Evaluation of topical morphine for treatment of oral mucositis in cancer patients

Design

Randomized, double-blind, triple-masked, multicenter, controlled trial

N= 60

Objective

To investigate the peripheral analgesic effect of an oromucosal solution (OM) of morphine versus a bolus of intravenous (IV) morphine or placebo as an add-on to morphine patient-controlled analgesia (PCA) therapy in cancer patients with oral mucositis

Study Groups

Oromucosal morphine (n= 30)

IV morphine (n= 15)

Placebo (n= 15)

Inclusion Criteria

Children aged 0-17 years admitted to a pediatric cancer ward or adults admitted to hematopoietic stem-cell transplantation (HSCT) wards; treated with chemotherapy for cancer; oral mucositis (grade ≥1); oral pain intensity ≥3 at rest or ≥5 during activity (eating or oral hygiene) despite analgesic treatment

Exclusion Criteria

Methods

Eligible patients were randomized 2:1:1 to revive either oral morphine solution plus IV placebo (saline), a placebo oral solution plus IV morphine, or oral placebo plus IV placebo as add-on to PCA; all patients were equipped with a morphine PCA pump and the participating patients were instructed to use this pump as an escape. The randomized treatments were administered at 3-hour intervals with 3-4 administrations planned. To standardize non-opioid treatment, all patients received acetaminophen 10-15 mg/kg orally or IV per the standard of care at the participating wards. 

The oral morphine solution contained morphine 2 mg/mL with 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 was used to administer a dose corresponding to 50 mcg/kg every 3 hours and patients were encouraged to keep the solution in their mouth for 10 seconds before spitting it out.

The IV morphine solution was diluted to morphine 1 mg/mL and administered as a bolus of morphine of 50 mcg/kg every 3 hour by pump.

Duration

December 2007 to December 2013

Treatment: up to 4 doses every 3 hours (maximum 12 hours)

Outcome Measures

Primary: morphine consumption via PCA

Secondary: pain scores, safety

Baseline Characteristics

Oral morphine (n= 30)

IV morphine (n= 15)

Age, years (IQR)

Adults ≥ 18 years

16.0 (8.0–26.0)

40%

15.0 (10.0–23.0)

33%

13.0 (10.5–33.5)

33%

0.91

0.88

0.35

Weight, kg

Diagnosis

HSCT

Leukemia

Lymphoma

Sarcoma

Carcinoma

Blastoma

43%

17%

30%

7%

0

3%

47%

7%

17%

0

0

13%

47%

20%

0

20%

13%

0

Oral mucositis grade

1

2

3

4

10%

10%

50%

30%

13%

20%

40%

27%

0

27%

47%

27%

Pain score (IQR)

6 (4–7)

5 (4–7)

5 (4–6)

Results

Endpoint

Oral morphine (n= 30)

IV morphine (n= 15)

Placebo (n= 15)

p-value (vs IV)

Morphine PCA consumption, mcg/kg/h (95% CI)

vs VI: 0.38

vs placebo: 0.82

Summed pain intensity difference

Dose 1

Dose 2

Dose 3

Dose 4

-0.5 (-1.0 to -0.23)

-1.1 (-2.1 to -0.5) 

-1.2 (-2.1 to -0.8) 

-1.4 (-2.1 to -0.8) 

-1.0 (-1.5 to -0.8)

-1.9 (-2.2 to -1.5) 

-2.7 (-3.5 to -2.0) 

-3.5 (-4.8 to -2.8) 

-0.75 (-1.2 to -0.13)

-1.3 (-1.8 to -0.5)

-1.3 (-2.1 to -0.4)

-2.0 (-2.7 to -1.0)

0.0276

0.0693

0.0072

0.0180

Pain score difference during oral hygiene (IQR)

1.8 (0–4.3) 

1.0 (0–1) 

0.0 (0–1)

0.51

While there was no difference between the 3 groups in terms of morphine PCA usage, there was a significant difference between the oral and IV treatments after doses 1, 3, and 4 favoring the positive control of IV morphine.

Study Author Conclusions

InpharmD Researcher Critique

While in vitro data suggests peripheral opioid receptors are upregulated during inflammatory painful conditions like oral mucositis, the negative results of this study may be due to lower absorption from ulcerated mucosa (dependent on pH, lipid solubility, drug concentration, and contact time). Morphine is less lipophilic than other opioids and is ionized in the lower pH environment of damaged oral mucosa.

Limitations of this study include the small sample size primarily including pediatric patients and the short study duration. Strengths of this trial include the triple-blinded approach and utilizing both a positive and negative control.

