Abstract
Introduction:
Oral mucositis is a painful side effect to chemotherapy. Orally applied opioids may offer analgesia with fewer side effects than systemic opioids.
Methods:
A randomized trial comparing the analgesic effect of a morphine oromucosal solution (OM) to placebo and a positive control group receiving intravenous (IV) morphine as an add-on treatment to morphine patient-controlled analgesia (PCA) in a mixed population of paediatric and adult haematology patients. All patients in the study were equipped with a morphine PCA pump and the participating patients were instructed to use this pump as an escape. Primary outcome was morphine consumption (mg/kg/hour) on the PCA pump. Secondary outcomes included pain intensity difference at rest and when performing oral hygiene, time to first PCA bolus, nutrition intake and adverse events.
Findings:
A total of 60 patients (38 children <18 years) were randomized. Thirty patients were allocated to morphine OM/placebo IV (group MO), 15 patients to placebo OM/morphine IV (group MI) and 15 patients to placebo OM/placebo IV (group P). The median morphine consumption in the MO group (22.7 mcg/kg/hour 95% confidence interval (CI) 19.4–29.4 mcg/kg/hour, p = 0.38) was not significantly different from the placebo group (24.6 mcg/kg/hour 95% CI 16.8–34.4 mcg/kg/hour, p = 0.44) or the MI group (13.7 mcg/kg/hour 95% CI 9.7–37.8 mcg/kg/hour). For the secondary outcomes, the analysis of summed pain intensity difference after the first, third and fourth administrations of study medication indicated a reduction in pain for the MI group compared to the P and MO groups. No serious adverse events were reported.
Conclusion:
The findings indicate that the analgesic effect of peripherally applied morphine is not significantly different from placebo, and parenteral opioids should continue to be the standard of care.
Keywords: Oral mucositis, morphine, peripheral, cancer, children
Introduction
In children and adults diagnosed with cancer treatment–related pain including oral mucositis remains a significant clinical problem with no effective standard of care.1,2 Oral mucositis is a well-known side effect of chemotherapy and presents as erythematous atrophic lesions in the mild form to ulcerative lesions that penetrate the submucosa in more severe cases. 1 Oral mucositis induces considerable pain that often necessitates opioid analgesics, compromises oral intake, increases the need for nasogastric tube and affects quality of life.3,4 Furthermore, oral mucositis and loss of mucosal integrity represent a risk factor for the development of infections. 5
Morphine in oral formulations, intravenous (IV) continuous infusion, or patient-controlled analgesia (PCA), is often used for treatment of painful oral mucositis.6–9 However, systemic opioid analgesics may not provide sufficient pain relief and are commonly associated with side effects including sedation, nausea, vomiting, constipation and pruritus. Systemically administered opioids act at opioid receptors in the central nervous system, but several studies suggest that peripherally applied opioids can produce analgesia by binding to opioid receptors on the peripheral terminals of sensory neurons. 10 Peripheral opioid receptors are believed to be upregulated during inflammatory painful conditions like oral mucositis.10,11 In this randomized controlled clinical trial, we investigate the peripheral analgesic effect of an oromucosal solution (OM) of morphine versus a bolus of IV morphine or placebo as an add-on to morphine PCA therapy in cancer patients with oral mucositis.
Methods
The clinical trial was approved by The Research Ethics for the Capital Region of Denmark (KF 02 312604), The Danish Medicines Agency (EudraCT 2006-003260-53) and registered with the clinical trials registry sponsored by the US National Library of Medicine (http://www.clinicaltrials.gov, study identifier NCT00357942). The study was conducted according to current International Conference on Harmonization and Good Clinical Practice guidelines in accordance with the World Medical Association’s Declaration of Helsinki and monitored by the Good Clinical Research Practice (GCP) Unit of the Copenhagen University Hospital. Written informed parental consent and verbal child assent, when possible, were obtained before inclusion into the study.
