Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Post-Transplant Events

Randomized controlled trial of pilocarpine hydrochloride for the moderation of oral mucositis during autologous blood stem cell transplantation

Bone Marrow Transplantation volume 35, pages 713–720 (2005)Cite this article

Summary:

Pilocarpine hydrochloride has been reported to increase salivation and decrease oral mucositis in patients receiving head and neck radiotherapy, but there is only one report of its use in a cancer chemotherapy patient population. This prospective, double-blinded, randomized, placebo-controlled trial was undertaken to determine the efficacy of pilocarpine for the moderation of oral mucositis during autologous blood stem cell transplantation. Subjects were randomized to receive a 5 mg tablet of pilocarpine, or a placebo, during and following chemotherapy. Subjects were seen every other day and evaluated for gingival, oral, and oropharyngeal mucositis; nutrition; oral hygiene; eating; speaking; sleeping; pain at rest and/or with swallowing; and mouth dryness. We recorded the mean and highest scores and duration of problems, along with white blood cell counts and differentials, and the use of systemic narcotics for oral mucosal pain. We enrolled and randomized 36 subjects, and there were no statistically or clinically significant differences for the primary outcome of severity of mucositis and no clinically significant differences in any of the other outcome measures. Pilocarpine has no benefit for the moderation of the incidence, severity, or duration of mucositis in patients receiving autologous blood stem cell transplantation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Juttner CA, To LB . Autologous peripheral blood stem cell transplantation: potential advantages, practical considerations and initial clinical results. In: Atkinson K (ed.). Clinical Bone Marrow Transplantation. Cambridge University Press: London, 1994, pp 142–152.

    Google Scholar 

  2. Heimdahl A, Mattsson T, Dahllöf G et al. The oral cavity as a port of entry for early infections in patients treated with bone marrow transplantation. Oral Surg Oral Med Oral Pathol 1989; 68: 711–716.

    Article  CAS  Google Scholar 

  3. Connolly SF, Lockhart PB, Sonis ST . Severe oral hemorrhage and sepsis following bone marrow transplant failure. Oral Surg Oral Med Oral Pathol 1983; 56: 483–486.

    Article  CAS  Google Scholar 

  4. Elting LS, Bodey GP, Keefe BH . Septicemia and shock syndrome due to viridans streptococci: a case-control study of predisposing factors. Clin Infect Dis 1992; 14: 1201–1207.

    Article  CAS  Google Scholar 

  5. Perry MC . Genitourinary, gastrointestinal, endocrine, nervous system, and coagulation complications. In: Armitage JO, Antman KH (eds). High-Dose Cancer Therapy. Pharmacology, Hematopoietins, Stem Cells. Williams and Wilkins: Baltimore, 1995, pp 609–618.

    Google Scholar 

  6. Schubert MM, Sullivan KM, Izutsu KT et al. Oral complications of bone-marrow transplantation. In: Peterson DE, Sonis ST (eds). Oral Complications of Cancer Chemotherapy. Martinus Nijhoff Publishing: Boston, 1983, pp 93–112.

    Chapter  Google Scholar 

  7. Woo S, Sonis ST, Monopoli MM et al. A longitudinal study of oral ulcerative mucositis in bone marrow transplant recipients. Cancer 1993; 72: 1612–1617.

    Article  CAS  Google Scholar 

  8. Chapko MK, Syrjala KL, Schilter L et al. Chemoradiotherapy toxicity during bone marrow transplantation: time course and variation in pain and nausea. Bone Marrow Transplant 1989; 4: 181–186.

    CAS  Google Scholar 

  9. Schubert MM, Peterson DE, Flournoy N et al. Oral and pharyngeal herpes simplex virus infection after allogeneic bone marrow transplantation: analysis of factors associated with infection. Oral Surg Oral Med Oral Pathol 1990; 7: 286–293.

