PCA analgesia for children with chemotherapy-related mucositis: a double-blind randomized comparison of morphine and pethidine

ARTICLE

bdc.2011.1313

Auteur(s) : Caroline Oudot¹ oudot_caroline@yahoo.fr, Agnès Laplanche², Daniel Orbach³, François Pein⁴, Jean Michon³, Graziella Raimondo⁴, Évelyne Pichard-Leandri⁵, Caroline Allonier², Sylviane Iacobelli², Anne Pagnier⁶, Sylvie Demirdjian⁷, Olivier Hartmann^4,†

¹ Hôpital Mère-Enfant, Pediatric Oncology, 8, rue Dominique-Larrey, 87042 Limoges Cedex, France

² Institut Gustave-Roussy, Public Health Department, 39, rue Camille-Desmoulins, 94800 Villejuif, France

³ Institut Curie, Pediatric Oncology, 26, rue Ulm, 75005 Paris, France

⁴ Institut Gustave-Roussy, Pediatric Oncology, 39, rue Camille-Desmoulins, 94800 Villejuif, France

⁵ Institut Gustave-Roussy, Analgesia Department, 39, rue Camille-Desmoulins, 94800 Villejuif, France

⁶ CHU de Grenoble, Clinique de pédiatrie, Pediatric Oncology, BP 217, 38043 Grenoble Cedex 09, France

⁷ Institut Gustave-Roussy, Clinical Pharmacy Department, 39, rue Camille-Desmoulins, 94800 Villejuif, France

Reprint: C. Oudot

^† Deceased author.

Introduction

Oropharyngeal mucositis is a common, painful toxic side effect of numerous chemotherapies, be they conventional such as those used in B lymphoma induction therapies, or bone or soft-tissue sarcoma chemotherapies or high-dose regimens with peripheral blood stem cell support, such as busulfan-melphalan or busulfan-thiotepa [1-3]. Severe mucositis always requires hospitalization for the administration of intensive analgesic treatment and to provide nutritional parenteral support to children who are unable to swallow. Mucositis is a dose-limiting factor in some drug regimens, because of significant morbidity and impaired nutrition [4, 5].

With patient-controlled analgesia (PCA), patients control drug administration themselves. Several studies have shown that PCA using an opium-based bolus resulted in at least as good pain control as staff-decided administration, but opioid consumption was lower, therefore resulting in fewer side effects [6-11]. Certain factors such as the patient's age, capacity to use a PCA pump and cognitive ability to evaluate pain restrict the use of this technique. However PCA can be used extensively in children over five-year of age [12, 13].

Nowadays, morphine is the standard opium-based analgesic [14, 15]. Several other compounds have been used to alleviate pain in children: alfentanil, hydromorphone, sufentanil, fentanyl or pethidine [16-19]. Morphine is a very efficient, well-known analgesic, whose dose-effect relationship is virtually always proportional. Side effects are common and can be severe. Digestive disorders predominate: constipation can be severe, resulting in paralytic ileus and may be problematic in children with hematological aplasia. This constipation can be responsible for a third sector of stercoral stasis. Then, there is a risk of bacterial or fungal proliferation, and therefore a risk of septicemia translocating from the intestinal tract. Other frequent side effects are nausea, vomiting, acute urine retention, pruritis, rashes, drowsiness, or even respiratory collapse. Pethidine or meperidine (Dolosal^®) is another opioid, supposedly slightly less efficient than morphine, which exhibits a threshold effect [15, 20-27]. Doses exceeding 10 or 12 mg/kg per day do not increase the analgesic effect. Its toxicity, which is mainly neurological, differs from that of morphine. Seizures may be due to pethidine metabolites as norpethidine and can be prevented with clonazepam (Rivotril^®).

We report here the results of a randomized double-blind trial comparing the efficacy and toxicity of morphine and pethidine in children requiring an analgesic treatment for chemotherapy-induced mucositis.