Study design and participants
This randomized controlled trial was designed to investigate the effect and safety of morphine OM versus IV morphine or placebo in a mixed population of paediatric and adult cancer patients. Patients were randomized to receive either IV morphine and placebo OM (active comparator); IV sodium chloride/placebo and morphine OM (intervention); or IV sodium chloride/placebo and placebo OM (placebo) as an add-on treatment to morphine PCA. All patients were equipped with a morphine PCA pump and the participating patients were instructed to use this pump as an escape. Study medication was administered at 3-hour intervals with three to four planned consecutive administrations. We included 60 patients admitted to paediatric haematology/oncology ward or the hematopoietic stem-cell transplantation (HSCT) units at the Copenhagen University Hospital Rigshospitalet from December 2007 to December 2013. Enrolment was initiated at the paediatric wards enrolling children 0–17 years but expanded to enrol adults at the adult HSCT ward for the conduction of the study in a timely manner. No age-related differences in the pathophysiology of oral mucositis were expected. Also, to increase enrolment, the clinical trial protocol was approved by the Swedish authorities in 2008 (Regional Ethical Review Board in Lund (Dnr. 487/2007), the Swedish Medicinal Products Agency (EudraCT 2006-003260-53)), but enrolment of patients at Lund University Hospital was terminated early in 2011 since no patients were enrolled into the study at that time. Inclusion criteria included treatment with chemotherapy for a cancer disease; ability to speak or understand Danish; oral mucositis (World Health Organization Scale Grade 1 or more), 12 oral pain intensity score ⩾3 at rest or ⩾5 during activity (oral hygiene or eating) despite analgesic treatment and negative pregnancy test, if relevance. Pain intensity was measured using validated age-appropriate pain scales, that is, in preverbal children (approximately 4 years of age and below) by the FLACC (face, leg, activity, cry, consolability) scale which consists of five behavioural components that provide a pain score ranging from 0 (no pain) to 10 (worst pain);13,14 for children of approximately 5–8 years, the Wong–Baker Faces Pain Rating Scale with six faces was used and a numerical value from 0 to 10 (0–2–4–6–8–10) was assigned to each face.14–16 For children above 8 years and adults, the Visual Analogue Scale (VAS) was applied.14,17
Exclusion criteria included known allergies to morphine or the excipients in the study medication. The protocol did not specify opioids for treatment of pharyngeal pain before meeting the inclusion criterion for oral pain intensity and enrolment into the trial as an exclusion criterion. However, patients with long-term opioid use were not considered for the trial.
The study medication contained IV solution of morphine hydrochloride 2 mg/mL or placebo (isotonic sodium chloride) and OM of morphine 2 mg/mL, pH 5 or placebo (The Capital Region Pharmacy, Herlev, Denmark). The IV solution of morphine or placebo was diluted to morphine 1 mg/mL and administered as a bolus of morphine of 50 mcg/kg every 3 hour by pump (CADD legacy 6500; Smiths Medical, Minneapolis, MN, USA). The OMs contained the artificial sweeteners xylitol and potassium acesulfame to mask the bitter taste of morphine. A plastic syringe with a custom-made, Luer-Lock, 360-degree atomizing spray device (CODAN Medical, Rødby, Denmark), was used to administer a dose of the OM corresponding to 50 mcg/kg every 3 hour and patients were encouraged to keep the solution in the mouth 10 seconds before spitting it out. The dose of morphine OM was based on a dose-finding study with the same formulation. 18
To standardize non-opioid treatment, all patients received acetaminophen 10–15 mg/kg orally or intravenously according to standard of care at the participating wards. Due to ethical considerations, all patients had a morphine PCA/NCA (nurse-controlled analgesia) pump (CADD legacy PCA 6300; Smiths Medical, for paediatric patients and Baxter APII PCA infusion pump; Baxter, Deerfield, IL, USA, for adult patients) activated on demand (0.025 mg/kg of morphine on demand, lockout period of 8 minutes) as rescue medication during the study. The type of PCA/NCA pump used for paediatric patients recorded the time of first PCA bolus. This information was, however, not available from the PCA pump used in adult patients. Patients were monitored according to clinical guidelines at the participating departments. The Pain Service on daily rounds at the hospital identified eligible patients.