    Article  Google Scholar 

  10. Sonis ST, Oster G, Fuchs H et al. Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol 2001; 19: 2201–2205.

    Article  CAS  Google Scholar 

  11. Bearman SI, Appelbaum FR, Buckner CD et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1988; 6: 1562–1568.

    Article  CAS  Google Scholar 

  12. Elad S, Garfunkel AA, Or R et al. Time limitations and the challenge of providing infection-preventing dental care to hematopoietic stem-cell transplantation patients. Support Care Cancer 2003; 11: 674–677.

    Article  Google Scholar 

  13. Guggenheimer J, Verbin RS, Appel BN . Clinicopathologic effects of cancer chemotherapeutic agents on human buccal mucosa. Oral Surg Oral Med Oral Pathol 1977; 44: 58–63.

    Article  CAS  Google Scholar 

  14. Lockhart PB, Sonis ST . Alterations in the oral mucosa caused by chemotherapeutic agents: a histologic study. J Dermatol Surg Oncol 1981; 7: 1019–1025.

    Article  CAS  Google Scholar 

  15. Sonis ST . Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 1998; 34: 39–43.

    Article  CAS  Google Scholar 

  16. Sonis ST, Van Vugt AG, Brien JPO et al. Transforming growth factor-â3 mediated modulation of cell cycling and attenuation of 5-fluorouracil induced oral mucositis. Oral Oncol 1997; 33: 47–54.

    Article  CAS  Google Scholar 

  17. Sonis ST . The biologic role for nuclear factor-kappaB in disease and its potential involvement in mucosal injury associated with anti-neoplastic therapy. Crit Rev Oral Biol Med 2002; 13: 380–389.

    Article  Google Scholar 

  18. Tabak LA . In defense of the oral cavity: structure, biosynthesis, and function of salivary mucins. Annu Rev Physiol 1995; 57: 547–564.

    Article  CAS  Google Scholar 

  19. Almstahl A, Wikstrom M . Oral microflora in subjects with reduced salivary secretion. J Dent Res 1999; 78: 1410–1416.

    Article  CAS  Google Scholar 

  20. Bardow A, Moe D, Nyvad B et al. The buffer capacity and buffer systems of human whole saliva measured without loss of CO2. Arch Oral Biol 2000; 45: 1–12.

    Article  CAS  Google Scholar 

  21. Epstein JB, Tsang AH, Warkentin D et al. The role of salivary function in modulating chemotherapy-induced oropharyngeal mucositis: a review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002; 94: 39–44.

    Article  Google Scholar 

  22. Jensen SB, Pedersen AM, Reibel J et al. Xerostomia and hypofunction of the salivary glands in cancer therapy. Support Care Cancer 2003; 11: 207–225.

    PubMed  Google Scholar 

  23. Pedersen AM, Bardow A, Jensen SB et al. Saliva and gastrointestinal functions of taste, mastication, swallowing and digestion. Oral Dis 2002; 8: 117–129.

    Article  CAS  Google Scholar 

  24. Köstler WJ, Hejna M, Wenzel C et al. Oral mucositis complicating chemotherapy and/or radiotherapy: options for prevention and treatment. CA Cancer J Clin 2001; 51: 290–315.

    Article  Google Scholar 

  25. Gordon B, Spadinger A, Hodges E et al. Effect of granulocyte-macrophage colony-stimulating factor on oral mucositis after hematopoietic stem-cell transplantation. J Clin Oncol 1994; 12: 1917–1922.

    Article  CAS  Google Scholar 

  26. Epstein JB, Schubert MM . Oropharyngeal mucositis in cancer therapy. Review of pathogenesis, diagnosis, and management. Oncology 2003; 17: 1767–1792.

    PubMed  Google Scholar 

  27. Clarkson JE, Worthington HV, Eden OB . Interventions for preventing oral mucositis or oral candidiasis for patients with cancer receiving chemotherapy (excluding head and neck cancer). The Cochrane Database of Systematic Reviews 2003; 1.

