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Rectal Administration of Baclofen at the End of Life

Open ArchivePublished:August 07, 2018DOI:https://doi.org/10.1016/j.jpainsymman.2018.07.023
      To the Editor:
      Spasticity can be a complicating symptom of a variety of neurological conditions such as multiple sclerosis, motor neuron disease, Creutzfeldt-Jakob disease, or poststroke. Several pharmacological treatment options are available, including baclofen, tizanidine, gabapentin, botulinum toxin A, and tetrahydrocannabinol/cannabidiol.
      • Otero-Romero S.
      • Sastre-Garriga J.
      • Comi G.
      • et al.
      Pharmacological management of spasticity in multiple sclerosis: Systematic review and consensus paper.
      • Kamen L.
      • Henney 3rd, H.R.
      • Runyan J.D.
      A practical overview of tizanidine use for spasticity secondary to multiple sclerosis, stroke, and spinal cord injury.
      However, treatment feasibility decreases as the end of life approaches, for example, when patients are no longer able to tolerate oral medications, the onset of action would be too long, or the initiation of parenteral drug therapy (intravenous, intrathecal) is no longer indicated or appropriate. In these patients, alternative routes for drug administration are required. We report the pharmacological management of two patients with severe, painful spasticity due to progressive neurodegenerative disease with rectal baclofen.

      Case Report

      Case 1

      The first patient was a 76-year-old man who had been diagnosed with Parkinson's syndrome two years earlier. During the last six months, he had developed progressive cognitive and physical deficits with repeated falls. Physical examination at that time revealed vigilance decrement, visual hallucinations, delusions, and myoclonus. Electroencephalography had been recorded on several occasions, showing isolated triphasic waves. Computed tomography showed no pathology. Magnetic resonance imaging (MRI) showed no changes typical for Creutzfeldt-Jakob disease (CJD). Examination of the spinal fluid revealed normal cell counts and little increase of protein (51 mg/dL). Parameters for autoimmune encephalitis and onconeuronal antibodies were unverifiable. 14-3-3 protein was negative. Tau, phosphotau, and beta-amyloid were within normal limits. FDG-PET showed a widespread cortical hypometabolism.
      During a hospitalization, the patient developed dysphagia, and severe and painful spasticity. He subsequently deteriorated to a state of akinetic mutism. According to the patient's presumptive wishes, a palliative regimen with a focus on symptomatic treatment was started. The analgesic regimen consisted of hydromorphone 3 mg/24 hours, metamizole (dipyrone) 2.5 g/24 hours, and midazolam 30 mg/24 hours as a continuous subcutaneous infusion. With these drugs, severe spasticity remained the leading problem and baclofen was considered.
      As enteral administration was not feasible and the intrathecal application was considered inappropriate, we decided to administer baclofen rectally and to use the Modified Ashworth Scale (MAS)
      • Rekand T.
      Clinical assessment and management of spasticity: a review.
      to document the therapeutic effect. Informed consent for performance and publication was obtained from the health care agent of the patient. Regular baclofen tablets were used and covered in petroleum jelly to facilitate rectal insertion. At baseline (day 0), the upper extremity was rigid in flexion and the lower extremity rigid in extension (MAS scoring: 4). Baclofen was initiated starting at 5 mg rectally three times per day. On day 2, a marked improvement of spasticity (scoring: 1+) could be observed. On day 4, the increased muscle tone had subsided entirely (scoring: 0). The patient seemed calm, and his symptoms were well controlled. Rectal baclofen was tolerated well. On day 3, serum concentrations of baclofen were at 210 μg/L (reference: 100–600 μg/L). As baclofen has a short half-life, the blood sample was taken 2 hours after the third administration.
      The treatment was continued successfully until the patient died 8 days later. There was no recurrence of spasticity, and there were no signs of side effects. Autopsy was declined by the patient's relatives.