Randomization and masking
Patients were allocated according to a computer-generated allocation list (The Capital Region Pharmacy, Herlev, Denmark). Patients were randomly assigned 2:1 (morphine OM/placebo IV: 1 and placebo OM/placebo IV: 1 (placebo OM/morphine IV)) stratified for pain assessment tool (VAS/FLACC) and HSCT with the aim to limit baseline imbalance for these variables. Block size in randomization was 12 patients. A consecutive randomization number was assigned and the corresponding sequentially numbered study medication package containing morphine OM/placebo IV, placebo OM/morphine IV or OM placebo/placebo IV was selected. The OM morphine and OM placebo bottles were similar, containing clear liquid and were packed and labelled with randomization number (The Capital Region Pharmacy, Herlev, Denmark). This was similar for the IV morphine and IV placebo vials. Primary investigator for emergency unblinding kept opaque envelopes; however, no patients were unblinded. The trial was masked to all participants, investigators and healthcare professionals.
Outcomes
Primary outcome was morphine consumption on the PCA/NCA pump (mcg/kg/hour). Secondary outcomes included pain intensity score at rest (pain intensity scores were obtained before administration of the study drug and 30 minutes after), pain intensity score while performing oral hygiene (pain intensity scores obtained before oral hygiene and during oral hygiene), time to first PCA/NCA bolus (data from pump), nutrition intake (baseline and end of inclusion) and adverse events including frequency and severity of systemic opioid adverse events in terms of sedation (the University of Michigan Sedation Scale (UMMS)), 19 obstipation (common toxicity criteria (CTC) toxicity scale for obstipation), 19 pruritus (CTC toxicity scale for pruritus), 19 vomiting (CTC toxicity scale for vomiting), 19 and nausea (yes/no). Any adverse events were recorded 24 hours post dose.
Statistical analyses
The sample size calculation was based on a clinical meaningful difference in morphine consumption of 30%. A sample size of 60 was calculated based on 80% power to detect a mean difference of 30% in primary outcome with a significance level of 5% (GraphPad StatMate version 1.01).
Due to the length of the data collection period, an interim analysis on primary outcome was performed after randomization of 30 patients without unmasking the allocation groups to sponsor, investigator and sub-investigators. The interim analysis was performed by an independent statistician (Biostatistics, University of Copenhagen, Denmark) and based on the analysis, he was asked to recommend continue or to stop the trial. The recommendation was to continue the trial. The additional funding for the statistical analyses in the trial was delayed, causing a considerable delay in the finalization of the study. The results for primary and secondary outcomes were analysed based on the intention-to-treat population. For the descriptive analyses, Fischer’s exact test for count data or Kruskal–Wallis rank sum test was used, as appropriate.
For the primary outcome, morphine consumption on PCA/NCA pump conditions for linearity was not applicable, and thus, analysis was done by quantile regression. The secondary outcome, pain intensity, was measured before and 30-minute administration of study medication at three to four consecutive administrations every 3 hour. Pain intensity differences were calculated as ‘Pain score after’ – ‘pain score before’, and the time adjusted pain intensity differences were analysed using the analysis of covariance (ANCOVA) with treatment group as fixed factor and baseline pain intensity score as covariate. Analyses were performed after the first, second, third and fourth administrations of study medication, and a two-sided Dunnett’s test was applied to adjust for multiple comparisons. Secondary outcomes including time to first PCA/NCA bolus, nutritional intake and adverse events were summarized. Systemic opioid-related side effects were compared between groups with the Kruskal–Wallis rank sum test and within groups (baseline vs end of trial) with McNemar’s test. A p-value of 0.05 was considered the threshold for statistical significance.