  28. Rocke LK, Loprinzi CL, Lee JK et al. A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer 1993; 72: 2234–2238.

    Article  CAS  Google Scholar 

  29. Cascinu S, Fedeli A, Fedeli SL et al. Oral cooling (cryotherapy), an effective treatment for the prevention of 5-fluorouracil-induced stomatitis. Eur J Cancer B Oral Oncol 1994; 30B: 234–236.

    Article  CAS  Google Scholar 

  30. Fox PC, Atkinson JC, Macynski AA et al. Pilocarpine treatment of salivary gland hypofunction and dry mouth (xerostomia). Arch Intern Med 1991; 151: 1149–1152.

    Article  CAS  Google Scholar 

  31. Wiseman LR, Faulds D . Oral pilocarpine: a review of its pharmacological properties and clinical potential in xerostomia. Drugs 1995; 49: 143–156.

    Article  CAS  Google Scholar 

  32. Vivino FB, Al-Hashimi I, Khan Z et al. Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjögren syndrome: a randomized placebo-controlled fixed-dose multicenter trial. Arch Intern Med 1999; 159: 174–181.

    Article  CAS  Google Scholar 

  33. Greenspan D, Daniels TE . Effectiveness of pilocarpine in postradiation xerostomia. Cancer 1987; 59: 1123–1125.

    Article  CAS  Google Scholar 

  34. Johnson JT, Ferretti GA, Nethery WJ et al. Oral pilocarpine for post-irradiation xerostomia in patients with head and neck cancer. N Engl J Med 1993; 329: 390–395.

    Article  CAS  Google Scholar 

  35. LeVeque FG, Montgomery M, Potter D et al. A multicenter, randomized, double-blind, placebo-controlled, dose-titration study of oral pilocarpine for treatment of radiation-induced xerostomia in head and neck cancer patients. J Clin Oncol 1993; 11: 1124–1131.

    Article  CAS  Google Scholar 

  36. Rieke JW, Hafermann MD, Johnson JT et al. Oral pilocarpine for radiation-induced xerostomia: integrated efficacy and safety results from two prospective randomized clinical trials. Int J Radiat Oncol Biol Phys 1995; 31: 661–669.

    Article  CAS  Google Scholar 

  37. Horiot JC, Lipinski F, Schraub S et al. Post-radiation severe xerostomia relieved by pilocarpine: a prospective French cooperative study. Radiother Oncol 2000; 55: 233–239.

    Article  CAS  Google Scholar 

  38. Zimmerman RP, Mark RJ, Tran LM et al. Concomitant pilocarpine during head and neck irradiation is associated with decreased posttreatment xerostomia. Int J Radiat Oncol Biol Phys 1997; 37: 571–575.

    Article  CAS  Google Scholar 

  39. Valdez IH, Wolff A, Atkinson JC et al. Use of pilocarpine during head and neck radiation therapy to reduce xerostomia and salivary dysfunction. Cancer 1993; 71: 1848–1851.

    Article  CAS  Google Scholar 

  40. Haddad P, Karimi M . A randomized, double-blind, placebo-controlled trial of concomitant pilocarpine with head and neck irradiation for prevention of radiation-induced xerostomia. Radiother Oncol 2002; 64: 29–32.

    Article  CAS  Google Scholar 

  41. LeVeque F, Fontanesi J, Davi S et al. Salivary gland sheltering using concurrent pilocarpine (PC) in irradiated head and neck cancer patients. Proceedings of the Association of Surgical Clinical Oncologists 15, p 516, 1996 (Abstract).

  42. Warde P, O’Sullivan B, Aslanidis J et al. A phase III placebo-controlled trial of oral pilocarpine in patients undergoing radiotherapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2002; 54: 9–13.

    Article  CAS  Google Scholar 

  43. Nagler RM, Nagler A . Pilocarpine hydrochloride relieves xerostomia in chronic graft-versus-host disease: a sialometrical study. Bone Marrow Transplant 1999; 23: 1007–1011.

    Article  CAS  Google Scholar 

  44. LeVeque F, Dansey R, Klein B . Use of concurrent oral pilocarpine (OP) to treat mucositis during bone marrow transplantation (BMT): a pilot study. J Clin Oncol 1997; 16: 108a (proceedings) (Abstract).