Morphine mouthwash for the management of oral mucositis in patients with head and neck cancer

Design

Single-center, double-blinded, randomized, controlled study (Iran)

N= 28

Objective

To investigate the efficacy of topical morphine in comparison with a routine therapy (magic mouthwash) in the management of oral mucositis in patients with head and neck cancer

Study Groups

Morphine (n= 15)

Control (n= 13)

Inclusion Criteria

Head and neck cancer, Grade III or IV oral mucositis

Exclusion Criteria

History of severe renal or hepatic insufficiency, collagen-vascular disease, allergic reaction to morphine, current smokers or alcohol users, pregnant

Methods

Patients were randomized to morphine or magic mouthwash; the morphine patients used 10 mL of an oral 2% morphine solution of mouthwash every 3 h, or six times daily. The morphine solution was prepared by the local medical university. The magic mouthwash patients used 10 mL of a mouthwash consisting of 240 mL magnesium aluminum hydroxide, 25 mL 2% viscous lidocaine, and 60 mL diphenhydramine every 3 h, or six times daily. Patients were instructed to hold the solution in their mouth for at least two minutes and to not swallow. Patients did not receive steroids and/or antimicrobials before inclusion, although they all received the same professional oral care if needed (e.g., removal of dentures, debridement of necrotic tissues, etc.).

Duration

Between April and July 2011

Treatment: 6 days

Outcome Measures

World Health Organization (WHO) grading system of mucositis scores, drug effect maintenance, satisfaction

Baseline Characteristics

Morphine (n= 15)

Control (n= 13)

Age, years

Female

Treatment*

Radiotherapy

Chemotherapy

Chemoradiotherapy

5

8

2

3

5

5

Mucositis grade, III/IV

* Radiotherapy included a total dose of 70 Gy irradiation over 6-7 weeks. Chemotherapy included cisplatin-based therapy with 21-day intervals for four cycles. Concomitant chemotherapy consisted of weekly cisplatin (30 mg/m2) for 6-7 weeks. Of the patients included, some had already finished their treatment courses.

Results

Endpoint

Morphine (n= 15)

Control (n= 13)

p-value

WHO grading mucositis scores

Day 3

Day 6

2.00 ± 0.70

1.71 ± 0.60

2.46 ± 1.05

2.46 ± 1.26

0.161

0.045

Drug effect maintenance

< 1 h

1-2 h

8

7

8

5

0.479

Satisfaction

Satisfied

Tolerable

Intolerable

8

6

1

7

4

2

0.008

Serum therapy

The trend of change in mucositis severity in the two studied groups is depicted in graph form, where the Freidman test showed a decrease in both morphine (p< 0.001) and magic (p= 0.049) groups.

Adverse Events

Mild adverse events were reported, including oral burning/itching during the rinse. One patient in the morphine and two in the magic group reported intolerable taste of the mouthwash.

Study Author Conclusions

Topical morphine is more effective and more satisfactory to patients than the magic mouthwash in reducing severity of cancer treatment-induced oral mucositis. More studies with larger sample size and longer follow-up are required in this regard.

InpharmD Researcher Critique

A limited sample size and short study duration are factors that may prevent this study from being able to detect a sizeable treatment difference.

Topical morphine for oral mucositis in children: dose finding and absorption

Design

Prospective cohort study

N= 12

Objective

To investigate the dose-response relationship and the potential absorption of topical morphine across oral mucosa in children with oral mucositis

Study Groups

Absorption study (n= 5)

Dose-finding study (n= 7)

Inclusion Criteria

Aged 2 to 17 years, chemotherapy-induced oral mucositis

Exclusion Criteria

Not disclosed

Methods

Patients received an oromucosal solution containing morphine 1 or 2 mg/mL and were encouraged to hold the solution in the mouth for 10 seconds before spitting it out. All children received acetaminophen 10–15 mg/kg orally or intravenously or 20–25 mg/kg rectally every six hours, and were also allowed supplemental opioid analgesics, including morphine administration in a patient-controlled analgesia (PCA) pump activated on demand (0.025 mg/kg of morphine, lockout period of eight minutes).

In the dose-response study, an initial morphine dose of 0.4 mg/kg was added to regularly administered acetaminophen. The starting dose received by the first patient was followed by relative decrements/increments in dose for each subsequent patient (i.e., each patient received a different dose, and the dose for a patient was determined by the response of the previous patient). Three subsequent administrations at 3 h intervals were planned for each patient, with a "stopping" dose of 0.025 mg/kg of morphine or when 10 patients completed the study per protocol.