Methods and patients

Eligibility criteria

The protocol was approved by the Ethics Committee for the protection of persons undergoing biomedical research in Bicêtre Hospital and the study was conducted in two French comprehensive cancer centers: Institut Gustave-Roussy (Villejuif) and Institut Curie (Paris). Children were enrolled from March 2000 to November 2003 if they were aged five or older, weighed more than 20 kg and were suffering from intense pain due to chemotherapy-related oropharyngeal mucositis requiring opioid analgesia during hospitalization. All parents of minors and patients older than 18 years gave their written informed consent before randomization. Non-inclusion criteria were: failure to understand the PCA administration protocol and/or pain measurement with a Visual Analogue Scale (VAS); on-going opioid medication and/or clonazepam medication (if the total dose exceeded 0.1 mg/kg per day). WHO mucositis scoring was registered at inclusion [28] and patient's general status was evaluated by the Lansky's et al. score [29].

Randomization and treatment

A pharmacist prepared a set of 100 mL opioid solutions, containing either morphine chlorhydrate (1 mg/1 ml) or pethidine chlorhydrate (5 mg/1 ml), which were, administered double blindly. We chose a 1-mg morphine: 5 mg pethidine ratio. Children were randomly assigned to receive either morphine or pethidine and the randomization procedure was stratified by treatment center. The code was broken once all patients had completed the trial.

PCA pumps were used to deliver opioids intravenously. A bolus charging dose of 0.1 ml/kg was first delivered for rapid pain control. If pain was not controlled after 15 minutes, another dose of 0.025 ml/kg was used and repeated when necessary (maximum total of 0.15 ml/kg). Then, the bolus dose was 0.015 ml/kg with a lockout time at 15 minutes, and a maximum of eight bolus doses per four-hour period. Pain was measured with a VAS during the whole duration of treatment with PCA. The bolus dose was then adapted to the intensity of pain. If VAS was above 70/100 once or above 50/100 for a duration of three hours, the bolus dose was increased to a second level (0.025 ml/kg); to a third one (0.035 ml/kg); and then to a fourth level (0.04 ml/kg). If pain was not controlled with a bolus dose of 0.04 ml/kg, treatment was considered to have failed and another analgesic treatment as fentanyl (Durogesic^®) could be prescribed.

In order to prevent the neurological toxicity of the pethidine, each patient received 0.02 mg/kg per day of clonazepam as continuous infusion. Any other analgesic drug was forbidden except level 1 analgesic and in case of failure of PCA treatment.

Patients received systematic chlorhexidine-based mouthwashes without analgesic agent incorporated, four to six times a day according to local practices. Only additional oral or intravenous paracetamol according to fever was allowed.

End-points and follow-up

Pain intensity was measured with a VAS four times a day (at 8 a.m., 12 a.m., 4 p.m. and 8 p.m.). The primary end-point was the Mean Pain Score (MPS): mean of these four daily pain measures over the four-day period (day 2 to day 5). Secondary end point was to compare adverse events. Nurses recorded the total amount of PCA analgesics delivered from day 1 to day 5 of PCA as well as the occurrence of side effects: constipation, vomiting, nausea, consciousness disorders, drowsiness, pruritis or respiratory disorders.

Statistical analysis

The size of the trial was based on the primary end-point, namely the day 2-5 MPS using the VAS. It was estimated that at least 30 patients per group (i.e., a total of 60 subjects) would be necessary to demonstrate a minimum difference of 20 in the means of the MPS of the two groups (type I error = 5%, power = 95%, bilateral test) [28]. Results are expressed as percentages or medians (range). The two groups were compared using non-parametric tests (Kruskal-Wallis). All tests were two-sided.

Results

From March 2000 to November 2003, 35 children were randomly and double blindly assigned to the morphine group (18 patients) or the pethidine group (17 patients), after which accrual was stopped for difficulties of recruitment. Table 1 shows the main initial clinical characteristics by group. The median (range) interval between the beginning of last chemotherapy course and inclusion in the study was 10 (4-15) and 12 (5-74) days in the morphine and pethidine groups, respectively.

Table 1 Initial characteristics of study patients.

NHL: non-Hodgkin's lymphoma; HL: Hodgkin's lymphoma; PNET: primitive neuro-ectodermal tumor; CBV: cyclophosphamide, BCNU, VP16.

Five children (four in the morphine group and one in the pethidine group) did not receive any PCA therapy: three were wrongly included (mucositis not requiring opioid analgesia), one refused the PCA treatment after randomization, and the pump was defective in the last case.