    Google Scholar 

  45. Awidi A, Homsi U, Kakail RI et al. Double-blind, placebo-controlled cross-over study of oral pilocarpine for the prevention of chemotherapy-induced oral mucositis in adult patients with cancer. Eur J Cancer 2001; 37: 2010–2014.

    Article  CAS  Google Scholar 

  46. Tardieu C, Cowen D, Thirion X et al. Quantitative scale of oral mucositis associated with autologous bone marrow transplantation. Eur J Cancer B Oral Oncol 1996; 32B: 381–387.

    Article  CAS  Google Scholar 

  47. Landis JR, Koch GG . The measurement of observer agreement for categorical data. Biometrics 1977; 33: 159–174.

    Article  CAS  Google Scholar 

  48. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 47: 207–214.

    Article  CAS  Google Scholar 

  49. Dens F, Boogaerts M, Boute P et al. Caries-related salivary microorganisms and salivary flow rate in bone marrow recipients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996; 81: 38–43.

    Article  CAS  Google Scholar 

  50. Amerongen AV, Veerman EC . Saliva – the defender of the oral cavity. Oral Dis 2002; 8: 12–22.

    Article  Google Scholar 

  51. Kaplan MD, Baum BJ . The functions of saliva. Dysphagia 1993; 8: 225–229.

    Article  CAS  Google Scholar 

  52. Mandel ID . The role of saliva in maintaining oral homeostasis. J Am Dent Assoc 1989; 119: 298–304.

    Article  CAS  Google Scholar 

  53. Baum BJ, Bodner L, Fox PC et al. Therapy-induced dysfunction of salivary glands: implications for oral health. Spec Care Dentist 1985; 5: 274–277.

    Article  CAS  Google Scholar 

  54. DeStefano F, Anda RF, Kahn HS et al. Dental disease and risk of coronary heart disease and mortality. BMJ 1993; 306: 688–691.

    Article  CAS  Google Scholar 

  55. Mansson-Rahemtulla B, Techanitiswad T, Rahemtulla F et al. Analysis of salivary components in leukemia patients receiving chemotherapy. Oral Surg Oral Med Oral Pathol 1992; 73: 35–46.

    Article  CAS  Google Scholar 

  56. Wolff A, Moreira JE, Marmary Y et al. Lack of acute effects of methotrexate on rat parotid salivary gland function. Arch Oral Biol 1989; 34: 109–115.

    Article  CAS  Google Scholar 

  57. McBride RK, Siegel IA . Effect of methotrexate on protein and amylase secretion by rat parotid and submandibular salivary glands. Arch Oral Biol 1988; 33: 245–249.

    Article  CAS  Google Scholar 

  58. Dens F, Boogaerts M, Boute P et al. Quantitative determination of immunological components of salivary gland secretion in transplant recipients. Bone Marrow Transplant 1996; 17: 421–423.

    CAS  PubMed  Google Scholar 

  59. Jankovic L, Jelic S, Filipovic-Ljeskovic I et al. Salivary immunoglobulins in cancer patients with chemotherapy-related oral mucosa damage. Eur J Cancer Part B, Oral Oncol 1995; 31B: 160–165.

    Article  CAS  Google Scholar 

  60. Mandel ID . The functions of saliva. J Dent Res 1987; 66: 623–627.

    Article  Google Scholar 

  61. McCarthy GM, Awde JD, Ghandi H et al. Risk factors associated with mucositis in cancer patients receiving 5-fluorouracil. Oral Oncol 1998; 34: 484–490.

    Article  CAS  Google Scholar 

  62. Harrison T, Bigler L, Tucci M et al. Salivary slgA concentrations and stimulated whole saliva flow rates among women undergoing chemotherapy for breast cancer: an exploratory study. Spec Care Dentist 1998; 18: 109–112.