In the absorption study, a single 0.050 mg/kg dose of morphine was chosen with a sample size of five patients. Children who received morphine within 48 h before inclusion were excluded.

Duration

Treatment: 180 minutes

Outcome Measures

Response, defined as 33% or more decrease in pain score

Baseline Characteristics

Dose-finding study (n= 7)

Absorption study (n= 5)

Age range, years

Female

White

Diagnosis

NHL

NBL

HSCT

ALL

1

2

1

3

1

1

0

3

Oral mucositis (WHO Scale)

Grade 2

Grade 3

3

4

1

4

Abbreviations: NHL= non-Hodgkin's lymphoma; NBL= neuroblastoma; HSCT= hematopoietic stem cell transplantation including concomitant radiation therapy; ALL= acute lymphoblastic leukemia; WHO= World Health Organization

^a WHO Scale Grade 0–4: 0=no oral mucositis and 4=severe oral mucositis

^b For the VAS, VAS faces, and FLACC scales, 0=no pain and 10=worst pain

Results

Dose of topical morphine and the response/non-response for patients are presented in a graph. No obvious dose-response effect of topical morphine (doses of 0.025–0.400 mg/kg) was found.

In the absorption study, concentrations of morphine in plasma at baseline and up to 180 minutes after were below or close to the limit of quantification, 0.5 ng/mL. The highest concentration of the metabolites M-6-G and M-3-G were detected 60-120 minutes after administration.

Adverse Events

Three of twelve patients reported a transient burning/itching sensation in the mouth after morphine solution administration. In four patients, three consecutive administrations of morphine oromucosal solution were not possible because of fever, nausea/vomiting, or tiredness.

Study Author Conclusions

No obvious dose-response effect was found for topical morphine doses of 0.025-0.400mg/kg, and topically applied morphine was not absorbed in clinically relevant doses. However, this study was limited by the small number of patients and the allowance of a systemic opioid as rescue medication. Thus, randomized controlled studies are needed to further investigate the analgesic properties of topical morphine.

InpharmD Researcher Critique

Limitations of this study include the small sample size and the short treatment duration. The inclusion of morphine PCA boluses, the use of several different validated pain scales, and the variability of methods due to the combination of study designs may also limit applicability of these findings. 

Effect of topical morphine (mouthwash) on oral pain due to chemotherapy- and/or radiotherapy-induced mucositis: a randomized double-blinded study

Design

Randomized, double-blinded crossover study

N= 9

Objective

To determine if mouthwashes with a morphine-containing solution decrease oral pain associated with radiotherapy- and/or chemotherapy-induced oral mucositis (OM)

Study Groups

Morphine solution

Placebo

Inclusion Criteria

Exclusion Criteria

Risk of swallowing mouthwash solution, cognitive impairment, refusal to stop mouthwash with local anesthetic

Methods

Patients were randomized to one of the two treatments for 3 days, after which they were crossed over to the alternative treatment for another 3 days. Patients received 15 mL of morphine 2% or placebo (quinine diHCl 50 mg/15 mL to mimic the bitter taste of morphine) regularly 6 times daily. They were instructed not to swallow during rinses while holding mouthwash for 2 minutes. 

Duration

Trial: May 2007 to October 2007

Intervention: 6 days

Outcome Measures

Primary: mean difference in pain alleviation at 1 hour from administration

Secondary: duration of pain relief, requirement for supplementary analgesia, severity of local symptoms related to morphine mouthwash

Baseline Characteristics

Full cohort (N= 9)

Age, years

Female

Primary cancer site

Head and neck

Breast

8

1 

Therapy

Chemo

Radiation

9

7

WHO score

Grade 2

Grade 3

8

1

Results

Endpoint

Morphine

Placebo

p-value

Pain relief duration, min

Pain alleviation at 1 hour after administration of mouthwash was significantly influenced by treatment arm (p= 0.000). A carryover effect was noted for morphine when administered as the initial treatment. 

Intensity of symptoms were not significantly different between groups or over the 6 days of treatment duration. No significant differences were noted within groups for change in pain, nausea, mouth dryness, or loss of taste from Day 1 to Day 7. 

Adverse Events

Study Author Conclusions

Results suggest a possible analgesic effect of topical morphine in line with previous studies. However, more effort must be made for the adjustment of systemic analgesics and new alternatives have to be developed to treat local pain associated with oral mucositis.

InpharmD Researcher Critique