Among patients receiving at least one day of PCA, the median (range) number of days of PCA therapy was 6.5 (2-15) and 5.5 (1-14) in the morphine and pethidine groups respectively (table 2). Comparisons were therefore performed between 14 (morphine group) and 16 patients (pethidine group). The fourth PCA level was reached in three and four cases in the morphine and pethidine groups respectively. Ten children received less than five days of PCA (four in the morphine group and six in the pethidine group) because of early failure to control pain (three and four patients, respectively) or mucositis resolved (one and two patients, respectively) (table 2). At the end of the procedure, treatment had failed in 10 cases, five in each group.

Table 2 Characteristics of the opioid PCA treatment.

^a Among the 14 (morphine arm) and 16 (pethidine arm) patients with at least one day of PCA.

As day 2-5 MPS could only be assessed on patients who received more than one day of PCA therapy, 4 children in the morphine group and 2 children in the pethine group were not included in the analysis (table 3). The medians (range) day 2-5 MPS were 44 (13-72) in the morphine group and 33 (3-89) in the pethidine group, P = 0.32. The total amount of opioid analgesics delivered was also not different (P = 0.53) (table 3).

Table 3 Pain control and consumption of analgesics (29 patients).

Global tolerance of both treatments was quite good. Table 4 details the maximum toxicity observed daily for each patient during the first five days of PCA therapy. Forty-three percent of the patients in the morphine group experienced vomiting more than three times a day, versus 13% in the pethidine group; the difference was not significant (P = 0.11). The occurrence of respiratory toxicity (O₂ saturation ≤ 95%), pruritis, drowsiness, hot flash sensation or psychological disorders, although always slightly more frequent in the morphine group, was not statistically different. Constipation requiring specific treatment was significantly higher in the morphine group (43%) than in the pethidine group (0%, P = 0.006).

Table 4 Frequency of side effects documented from day 1 to day 5.

Discussion

In the literature, PCA therapy has been used to treat pain related to chemotherapy-induced mucositis in children or adults receiving autologous, allogeneic bone marrow or peripheral blood stem cell transplantation, according to the malignancy under treatment [6, 7, 9, 12, 14, 17, 31-34]. Similarly, the children included in our trial presented mucositis induced by conventional chemotherapies or high-dose regimens with peripheral stem cell support. PCA therapy has also been used for children suffering from vaso-occlusive crisis associated with sickle cell disease or for post-operative analgesia [15, 18, 21, 35, 36].

Double-blind evaluation allows the doctor, the nurse, or the patient to interpret drug efficacy less subjectively and to appraise its potential unwanted side effects. Monitoring drug efficacy and toxicity remains objective throughout the duration of the treatment under study. The statistical results of such a study are therefore reliable, even if they do not reach statistical significance [37]. In our protocol, accrual was stopped before including the 60 patients deemed necessary to demonstrate a difference between the two groups, because patient's accrual was difficult and too slow. Patients had to be older than five to be enrolled in the trial but many intensive chemotherapy regimens were administered to younger children in the two participating centers. Moreover, in keeping with good statistical practice, each patient could only be included once in this trial. In addition, some adolescents refused to participate in this trial. Theses limitations make of course our results debatable.

No consensus exists for the exact equianalgesic dose. In adult literature, pethidine: morphine ratio used ranged from 1:7.5 [23] to 1:10 or 12 [21, 24-26]. In paediatric population the exact ratio is not well-known. Moreover, this ratio seems to be dependent on the PCA prescription as well as on the relative potency. For example, Plummer et al. found that the ratio can vary between 6 to 20.3 according to the dose of bolus used [15]. In this study, 1:5 ratio was used to avoid overdosage risk. Furthermore, our results validate retrospectively the pethidine:morphine (1:5) ratio with no apparent differences in opioid consumption between the two arms with the same pain relief. It is possible that more pethidine administration may possibly lead to more side effects but in terms of equianalgesia, this overdosage does not seem to be necessary in this experience.

