Also available as PDF (figures and tables appear in the PDF).
Oral mucositis is a frequent adverse effect of chemotherapy and radiation therapy in cancer patients. The mucositis impacts overall quality of life (QoL) by producing pain with variable intensity leading to difficulty in oral intake, lack of sleep, etc. A multimodal therapy is advocated for management of oral mucositis in cancer patients and includes certain preventive and therapeutic interventions aiming at symptom control. The systemic analgesics are frequently used but may be associated various side effects associated with analgesics including opioid. The use of oral submucosal route for opioids has been advocated in view of existence of peripheral opioid receptors for its analgesic property. We review the literature for use of morphine mouthwash for management of painful oral mucosisits.
Keywords: Morphine; Mouthwash; Adverse effects; Mucositis; Cancer
Volume 2 : Issue 2 Oral mucositis is a frequent adverse effect of chemotherapy and radiation therapy in cancer Article Ref. #: 1000PMHCOJ2115 patients. The mucositis impacts overall quality of life (QoL) by producing pain with variable intensity leading to difficulty in oral intake, lack of sleep, etc. A multimodal therapy is advo- Article History cated for management of oral mucositis in cancer patients and includes certain preventive and th Received: August 25th, 2016 therapeutic interventions aiming at symptom control. The systemic analgesics are frequently th Accepted: October 19th, 2016 used but may be associated various side effects associated with analgesics including opioid. th Published: October 19th, 2016 The use of oral submucosal route for opioids has been advocated in view of existence of pe- ripheral opioid receptors for its analgesic property. We review the literature for use of morphine mouthwash for management of painful oral mucosisits.
Citation Dutta K, Garg R. Morphine mouthwash in oral mucositis: A KEYWORDS: Morphine; Mouthwash; Adverse effects; Mucositis; Cancer. mini review. Palliat Med Hosp Care Open J. 2016; 2(2): 26-29. Cancer patients require multidisciplinary approach including chemotherapy and ra- doi: 10.17140/PMHCOJ-2-115 diation therapy. Apart from other therapy associated side effects, oral mucositis remains a ma- 1,2 jor concern for patient undergoing chemotherapy and/or radiation therapy.1,2 The incidence 1-4 of mucositis ranges 15-90%.1-4 The oral mucositis is associated with chemo-radiation of head and neck cancer primarily. The usual chemotherapeutic drug regimen for patients with unre- sectable, locally advanced cancer is combination of cisplatin and 5-fluorouracil (5-FU) with 5-8 9-11 concurrent radiation. The 5-FU-based chemotherapies have more risk of mucositis. The mucositis occurrence and its severity remain dose dependent (chemotherapeutic drugs, cumula- 8,11 tive radiation exposure).8,11 Continuous infusion of chemotherapeutic drugs leads to increased 8,12,13 risk of developing mucositis. The cancer patients receiving such combination of chemo- therapeutic drugs along with radiation therapy remains at risk of painful mucositis which may result in interruptions of subsequent treatment. Thus, such symptom may not only adversely affect quality of life (QoL) but also affect the disease outcome.
The treatment related oral mucositis remains painful with variable intensity and at times severe pain leading to patient distress. It may affect overall QoL with decrease oral in- 4,9,11 take, painful deglutition, affect sleep and may result in serious clinical complications. So such painful oral mucositis requires immediate intervention with various analgesics including paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. However, use of NSAIDs requires caution in view of chemotherapy induced hematopoeitc suppression and also may not be adequate for control of moderate to severe pain.1 Thus, need of opioid analgesics is 1,2 frequently required based on severity of pain of oral mucosisits.1,2 During the acute mucositis, oral intake remains painful and thus necessitating the intravenous administration of narcotic Copyright analgesics. Opioid administration is associated with various side effects commonly include se- ©2016 Garg R. This is an open ac- dation, dizziness, nausea, vomiting, constipation, respiratory depression, physical dependence cess article distributed under the 1,3 and tolerance. Therefore, effective use of systemic opioid requires balancing between pain Creative Commons Attribution 4.0 relief and the undesirable side effects. The use of other adjuvant therapy may help in reducing International License (CC BY 4.0), which permits unrestricted use, the opioid requirement for optimal pain relief. distribution, and reproduction in any medium, provided the original The use of topical anesthetics along with oral hygiene is useful for symptom manage- work is properly cited.
agents with analgesic properties have been reported to be effec- most potent when applied locally.15 Morphine has a predictable tive for management of painful oral mucositis. The opioid anal- low absorption through the trans-mucosal route. The sublingual gesics like morphine produces its analgesics effects by binding as well as trans-mucosal absorptions of drugs are dependent on 25,26 to opioid receptors in the central nervous system (CNS) and the both pH level and lipid solubility. Therefore, morphine being 15-17 peripheral terminals of afferent nerves. The literature reports less lipophilic (partition coefficient 0.00001) and ionized at the via various basic and clinical research about the analgesic ef- low pH level of the oral cavity (morphine pKa at 37 °C=7.9) is 27,28 ficacy of local application of exogenous opioid for management poorly absorbed. Evidence of the activation of opioid recep- 18-21 of painful inflammatory conditions. The oral and parenteral tors due to inflammatory change in tissues has led to the explo- 29,30 analgesic effect of opioid are well established with robust evi- ration of the potential analgesic effect of opioid peripherally.
