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Single-Dose Subcutaneous Benzodiazepines for Insomnia in Patients With Advanced Cancer

Open AccessPublished:March 28, 2015DOI:https://doi.org/10.1016/j.jpainsymman.2015.02.018
      To the Editor:
      Insomnia is one of the most common complications affecting patients with advanced cancer.
      • Kvale E.A.
      • Shuster J.L.
      Sleep disturbance in supportive care of cancer: a review.
      • Sateia M.J.
      • Lang B.J.
      Sleep and cancer: recent developments.
      Severe insomnia has a highly negative impact on quality of life. Sleeplessness exacerbates pain, causing physical and mental discomfort (e.g., fatigue, daytime drowsiness, and day-night reversal). As with other symptoms, insomnia is distressing to patients, families, and caregivers. Furthermore, with the progression of disease, many patients with advanced cancer face difficulties taking oral medication, eventually requiring parenteral drug administration. The placement of an intravenous catheter is often uncomfortable and difficult for patients with advanced cancer. In such patients, single-dose subcutaneous administration is easier and less stressful as compared with intravenous administration.
      Benzodiazepines are commonly used hypnotic medications for inducing sleep in palliative care.
      • Holbrook A.M.
      • Crowther R.
      • Lotter A.
      • Cheng C.
      • King D.
      Meta-analysis of benzodiazepine use in the treatment of insomnia.
      • Hirst A.
      • Sloan R.
      Benzodiazepines and related drugs for insomnia in palliative care.
      • Matsuo N.
      • Morita T.
      Efficacy, safety, and cost effectiveness of intravenous midazolam and flunitrazepam for primary insomnia in terminally ill patients with cancer: a retrospective multicenter audit study.
      Midazolam and flunitrazepam as injectable solutions can be used in Japan. Midazolam is a short-acting and flunitrazepam an intermediate-acting benzodiazepine.
      • Pecking M.
      • Montestruc F.
      • Marquet P.
      • Wodey E.
      • Homery M.C.
      • Dostert P.
      Absolute bioavailability of midazolam after subcutaneous administration to healthy volunteers.
      • Mattila M.A.
      • Larni H.M.
      Flunitrazepam: a review of its pharmacological properties and therapeutic use.
      For the last eight years, we have successfully used midazolam and flunitrazepam for treating insomnia via single-dose subcutaneous administration. Single-dose administration is advantageous because it does not need specialized equipment, being simple and useful for patients and medical institutions, including patients receiving home care. However, to the best of our knowledge, single-dose subcutaneous administration of midazolam and flunitrazepam for treating insomnia has not been reported thus far.
      This retrospective analysis was carried out at the palliative care unit of JCHO Tokyo Shinjuku Medical Center (formerly Tokyo Kosei Nenkin Hospital). We reviewed the electronic medical records of patients admitted from January 2012 to December 2012 who fulfilled the following inclusion criteria: 1) diagnosis of advanced cancer and hospitalized in the palliative care unit, 2) difficulty taking medications orally, 3) complaining of poor sleep, and 4) agreeing to receive a benzodiazepine via single-dose subcutaneous injection. The approximate total sleep time, number of awakenings, and occurrence of adverse effects during the night were measured by the palliative care nursing staff. The study was approved by the Institutional Review Board of Tokyo Kosei Nenkin Hospital.
      During the study period, 151 patients were admitted to the palliative care unit of our hospital. There were 22 women and 39 men, with an average age of 73.3 years (range 53–95 years) who received midazolam and 13 women and 15 men, with an average age of 71.3 years (range 53–91 years) who received flunitrazepam. Primary tumor sites included lung (n = 22); esophagus, breast and colon/rectum (n = 5); pharynx (n = 4); pancreas, stomach/duodenum, liver/bile duct, ovary/uterus and kidney (n = 3); brain, peritoneum and renal pelvis (n = 2); and liposarcoma and adrenal (n = 1). The average duration of hospitalization in the palliative care unit was 35.9 days (median 16.0 days). Administration of midazolam and flunitrazepam is shown in Table 1.
      Table 1Administration of Midazolam and Flunitrazepam
      Midazolam (n = 61)Flunitrazepam (n = 28)
      Mean (SD)Median (Range)Mean (SD)Median (Range)
      One dose (mg)2.2 (.28)2 (1.5–2.5)0.88 (.12)0.8 (0.6–1)
      Total dosing days2.7 (2.1)2 (1–10)3.4 (3.5)2 (1–17)
      Dose frequency/day1.1 (.28)1 (1–2)1.1 (.22)1 (1–2)
      The rate of patients who could sleep more than six hours in total was 57% (midazolam) and 75% (flunitrazepam). Three patients complained of mild and transient pain at the time of the subcutaneous injection. No incidents of falling or critical events occurred among any of the patients.
      Benzodiazepines are one of the most commonly used hypnotic agents for treating insomnia; however, they cause various side effects.
      • Hirst A.
      • Sloan R.
      Benzodiazepines and related drugs for insomnia in palliative care.
      • Matsuo N.
      • Morita T.
      Efficacy, safety, and cost effectiveness of intravenous midazolam and flunitrazepam for primary insomnia in terminally ill patients with cancer: a retrospective multicenter audit study.
      In the palliative care population, where life expectancy is limited and patients experience severe pain and other problems, the goal of symptomatic relief possibly overrides the concerns of side effects. Previous reports have discussed the lack of an ideal hypnotic drug for patients with advanced cancer,
      • Kvale E.A.
      • Shuster J.L.
      Sleep disturbance in supportive care of cancer: a review.
      and an appropriate drug needs to be chosen for each patient based on individual medical status. The dosing period of the benzodiazepine was very short. The treatment with a single dose of benzodiazepine was intended to improve insomnia. Most of the patients faced difficulty in taking medications orally and had poor prognoses.
      We realize that our data are clearly tentative and preliminary; nonetheless, we consider that the high percentage of patients who could sleep more than six hours in total (57% and 75%) demonstrates the potential of single-dose subcutaneous administration of midazolam and flunitrazepam as a helpful method in patients with advanced cancer with insomnia. Further trials, including randomized placebo-controlled trials, are required for validating our results.

      Disclosures and Acknowledgments

      The authors express their gratitude to Dr. Asao Ogawa from the Research Center for Innovative Oncology of the National Cancer Center Hospital East for his contribution to this study. Special thanks also are given to the patients and hospice professionals who took part in the study.

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