurement	Median	IQRa	Median	IQR
Total Opioids (mg/kg)	1.14	(0.93–1.68)	1.50	(1.32–1.80)
Total Diphenhydramine (mg/kg)	0.95	(0–1.5)	1.45	(0.48–2.35)
24 Hour Average Pain Score (0–5)	3.3	(2.0–4.1)	3.4	(2.6–4.3)
Team Pain Worst (0–5)	5	(4–5)	5	(4–5)
VAS Pain Now (cm) (0–10)	6.8	(4.5–7.6)	7.1	(3.9–8.8)
VAS Pain Worst (cm) (0–10)	9.6	(8.2–10.0)	8.9	(8.4–10.0)
Team Itch Worst (0–5)	5	(3.5–5)	4	(3.8–5)
VAS Itch Now (cm) (0–10)	5.8	(3.6–8.8)	6.6	(3.3–8.6)
VAS Itch Worst (cm) (0–10)	7.3	(5.6–9.8)	9.3	(5.9–10.0)

^aIQR, Inter-quartile range.

TABLE II.

Number of Subjects Who Reported Their Pain or Pruritus to be Controlled the Same As or Better Than a Previous Hospitalization

Dose group	Scale	Day 1	Day 2
		N = 9	N = 9
Low-dose	Pain	6	6
	Pruritus	5	4
		N = 5	N = 3a
High dose	Pain	5	3
	Pruritus	2	2

^aTwo patients had sufficient pain relief to transition to intermittent morphine administration by day 2.

The “team FACES pain worst” and the “team VAS pain worst” scores had a strong degree of correlation, with a correlation coefficient of 0.813 (P < 0.001), supporting the construct validity of these scores for the measurement of pain [16]. The “team itch worst” score had a strong correlation with the “team VAS itch worst”, with a correlation of 0.870 (P < 0.001), supporting the construct validity of these scores for the measurement of itching [16].

Frequency of other adverse effects

Nausea occurred in 10 of the 16 patients (63%) on day 1 and 7 of 14 (50%) patients still on continuous infusion morphine on day 2. Vomiting occurred in 7 of 16 patients (44%) on day 1 and 2 of 14 (14%) on day 2. There were no episodes of respiratory depression during the trial.

Dose comparison

Although the study was not powered to detect a difference between groups, we compared the itching scores and diphenhydramine use between the high and low dose naloxone groups. The high dose group had a lower median “team VAS itch now” on day 1 (4.8 vs. 7.3, P 5 0.08) and used less diphenhydramine (median of 0 vs. 1 mg/kg, P = 0.31 on day 1, and 0.4 vs. 1.6 mg/kg, P = 0.04 on day 2).

Discussion

We have shown that it is feasible and acceptable to children with sickle cell disease to receive naloxone and morphine as continuous infusions during severe painful crisis. No adverse effects were noted. The high-dose (1 mcg/kg·hr) naloxone group used less diphenhydramine and rated their pruritus as less severe on one scale than the low-dose naloxone group (0.25 mcg/kg·hr).

Many mechanisms have been postulated to explain why a receptor antagonist might reduce symptoms and improve pain control. Gan et al. [5] proposed naloxone might inhibit presynaptic autoinhibition of enkephalin release by endogenous enkephalin [17]. Naloxone has also been shown to inhibit histamine release from basophils [18], which may account for decreased itching. More recently, Crain and Shen [19–22], have demonstrated that opioids act bimodally on sensory neurons, and that when given in very low doses, can cause hyperalgesia. This hyperalgesia is usually masked by high dose opioid effect which results in potent analgesia. Small doses of opioid antagonists may decrease opioid-induced side effects and improve pain control by inhibiting only the receptors responsible for hyperalgesia [7,19].

Seven prior studies, only one involving children, have examined the use of opioid antagonists to reduce adverse effects associated with intravenous morphine administration [5–7,11–14]. No prior studies have included patients with sickle cell disease. Gan et al. [5] randomized adult postoperative patients to receive either 0.25 mcg/kg·hr naloxone (low dose), 1.0 mcg/kg·hr naloxone (high dose), or saline (placebo) as a continuous infusion in addition to narcotic analgesia. The incidence of pruritus, nausea, and vomiting were significantly lower in both groups treated with naloxone. In addition, cumulative morphine use at 24 hr was lower in the low dose naloxone group than in either the placebo or high-dose naloxone group. Three studies [5–7,11], all performed in postoperative patients, also demonstrated that the use of small-dose opioid antagonists combined with IV morphine infusion significantly reduced the adverse effects associated with morphine administration compared to placebo in opioid naïve patients.

Three other studies [12–14] in which the morphine and naloxone were mixed and given as intermittent doses as opposed to continuous infusion, did not find significant differences in side effect profiles in patients receiving opioid antagonists along with IV morphine infusion.

Inference from our pilot study is significantly limited by the small number of patients and the real possibility of inaccurate or biased recall of symptoms from previous admissions. Relying on patient memory as opposed to a control comparison group significantly limits the conclusions that can be drawn from the data presented. The purpose of this work was to provide a first step showing that it is feasible to further explore administering these two agents in combination to sickle cell patients in pain crisis.