dence, but no unified approach with concrete evidence exists for This suggest that morphine mouthwash would provide optimal 3,9,22 topical treatments. It has been shown that the opioid recep- analgesia without getting absorbed systemically and thus less tors exists in peripheral sensory neurons and thus can be acti- adverse effects. The literature supports the effectiveness of mor- vated by topical analgesics resulting pain relief.23 It has also been phine mouthwash for treatment of oral mucositis in cancer pa- reported that oral epithelial cells contain opioid receptors.24 The tients (Table 1). The overall literature suggests that morphine opioid ligands with a preference for µ-receptors are generally mouthwash (1-2%) provide effective pain relief for 30-120 min- Study Intervention Study design Results Adverse effects Remarks 30 patients with oral muco- th sitis Grade 3 or 4 received At the 6 day, more reduction was Topical morphine is more morphine sulfate 2% or observed in mucositis severity in effective and more sat- magic solution (magne- the morphine compared with magic 31 Prospective isfactory to patients than Mostafa et al sium aluminum hydroxide, group (p=0.045). Patients in the Nil reported randomized study the magic mouthwash in viscous lidocaine, and morphine group were more satisfied reducing severity of oral diphenhydramine), 10 ml by their treatments than those in the mucositis.
for every 3 h, six times a magic group (p=0.008).
Pain alleviation 1 hour after mouth- 9 patients with oral wash was significantly influenced Burning sensation mucositis of at least grade by the gesture of the mouthwash by topical Randomized Authors suggest a possible Vayne-Bossert P II received 15 ml of 2% (p<0.001) with either morphine or morphine caused 32 double-blinded analgesic effect of topical et al morphine mouthwash or placebo) and almost by the efficiency one patient to crossover study morphine.
placebo, 6 times a day, for of morphine (p=0.020). Duration of drop out from the 4-6 days. pain relief was 123.7±98.2 min with study morphine.
MG group Duration of severe pain was 3.5 days reported nausea less in the MO group compared with (1), loss of taste the MG group (p= 0.032). Intensity of (3), viscous saliva 26 patients were randomly oral pain was also lower in the MO (2), dry mouth (2) MO is a simple and effective assigned to morphine group compared with the MG group Randomize, and excessive treatment to decrease the 33 mouthwash (MO group=14 (p=0.038). More patients in the MG Cerchietti et al controlled, parallel anesthesia (1) severity and duration of patients) or magic group needed supplementary (oral comparative study pain and the duration of mouthwash (MG group=12 or parenteral) analgesia compared MO group functional impairment patients) with the MO group (p=0.019). There reported dry was a significant difference in dura- mouth and a tion of severe functional impairment burning sensation (p=0.017).
Patients reported 10 patients rinsed with 5 difficult rinsing Oral morphine rinse resulted mg morphine sulphate in 15 initially because in effective of pain relief and 34 ml of diluent solution every Good pain relief lasting for 30-60 Saroja S et al Open label study of the restricted improved opening of mouth 2 hour and instructed to min.
movement of in cancer patients with keep it in mouth for 5 min mouth opening mucositis.
12 children received oral Pain decreased by 36% after 30 min morphine as atomizer oral Prospective of topicalization. The serum Oral morphine topicalization Nielsen BN et al spray. The morphine spray observational morphine and its metabolites levels None reported provides effective pain relief.
was retained in mouth for sequential study. were well below the effective 10 seconds before spitting. analgesics levels.
Conducted in two blocks: dose response and One patient in the efficacy/safety study. Ten Oral rinse with 2% morphine pro- 1% group and 2 patients received 15 mL of vides better pain relief as compared in the 2% group Morphine oral rinse provides 36 Prospective Leamdro CA et al 1-2% morphine oral rinse. to 1% (80% vs. 60%, p=0.024). No complained of a optimal pain relief without randomized Of the 22 patients, serum systemically active detectable mor- local side effect systemic absorption. morphine concentration phine concentration was observed. like burning/itch- was estimated in 5 ing sensation.
utes. Thus, mouthwash may be repeated every 2 hourly along Oncol. 1991; 9: 458-463. Web site. http://jco.ascopubs.org/con- with other components of multimodal management.
tent/9/3/458.short. Accessed August 24, 2016.
To conclude, we suggest that morphine mouthwash 9. Epstein JB, Schubert MM. Managing pain in mucosi- may be considered as an effective management strategy as a tis. Semin Oncol Nurs. 2004; 20(1): 30-37. doi: 10.1053/j.
part of multimodal treatment of oral mucositis in cancer patients soncn.2003.10.006 receiving chemotherapy and/or radiation therapy. The effec- tive pain relief may be achieved with 10-15 ml of 2% morphine 10. Epstein JB, Silverman S Jr, Paggiarino DA, et al. Benzyda- aqueous solution and can be used 2-3 hourly as mouthwash in mine HCl for prophylaxis of radiation-induced oral mucositis: patients with mucositis pain.
Results from a multicenter, randomized, double-blind, place- bo-controlled clinical trial. Cancer. 2001; 92(4): 875-885. doi: CONFLICTS OF INTEREST 10.1002/1097-0142(20010815)92:4<875::AID-CNCR1396> 3.0.CO;2-1 The authors declare that they have no conflicts of interest.
11. Rosenthal DI. Consequences of mucositis-induced treatment