Results
A total of 60 patients were randomized, 30 patients were allocated to morphine OM/placebo IV, 15 patients to placebo OM/morphine IV (active comparator) and 15 patients to placebo OM/placebo IV (placebo group). In the intervention group, two dropouts were reported due to side effects and one withdrawal due to lack of analgesic effect. In the active comparator group as well as the placebo group, one patient dropout due to side effects was reported in each group (Supplemental Figure S1).
Characteristics of the participating patients by group are listed in Table 1. There was no statistically significant imbalance between groups (Table 1).
Table 1.
Patient characteristics.
| Characteristics | Group MO (n = 30) | Group MI (n = 15) | Group P (n = 15) | p-value |
|---|---|---|---|---|
| Age, years, median (IQR) | 16.0 (8.0–26.0) | 15.0 (10.0–23.0) | 13.0 (10.5–33.5) | 0.91 |
| Weight, kg, mean (SD) | 54.9 (28.6) | 49.2 (19.0) | 54.2 (24.8) | 0.81 |
| Gender, % (n) | 0,35 | |||
| Female | 23% (7) | 47% (7) | 27% (4) | |
| Male | 77% (23) | 53% (8) | 73% (11) | |
| Patients, % (n) | 0.88 | |||
| <18 years | 60% (18) | 67% (10) | 67% (10) | |
| ⩾18 years | 40% (12) | 33% (5) | 33% (5) | |
| Medical diagnosis, % (n) | ||||
| HSCT | 43% (13) | 47% (7) | 47% (7) | 1.00 |
| Non-HSCT | 53% (16) | 53% (8) | 53% (8) | |
| Leukaemia | 17% (5) | 7% (1) | 20% (3) | |
| Lymphoma | 30% (9) | 17% (5) | 0% (0) | |
| Sarcoma | 7% (2) | 0% (0) | 20% (3) | |
| Carcinoma | 0% (0) | 0% (0) | 13% (2) | |
| Blastoma | 3% (1) | 13% (2) | 0% (0) | |
| Neutropenia (neutrophils <0.5) | 87% (26) | 100% (15) | 87% (13) | 0.41 |
| Oral mucositis grade, % (n) | 0.71 | |||
| 1 | 10% (3) | 13% (2) | 0% (0) | |
| 2 | 10% (3) | 20% (3) | 27% (4) | |
| 3 | 50% (15) | 40% (6) | 47% (7) | |
| 4 | 30% (9) | 27% (4) | 27% (4) | |
| Pain intensity assessment scale, number of patients, % (n) | 0.83 | |||
| VAS/modified VAS | 80% (24) | 80% (12) | 80% (12) | |
| FLACC | 20% (6) | 20% (3) | 20% (3) | |
| Pain intensity score, median (IQR) | 6 (4.0–7.0) | 5 (4.0–7.0) | 5 (4.0–6.0) | 0.57 |
| Other than oral pain, % (n) | 0.57 | |||
| Abdominal | 3% (1) | 13% (2) | 0% (0) | |
| Pharyngeal | 73% (22) | 73% (11) | 80% (12) | |
| Other | 3% (1) | 7% (1) | 0% (0) | |
| Dysphagia grade, median (IQR) | 3 (2.0–3.0) | 2 (1.5–3.0) | 3 (2.5–3.0) | 0.24 |
| Herpes simplex virus, blood, % (n) | 0.30 | |||
| Positive | 33% (10) | 20% (3) | 20% (3) | |
| Negative | 53% (16) | 73% (11) | 47% (7) | |
| ND | 13% (4) | 6% (1) | 33% (5) | |
SD: standard deviation; MO: morphine oromucosal; MI: morphine intravenous; P: placebo; HSCT: hematopoietic stem-cell transplantation; VAS: Visual Analogue Scale; FLACC: face, leg, activity, cry, consolability; IQR: interquartile range; ND: not done.