    Article  CAS  Google Scholar 

  63. Patterson AJ, Ritschel WA, Zellner D et al. Methotrexate serum and saliva concentrations in patients. Int J Clin Pharmacol, Therapy, Toxicol 1981; 19: 381–385.

    CAS  Google Scholar 

  64. Ishii E, Yamada S, Higuchi S et al. Oral mucositis and salivary methotrexate concentration in intermediate-dose methotrexate therapy for children with acute lymphoblastic leukemia. Med Pediatr Oncol 1989; 17: 429–432.

    Article  CAS  Google Scholar 

  65. Bressolle F, Jacquet JM, Galtier M et al. Doxorubicin and doxorubicinol plasma concentrations and excretion in parotid saliva. Cancer Chemother Pharmacol 1992; 30: 215–218.

    Article  CAS  Google Scholar 

  66. Milano G, Thyss A, Santini J et al. Salivary passage of 5-fluorouracil during continuous infusion. Cancer Chemother Pharmacol 1989; 24: 197–199.

    Article  CAS  Google Scholar 

  67. Oliff A, Bleyer WA, Poplack DG . Methotrexate-induced oral mucositis and salivary methotrexate concentrations. Cancer Chemother Pharmacol 1979; 2: 225–226.

    Article  CAS  Google Scholar 

  68. Parulekar W, Mackenzie R, Bjarnason G et al. Scoring oral mucositis. Oral Oncol 1998; 34: 63–71.

    Article  CAS  Google Scholar 

  69. Schubert MM, Williams BE, Lloid ME et al. Clinical assessment scale for the rating of oral mucosal changes associated with bone marrow transplantation. Development of an oral mucositis index. Cancer 1992; 69: 2469–2477.

    Article  CAS  Google Scholar 

  70. Sonis ST, Eilers JP, Epstein JB et al. Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Cancer 1999; 85: 2103–2113.

    Article  CAS  Google Scholar 

  71. Donnelly JP, Muus P, Schattenberg A et al. A scheme for daily monitoring of oral mucositis in allogeneic BMT recipients. Bone Marrow Transplant 1992; 9: 409–413.

    CAS  Google Scholar 

  72. McGuire DB, Peterson DE, Muller S et al. The 20 item oral mucositis index: reliability and validity in bone marrow and stem cell transplant patients. Cancer Invest 2002; 20: 893–903.

    Article  Google Scholar 

  73. Scientific Advisory Committee of the Medical Outcomes Trust. Instrument Review Criteria, Medical Outcomes Trust Bulletin 1995; September: 1–4.

  74. Papas AS, Sherrer YS, Charney M et al. Treatment of dry mouth and dry eye symptoms in Sjögren's syndrome patients with oral pilocarpine – a randomized, placebo-controlled, dose adjustment study. J Clin Rheumatol 2004; 10: 169–177.

    Article  Google Scholar 

Download references

Acknowledgements

We acknowledge Dr Dorothy Keefe for her critical reviews of the manuscript, and Dr Howell Sasser for his help with data analysis. This study was funded by the Charlotte-Mecklenburg Health Services Foundation, Carolinas Medical Center, Charlotte, NC 28239, USA.

Author information

Authors and Affiliations

  1. Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC, USA

    P B Lockhart, M T Brennan, M L Kent & P C Fox

  2. Department of Internal Medicine, Carolinas Medical Center, Charlotte, NC, USA

    C H Packman & G Frenette

  3. Department of Biostatistics, Carolinas Medical Center, Charlotte, NC, USA

    H J Norton

Authors
  1. P B Lockhart
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M T Brennan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M L Kent
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C H Packman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H J Norton
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P C Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G Frenette
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P B Lockhart.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lockhart, P., Brennan, M., Kent, M. et al. Randomized controlled trial of pilocarpine hydrochloride for the moderation of oral mucositis during autologous blood stem cell transplantation. Bone Marrow Transplant 35, 713–720 (2005). https://doi.org/10.1038/sj.bmt.1704820

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1704820

Keywords

This article is cited by

Search

Advanced search

Quick links