This pilot study demonstrates that concomitant administration of continuous infusion naloxone with continuous infusion morphine in pediatric patients with sickle cell disease and pain crisis is feasible. We present preliminary evidence that control of pruritus might be better and that control of pain did not seem to be compromised by co-infusion. Further, we demonstrate that use of a quantitative pruritus scale is valid and allows for objective assessment of this side effect of opioid administration. Because there have been few recent advances in the therapy of painful crisis, new treatment strategies to ameliorate pain and reduce side effects must be pursued. This approach should be further evaluated in a blinded, randomized, placebo-controlled trial comparing 1 mcg/kg·hr naloxone infusion to placebo. Patient groups should be compared utilizing structured measures of pruritus, such as the scale we report here, to determine if pruritis can be decreased while maintaining adequate pain control. A larger study would also allow meaningful comparison of total morphine and diphenhydramine requirements, the length of hospital stay, and time to resolution of all pain symptoms.

Methods

Patients

We studied a convenience sample of patients with sickle cell disease, 5–21 years of age, who were admitted to Children's Medical Center Dallas between August 2003 and January 2005 for uncomplicated painful crisis (without fever, chest syndrome, recent surgery, or other problems) and who received a continuous infusion of morphine. Patients were excluded if they were receiving a program of chronic red blood cell transfusions, their pain was believed not to be due to sickle cell disease, they had known hepatic or renal disease that might alter the pharmacokinetics of naloxone, they were not developmentally able to rate the severity of their pain or pruritus, or they had previously been enrolled in this pilot study.

Written informed consent was obtained from parents, and assent was obtained from patients 10 years of age or older. The study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center Dallas.

Protocol

Continuous infusion morphine was initiated at 0.05 mg/kg·hr, and patients self-administered additional doses of 0.03 mg/kg morphine as needed every 20 min according to our institutional management protocol. Thereafter, morphine dosing was adjusted by the patient's care team as clinically needed. Ibuprofen was administered by mouth at 10 mg/kg every 4 hr. Diphenhydramine and hydroxyzine were available as needed for itching. Ondansetron and promethazine were available as needed for nausea.

Naloxone was administered using a separate pump, but infused through the same intravenous catheter. After enrolling 12 patients who received naloxone at 0.25 mcg/kg·hr (low dose), a planned interim analysis revealed that pruritus was still prominent and no significant adverse events had occurred. Six further patients were then treated with a continuous infusion of naloxone at 1 mcg/kg·hr (high dose). The naloxone infusion was discontinued when the continuous infusion of morphine was stopped.

Definitions and measurements

Demographic information (age, sex, race, sickle cell disease genotype, and the number of prior hospitalizations for painful crisis for which continuous morphine infusion was administered) was extracted from our institution's clinical sickle cell database [23] and individual medical records. The total daily doses of opioid analgesics (mg/kg of morphine or morphine equivalents of other opioids) and nonsteroidal anti-inflammatory agents were obtained from the medical record. The number of doses of “rescue” medication each subject received for pruritus (diphenhydramine or hydroxyzine) or nausea/vomiting (promethazine or ondansetron) was recorded.

Bedside pain scores collected by nursing staff and daily research team visits were used to measure pain in five ways. First, a “24-hr average pain score”, was computed, which was the mean of each patient's self-reported scores of severity of pain during every 24-hr interval of hospitalization. For this calculation, pain scores were obtained and recorded at 4-hr intervals by clinical nursing staff using the FACES scale (0–5, with 0 representing absence of symptoms and five representing “worst possible pain”) [24,25]. The second pain assessment was structured and obtained by the core study team every morning. Patients were asked to rate their pain “now” and the “worst pain in previous 24 hr” using the FACES scale (subsequently referred to as “team FACES pain now” and “team FACES pain worst”) and also using a visual analog scale (subsequently “team VAS pain now” and “team VAS pain worst”). Visual analog scale (VAS) scores were determined by the location of a patient made mark on a 10 cm line with “no pain at all” and “worst pain you can imagine” on opposite ends. The distance was measured and converted to a score for analysis.

Two methods were used to quantify itching. First, a quantitative pruritus score, based on an adaptation for pruritus of the McGill Pain Questionnaire which has been validated in patients with uremia [26,27], was obtained by the core research team daily. Patients rated their itching on a 0–5 scale, with 0 as no itching, 1 as occasional itching, 2 as itching sometimes, 3 as itching like a bad bug bite, 4 as very bad itching, and 5 as the worst itching one could imagine. Itching was assessed at the time of the core team's visit “now” and the “worst within the previous 24 hr” (subsequently “team itch now” and “team itch worst”). Second, patients were also asked to assess their itching by marking a 100-mm visual analog scale assessing their current itching (“team VAS itch now”) and worst itching within the previous 24 hr (“team VAS itch worst”).

Patients who were previously admitted for painful events during which they received continuous infusion morphine were asked daily to rate their degree of pain, nausea, and pruritus during the current admission (concomitant morphine-naloxone) compared with their recollection of previous admissions (morphine only). This was recorded using a three-point comparative scale (current vs. past admission): symptoms were the same; symptoms were better; and symptoms were worse.

Data analysis

Most patients (N = 12) were admitted and started on continuous infusion morphine and naloxone in the evening. For standardization, day 1 was considered the first full day of hospitalization, starting at 7:00 am. Data are presented for the first 2 full days of hospitalization only, because many subjects (N = 8) had been discharged or were no longer receiving a continuous infusion of morphine by their third day of hospitalization. Because the data were not normally distributed, all results are expressed as medians and interquartile ranges (25th–75th percentiles). Statistical comparisons were made between the two dosing groups using Mann-Whitney U analysis. Spearman's Rho was used to assess correlations between selected variables [16].