Analgesic effect
For the primary outcome morphine consumption on PCA/NCA pump (mcg/kg/hour), a box plot is shown in Figure 1. Analysis of morphine consumption by quantile regression indicates that the median morphine consumption on PCA/NCA pump in the morphine IV group 13.7 mcg/kg/hour (95% confidence interval (CI) 9.7–37.8 mcg/kg/hour) is not statistically significant different from the placebo (P) group 24.6 mcg/kg/hour (95% CI 16.8–34.4 mcg/kg/hour, p = 0.44) or the morphine oromucosal (MO) group 22.7 mcg/kg/hour (95% CI 19.4–29.4 mcg/kg/hour, p = 0.38). Furthermore, no statistically significant difference between groups MO and P was found (p = 0.82). Similar results were found with unadjusted and adjusted analysis. The results for the secondary outcomes are listed in Table 2. The summed pain intensity difference after the first (MO vs morphine intravenous (MI): −0.57 (95% CI −1.09 to −0.06)), the third (MO vs MI: −1.40 (95% CI −2.45 to −0.35)) and the fourth (MO vs MI: −2.59 (95% CI 4.77 to −0.42)) administrations of study medication was statistically significant, indicating that the positive control group MI had a significant decrease in pain intensity compared to groups P and MO. The median pain intensity difference for the groups related to dose 1, 2, 3 and 4 are presented in Supplemental Figure S2.
Figure 1.
Box plot for morphine consumption (mcg/kg/hour): MI (morphine intravenous), MO (morphine oromucosal) and P (placebo) groups.
Table 2.
Secondary outcomes.
| Group MO (n = 30) | Group MI (n = 15) | Group P (n = 15) | p-value | |
|---|---|---|---|---|
| SPID 1. Dose (n = 60), median (IQR) | −0.5 (−1.0 to −0.23) | −1.0 (−1.5 to −0.8) | −0.75 (−1.2 to −0.13) | MO vs MI: 0.0276* MO vs P: 0.8469 |
| SPID 1.+2. Dose (n = 56), median (IQR) | −1.1 (−2.1 to −0.5) | −1.9 (−2.2 to −1.5) | −1.3 (−1.8 to −0.5) | MO vs MI: 0.0693 MO vs P: 0.9691 |
| SPID 1.+2.+3. Dose (n = 56), median (IQR) | −1.2 (−2.1 to −0.8) | −2.7 (−3.5 to −2.0) | −1.3 (−2.1 to −0.4) | MO vs MI: 0.00719* MO vs P: 0.98449 |
| SPID 1.+2.+3.+4. Dose (n = 31), median (IQR) | −1.4 (−2.1 to −0.8) | −3.5 (−4.8 to −2.8) | −2.0 (−2.7 to −1.0) | MO vs MI: 0.0180* MO vs P: 0.9310 |
| Patients performing oral hygiene during project period, % (number) | 53% (16) | 27% (4) | 40% (6) | 0.24 |
| PID oral hygiene, median (IQR) | 1.8 (0.0–4.3) | 1.0 (0.0–1.0) | 0.0 (0.0–1.0) | 0.51 |
| Patients with data for time to first PCA/NCA bolus, % (number) | 67% (20) | 60% (9) | 67% (10) | |
| Time to first PCA/NCA bolus, hour, median (IQR) | 0.51 (0.22–1.14) | 0.88 (0.38–2.58) | 0.52 (0.22–0.57) | 0.46 |
| Nutrition, baseline | ||||
| Can drink | 50% (15) | 67% (10) | 33% (5) | 0.19 |
| Can eat | 10% (3) | 13% (2) | 13% (2) | 1.0 |
| Need NGT feeding | 47% (14) | 13% (2) | 13% (2) | 0.03* |
| Need parenteral nutrition | 43% (13) | 47% (7) | 60% (9) | 0.62 |
| Nutrition, end of trial | ||||
| Can drink | 80% (24) | 80% (12) | 73% (11) | 0.92 |
| Can eat | 33% (10) | 33% (5) | 47% (7) | 0.88 |
| Need NGT feeding | 43% (13) | 13% (2) | 20% (3) | 0.10 |
| Need parenteral nutrition | 50% (15) | 67% (10) | 53% (8) | 0.62 |
MO: morphine oromucosal; MI: morphine intravenous; P: placebo; SPID: summed pain intensity difference; PID: pain intensity difference; NGT: nasogastric tube; n: number; IQR: interquartile range; * indicating statistical significance.