      Case 2

      The second patient was a 64-year-old man who presented with rapid and progressive mental deterioration, and cerebellar and visual disturbances. He subsequently developed akinetic mutism and myoclonus. Magnetic resonance imaging showed high signal abnormalities in the caudate nucleus on diffusion-weighted imaging, and 14-3-3 protein was positive. Thus, clinical presentation and diagnostics led to the clinical diagnosis of CJD. This diagnosis was confirmed postmortem by neuropathological findings.
      The patient received a continuous subcutaneous infusion delivering midazolam 15 mg/24 hours for agitation, anxiety, and spasticity, and metamizole (dipyrone) 4 g/24 hours and hydromorphone 2 mg/24 hours for pain. Despite increasing the midazolam dose (20 mg/24 hours, with additional boluses of 2.5 mg), spasticity remained a major problem (MAS scoring 4). Owing to the lack of feasible treatment options, rectal baclofen was started at 5 mg three times per day. Informed consent for performance and publication was obtained from the health care agent of the patient. The mode of administration was similar to case 1. The dose was increased to 10 mg three times per day on day 3 and 20 mg three times on day 6. The treatment was tolerated well, but the spasticity remained unchanged (MAS scoring 4). The tablets did not dissolve in the rectum after administration, and the serum concentration of baclofen remained subtherapeutic at <20 μg/L on day 6. The patient died 10 days after baclofen treatment was started, four months after onset of CJD symptoms.

      Discussion

      Baclofen is a GABAB-receptor agonist. It acts primarily by decreasing the release of excitatory neurotransmitters in the spinal cord and the brain
      Trevor. BKSMA
      Basic and Clinical Pharmacology.
      and is licensed for spasticity from multiple sclerosis, spinal disease, or trauma. It is commercially available in tablets for oral administration and in solution for intrathecal drug administration. After oral administration, the onset of action is seen within days.
      Treatment with baclofen is compromised if the oral route is unavailable and intraspinal therapy is not appropriate. Our patients lost the oral route, and due to rapid deterioration, management strategies that involved an extended period of time for onset of action (e.g., gabapentin, cannabis) or invasive procedures to gain access for drug administration (e.g., enteral feeding tube, intrathecal access) were deemed to be inappropriate.
      Although the successful subcutaneous administration of baclofen in one patient has been reported,
      • Remi C.
      • Albrecht E.
      Subcutaneous use of baclofen.
      this approach is cost-intensive and a second subcutaneous needle might be necessary as compatibility data with other drugs are very limited. For this reason, and despite a published report describing no measurable absorption of baclofen after rectal administration to six healthy volunteers,
      • Kriel R.L.
      • Krach L.E.
      • Hoff D.S.
      • Gormley M.
      • Jones-Saete C.
      Failure of absorption of baclofen after rectal administration.
      we decided to try the rectal route. There was no reasonable alternative available, no negative effects were expected (e.g., local irritation in the rectum), and the worst potential outcome was no therapeutic effect.
      Rectal administration appeared successful in Case 1 and unsuccessful in Case 2. These differing outcomes might be explained by the heterogeneous conditions in the rectum. The absorbing surface area in the rectum is relatively small compared with the small intestine. Blood supply of the upper part of the rectum drains into the portal vein; blood supply in the middle and inferior part of the rectum drains into the inferior vena cava, thus avoiding hepatic first pass metabolism. However, the presence of feces can impair drug absorption.
      • Warren D.E.
      Practical use of rectal medications in palliative care.
      Furthermore, to be absorbed a drug has to be dissolved; but only 1–3 mL of mucus is present in the rectum.
      • Bauer K.H.
      • Frömming K.-H.
      • Führer C.
      Pharmazeutische Technologie: Mit Einführung in Biopharmazie und Biotechnologie.
      Volumes up to 25 mL can usually be retained by the patient, although there is always a risk of spontaneous expulsions especially in an unconscious patient.
      These observations suggest that rectal baclofen will be sufficiently absorbed in some patients to yield therapeutic serum levels. For this reason, a trial of the rectal route might be considered as a practical alternative when neither the oral nor the parenteral route of drug administration is an option. Although our experience is limited to two patients and has limited generalizability, it raises the possibility of an interesting alternative when other therapeutic options are neither indicated nor available. A therapeutic trial of rectal administration of baclofen at the end of life can be justified if no other therapeutic options are available and the individual risk-benefit ratio favors its use. Further research is necessary to learn more about this route of administration for baclofen.

      Disclosures and Acknowledgments

      Charlotte Selge, Claudia Bausewein, and Constanze Remi report no disclosures.
      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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