In this study, level 1 analgesic administration was not strictly registered as all patients with fever during neutropenia received systematic intravenous administration of paracetamol as antipyretic agent. Level of pain related to severe chemotherapy-induced-mucositis is very important in pediatric population [13]. This may explain the high rate of failure in this study: 10 among 35 patients. All experienced teams agree that it is extremely difficult to minimize or prevent chemotherapy-induced mucositis and to avoid its complications (primarily pain but also infectious complications) [4, 38-41]. Nowadays, oral hygiene care and chlorhexidine-based mouthwashes are among the most commonly prescribed treatments, often following chemotherapy-induced mucositis, which can be more or less severe [42, 43]. However, the efficacy of such treatments has never been proven compared to a placebo, salt and soda or plain water [42, 44-46]. Chlorhexidine-based mouthwashes associated with topical hematopoietic growth factors (GM-CSF directly mixed with the mouthwash) [47, 48], other growth factors [49, 50], topical vitamin E [51], sucralfate [52] or homeopathic medication [53] may shorten the duration of the mucositis, or even prevent it. Reducing the dose of chemotherapy causing mucositis, in keeping with patient tolerance is an option, but there is a risk of decreasing drug efficacy against the malignant disease.

When mucositis occurs, curative methods can be used to control mucositis-related pain. Morphine-based mouthwashes (diluted morphine syrups) are efficient in obtaining local, direct and fast pain relief. They also tend to decrease intravenous analgesic requirements [54-57]. However, major analgesics are most often necessary and unavoidable (level 3 in the WHO classification) in case of severe chemotherapy-induced mucositis. Depending on the underlying disease affecting the child, his/her age or ability to press a button, it may be advisable either to use a PCA pump, or another pump controlled by the medical staff to administer analgesics. It is then possible to choose between continuous administration of analgesics associated with bolus doses, or bolus doses alone. The main problem of continuous administration is the risk of overdosing in adults and children [6, 7, 9, 11, 33, 58, 59]. Some studies have demonstrated that bolus doses without a background infusion are as efficient as continuous infusion and with the added advantage of significantly fewer side effects [7, 33, 58]. Morphine versus pethidine, administered in PCA or in a continuous infusion, has been compared in clinical studies following surgery or bone marrow transplantation in children or adults. Treatment efficacy was similar in two studies [21, 60] and morphine appeared to be more efficient in two others: morphine allowed better control of pain upon movement after surgery [24, 61].

Several side effects – which are potentially dangerous for the patient – may occur making it sometimes extremely difficult to prescribe some of these analgesics. These side effects vary in nature and intensity according to the drug. Previous studies comparing the side effects of morphine and pethidine resulted in unclear conclusions: in two studies, no difference was demonstrated in terms of side effects [60, 61]. Conversely, pruritis and drowsiness appeared more frequently following the use of morphine in two other studies [21, 24]. The present study demonstrates that gastro-intestinal disorders seem to occur more frequently following morphine than after pethidine therapy.

In this population, despite a low equianalgesic ratio chosen (1:5), pethidine was not inferior to morphine in terms of analgesia, although a larger study is warranted to demonstrate whether these two drugs differ in terms of pain relief in this indication. Despite the low statistical power of our study, the efficacy/toxicity ratio is better with pethidine in this indication. Therefore, it may appear justified to administer pethidine (Dolosal^®) as first-line treatment to alleviate mucositis-related pain.

Conclusion

This prospective double-blind randomized study using PCA suggests that pethidine is at least not inferior than morphine in controlling pain related to chemotherapy-induced mucositis in children. Furthermore, patients experienced significantly fewer gastro-intestinal side effects. Until now, morphine is considered the standard level 3 analgesic. Pethidine could can be discussed as an alternative when a level 3 drug for the treatment of pain related to severe mucositis is required especially in children who often suffer from digestive disorders or in whom there is a high risk of septicemia translocating from the intestinal tract.

Acknowledgements

This work was supported by a grant from “Programme hospitalier de recherche clinique”, contrat PHRC 1999 and by a grant from the Fondation de France, contrat 2000. Doctor C. Oudot was recipient of scholarship from the Fondation de France/Fédération nationale des centres de lutte contre le cancer. We thank L. Saint-Ange and G. Destot for editing.

Conflicts of interests: none.

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