Safety and adverse events
No serious adverse events were reported. The frequency of reported adverse events was similar in the intervention group MO (47%) and in the positive control group (47%) versus 20% in the placebo group. However, the nature of the adverse events differed. The reported adverse events are listed in Table 3. Observation of systemic opioid-related side effects indicated a decrease in sedation for the groups MO and P at the end of trial measurement compared to baseline; however, the difference was not statistically significant (Table 4).
Table 3.
Frequency of adverse events.
| Symptoms | Group MO (N = 30) | Group MI (N = 15) | Group P (N = 15) |
|---|---|---|---|
| Local irritation of oral mucosa | 9 | 3 | 2 |
| Vomiting | 1 | 1 | 1 |
| Headache | 1 | – | – |
| Fever | 1 | – | – |
| Itching | 1 | 1 | – |
| Unpleasant taste | 1 | – | – |
| Dizziness | – | 1 | – |
| Somnolence | – | 1 | – |
MO: morphine oromucosal; MI: morphine intravenous.
Table 4.
Systemic opioid-related side effects.
| Symptoms | Group MO (n = 30) | Group MI (n = 15) | Group P (n = 15) | p-value |
|---|---|---|---|---|
| Baseline, before trial | ||||
| Sedation, % (n) | 33% (10) | 13% (2) | 27% (4) | 0.35 |
| Grade, median (range) | 0 (0–2) | 0 (0–1) | 0 (0–1) | |
| Constipation, % (n) | 37% (11) | 40% (6) | 20% (3) | 0.44 |
| Grade, median (range) | 0 (0–3) | 0 (0–2) | 0 (0–2) | |
| Pruritus, % (n) | 40% (12) | 53% (8) | 47% (7) | 0.80 |
| Grade, median (range) | 0 (0–2) | 1 (0–2) | 0 (0–2) | |
| Vomiting, % (n) | 33% (10) | 33% (5) | 47% (7) | 0.51 |
| Grade, median (range) | 0 (0–3) | 0 (0–2) | 0 (0–3) | |
| Nausea, % (n) | 20% (6) | 13% (2) | 27% (4) | 0.42 |
| End of trial | ||||
| Sedation, % (n) | 17% (5) | 40% (6) | 20% (3) | 0.12 |
| Grade, median (range) | 0 (0–2) | 0 (0–2) | 0 (0–1) | |
| p-value* | 0.18 | 0.13 | 1.00 | |
| Constipation, % (n) | 40% (12) | 40% (6) | 20% (3) | 0.38 |
| Grade, median (range) | 0 (0–2) | 0 (0–2) | 0 (0–2) | |
| p-value* | 1.0 | 1.0 | 1.0 | |
| Pruritus, % (n) | 43% (13) | 73% (11) | 60% (9) | 0.19 |
| Grade, median (range) | 0 (0–2) | 1 (0–2) | 1 (0–1) | |
| p-value* | 1.0 | 0.25 | 0.5 | |
| Vomiting, % (n) | 23% (7) | 33% (5) | 33% (5) | 0.64 |
| Grade, median (range) | 0 (0–2) | 0 (0–2) | 0 (0–2) | |
| p-value* | 0.45 | 1.0 | 0.5 | |
| Nausea, % (n) | 30% (9) | 20% (3) | 20% (3) | 0.79 |
| p-value* | – | – | ||
MO: morphine oromucosal; MI: morphine intravenous; P: placebo.
p-value for comparison of etc. group MO sedation baseline versus sedation at end of trial with McNemar’s test.
Discussion
In this clinical trial, we did not find a statistically significant difference in morphine consumption on PCA/NCA pump between the MO group and the positive control group who received a bolus of MI or the P group. This is in contrast to other trials with local administration of morphine for treatment of oral mucositis pain in adult patients.20–23 A large interindividual difference in morphine consumption within groups was observed, and thus, wide 95% CIs may have contributed to the non-significant finding. A morphine PCA pump was used for rescue medication in this trial, allowing the patient to administer morphine when needed and to adjust the balance between achieving analgesic effect and side effects as sedation. This balance is individual and may contribute to the large interindividual differences in morphine consumption. Furthermore, patients may have received opioid for treatment of other than oral pain, most commonly throat/pharyngeal pain (73–80%), according to standard clinical practice before being eligible for participation in the trial (fulfilling inclusion criteria of VAS or FLACC ⩾3 for oral pain). The pathophysiology of oral mucositis is considered similar in children and adults and is not expected to contribute to the large interindividual differences in morphine consumption. We chose pain intensity as a secondary outcome in the trial and a statistically significant difference in summed pain intensity difference was found for the positive control group receiving a bolus of IV morphine versus placebo at the first, third and fourth administrations of study medication. Thus, pain intensity may be a more reliable outcome than supplemental opioid at PCA/NCA pump for future trials investigating interventions for treatment of oral mucositis pain in a mixed population of paediatric and adult patients. Opioid consumption on PCA pump as primary outcome in paediatric analgesic trials has been suggested, as pain intensity assessment may be difficult across age groups. 24
A solution of morphine for application on the oral mucosa was developed for this clinical trial. Masking the bitter taste of morphine was considered crucial for acceptance in children and was accomplished by an aquatic solution of a xylitol syrup and potassium acesulfame. Because of considerations of dental caries, xylitol syrup in combination with artificial sweeteners was preferred above saccharose syrup. A range of different flavours from peppermint to strawberry were added, but a sweet-tasting solution without additional flavours was chosen because flavour preference varies among children. Ideally, the OM of morphine should have a child-friendly taste, be preservative-free, isotonic and resemble the pH of saliva (pH 5–7) to minimize potential irritation related to oral ulcers. 25 However, prioritizing the taste, a preservative-free, hypertonic solution with a pH of 6 and a child-friendly taste was the final formulation of the morphine OM. The hypertonic solution may have contributed to adverse event reporting of ‘local irritation of oral mucosa’, but also morphine itself may contribute since 30% of patients reported this adverse event in the intervention group with morphine OM while only 13–20% of patients receiving placebo OM. Drug delivery was feasible in the entire paediatric population, including children who cannot gargle a mouthwash, due to the customized spray device.
Paediatric cancer patients and HSCT patients are fragile populations and the small sample size of the study is one of the major limitations. Furthermore, there was substantial heterogenicity for the participating patients with regard to chemotherapy regime; however, baseline pain was moderate (median pain intensity score ⩾5) in all groups as often recommended in acute pain trials. 14 It is unclear if the results of this trial, including paediatric haematology/oncology/HSCT and adult HSCT patients, may be generalized to other cancer patient populations. Other randomized controlled trials indicate a significant analgesic effect of morphine mouthwash versus, for example, magic mouthwash in head and neck cancer patients20–22 and morphine mouthwash has been recommended for treatment of painful oral mucositis in adult cancer patients in recent guidelines.26–28
Currently, there is no effective standard care for management of oral mucositis, but the use of oral care protocols is recommended.29–31 A number of interventions for symptomatic treatment and/or prevention of oral mucositis have been studied often with inconsistent results.32,33 Only one drug, keratinocyte growth factor, has a marketing authorization for the prevention of oral mucositis related to myeloablative therapy and HSCT in adult patients.
According to the peripheral opioid hypothesis, peripheral opioid receptors are believed to be upregulated during inflammatory painful conditions like oral mucositis.10,11 In vitro, the expression of opioid receptors on primary human oral epithelial cells has been demonstrated. 11 Furthermore, oral epithelial cells exposed to the ‘scratch assay’ followed by incubation with morphine showed evidence of a wound healing effect of morphine. 11 Absorption of a drug from ulcerated oral mucosa depends on pH, lipid solubility, drug concentration and contact time. 34 Morphine belongs to the less lipophilic opioids and is ionized at the decreased pH of damaged oral mucosa, which does not facilitate absorption across oral mucosa. 18
In conclusion, the findings in this trial indicate that the analgesic effect of peripherally applied morphine is not significantly different from placebo in a mixed population of paediatric haematology/oncology/HSCT patients and adult HSCT patients. This is in contrary to previous studies in adult head and neck cancer patients.
Supplemental Material
Supplemental material, sj-tiff-1-bjp-10.1177_2049463720975061 for Evaluation of topical morphine for treatment of oral mucositis in cancer patients by Bettina Nygaard Nielsen, Susanne Molin Friis, Kjeld Schmiegelow, Steen Henneberg and Janne Rømsing in British Journal of Pain
Supplemental material, sj-tiff-2-bjp-10.1177_2049463720975061 for Evaluation of topical morphine for treatment of oral mucositis in cancer patients by Bettina Nygaard Nielsen, Susanne Molin Friis, Kjeld Schmiegelow, Steen Henneberg and Janne Rømsing in British Journal of Pain
Acknowledgments
The authors thank the Department of Biostatistics, University of Copenhagen, Denmark professor Per Kragh Andersen, and associate professor Susanne Rosthøj for their help and support with the statistical analyses. Also, the authors thank the patients (and parents) who participated in the trial.
Footnotes
Author contributions: All authors (K.S., S.H., B.N.N., S.M.F. and J.R.) participated in the design of the study, while B.N.N., S.H. and S.M.F. collected data for the trial. Data analysis and interpretation of results were done by B.N.N., K.S., S.H. and J.R. All authors have read and approved the submitted manuscript.
Conflict of interest: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
Ethical approval: The clinical trial was approved by The Research Ethics for the Capital Region of Denmark (KF 02 312604).
Funding: The study has received a grant from the Hørslev Foundation, which is a private foundation that supports paediatric research. Also, the study received a grant from the Danish paediatric cancer foundation for initiating the clinical trial in Sweden.
Guarantor: B.N.N. is the guarantor of this study.
Informed consent: Written informed parental consent and verbal child assent, when possible, were obtained before inclusion into the study.
Trial registration: The trial registration can be found in http://www.clinicaltrials.gov, the study identifier Anonymized
ORCID iD: Bettina Nygaard Nielsen 
https://orcid.org/0000-0001-7848-4752
Supplemental material: Supplemental material for this article is available online.
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Supplementary Materials
Supplemental material, sj-tiff-1-bjp-10.1177_2049463720975061 for Evaluation of topical morphine for treatment of oral mucositis in cancer patients by Bettina Nygaard Nielsen, Susanne Molin Friis, Kjeld Schmiegelow, Steen Henneberg and Janne Rømsing in British Journal of Pain
Supplemental material, sj-tiff-2-bjp-10.1177_2049463720975061 for Evaluation of topical morphine for treatment of oral mucositis in cancer patients by Bettina Nygaard Nielsen, Susanne Molin Friis, Kjeld Schmiegelow, Steen Henneberg and Janne Rømsing in British Journal of Pain