IMPORTANCE The use of benzodiazepines to control agitation in delirium in the last days of life is controversial.OBJECTIVE To compare the effect of lorazepam vs placebo as an adjuvant to haloperidol for persistent agitation in patients with delirium in the setting of advanced cancer.DESIGN, SETTING, AND PARTICIPANTS Single-center, double-blind, parallel-group, randomized clinical trial conducted at an acute palliative care unit at MD Anderson Cancer Center, Texas, enrolling 93 patients with advanced cancer and agitated delirium despite scheduled haloperidol from February 11, 2014, to June 30, 2016, with data collection completed in October 2016.INTERVENTIONS Lorazepam (3 mg) intravenously (n = 47) or placebo (n = 43) in addition to haloperidol (2 mg) intravenously upon the onset of an agitation episode.MAIN OUTCOMES AND MEASURES The primary outcome was change in Richmond Agitation-Sedation Scale (RASS) score (range, -5 [unarousable] to 4 [very agitated or combative]) from baseline to 8 hours after treatment administration. Secondary end points were rescue neuroleptic use, delirium recall, comfort (perceived by caregivers and nurses), communication capacity, delirium severity, adverse effects, discharge outcomes, and overall survival.RESULTS Among 90 randomized patients (mean age, 62 years; women, 42 [47%]), 58 (64%) received the study medication and 52 (90%) completed the trial. Lorazepam + haloperidol resulted in a significantly greater reduction of RASS score at 8 hours (-4.1 points) than placebo + haloperidol (-2.3 points) (mean difference, -1.9 points [95% CI, -2.8 to -0.9]; P<.001). The lorazepam + haloperidol group required less median rescue neuroleptics (2.0 mg) than the placebo + haloperidol group (4.0 mg) (median difference, -1.0 mg [95% CI, -2.0 to 0]; P=.009) and was perceived to be more comfortable by both blinded caregivers and nurses (caregivers: 84% for the lorazepam + haloperidol group vs 37% for the placebo + haloperidol group; mean difference, 47%[95% CI, 14% to 73%], P=.007; nurses: 77% for the lorazepam + haloperidol group vs 30% for the placebo + haloperidol group; mean difference, 47%[95% CI, 17% to 71%], P=.005). No significant between-group differences were found in delirium-related distress and survival. The most common adverse effect was hypokinesia (3 patients in the lorazepam + haloperidol group [19%] and 4 patients in the placebo + haloperidol group [27%]).CONCLUSIONS AND RELEVANCE In this preliminary trial of hospitalized patients with agitated delirium in the setting of advanced cancer, the addition of lorazepam to haloperidol compared with haloperidol alone resulted in a significantly greater reduction in agitation at 8 hours. Further research is needed to assess generalizability and adverse effects.

10003 Background: Agitated delirium is a highly distressing neuropsychiatric syndrome common in the last days of life. The use of benzodiazepines for agitated delirium is highly controversial. We compared the effect of lorazepam versus placebo as an adjuvant to haloperidol for persistent agitated delirium. Methods: In this double-blind trial, we randomly assigned patients with advanced cancer admitted to an acute palliative care unit with agitated delirium despite scheduled haloperidol to either lorazepam 3 mg IV or placebo, in addition to haloperidol 2 mg IV upon the onset of agitation. The primary outcome was the Richmond Agitation Sedation Scale (RASS) over the first 8 hours, ranging from -5 (unarousable) to +4 (combative). Secondary endpoints were rescue neuroleptic use, perceived comfort, delirium-related distress, adverse effects and overall survival. 26 patients per arm provided 80% power to detect a between arm difference of 0.5 effect size in mean RASS with a=5%. We used the Wilcoxon Rank Sum test for primary comparison. Results: 52 of 58 (90%) patients who received the medications completed 8 h of observation. RASS decreased significantly within 30 min of treatment in both arms (Table). The lorazepam arm was associated with significantly greater reduction of RASS (Table), less rescue neuroleptics (mean haloperidol equivalent dose 1 mg v. 3 mg, P=0.02), and greater comfort as perceived by blinded caregivers (84% v. 37%, P=0.007) and nurses (77% v. 30%, P=0.005) compared to placebo. We found no significant between-group differences in delirium-related distress, adverse effects and overall survival (median 68 v. 73 h, P=0.56). Conclusions: The combination of lorazepam/haloperidol resulted in rapid and significant reduction of agitation compared to haloperidol alone. Our study supports the judicious use of single dose lorazepam/haloperidol for persistent agitated delirium. Clinical trial information: NCT01670097. [Table: see text]

Background: Limited information is available on the symptomatic complications that occur in the last days of life.Aim: We documented the frequency, clinical course, and survival for 25 symptomatic complications among patients admitted to acute palliative care units.Design: Prospective longitudinal observational study.Measurements: Their attending physician completed a daily structured assessment of symptomatic complications from admission to discharge or death.Setting/participants: We enrolled consecutive advanced cancer patients admitted to acute palliative care units at MD Anderson Cancer Center, USA, and Barretos Cancer Hospital, Brazil.Results: A total of 352 patients were enrolled (MD Anderson Cancer Center=151, Barretos Cancer Hospital=201). Delirium, pneumonia, and bowel obstruction were the most common complications, occurring in 43%, 20%, and 16% of patients on admission, and 70%, 46%, and 35% during the entire acute palliative care unit stay, respectively. Symptomatic improvement for delirium (36/246, 15%), pneumonia (52/161, 32%), and bowel obstruction (41/124, 33%) was low. Survival analysis revealed that delirium (p<0.001), pneumonia (p=0.003), peritonitis (p=0.03), metabolic acidosis (p<0.001), and upper gastrointestinal bleed (p=0.03) were associated with worse survival. Greater number of symptomatic complications on admission was also associated with poorer survival (p<0.001).Conclusion: Symptomatic complications were common in cancer patients admitted to acute palliative care units, often do not resolve completely, and were associated with a poor prognosis despite active medical management.

[The patient stated], ‘Let me up, get out of my way, I’m leaving. Get your hands off of me.’ Delirium had settled in with a vengeance now, and I wondered if it was the underlying disease, an infection, or an assemblage of causes that tangled his synapses and made us the enemy.

Clinicians have limited accuracy in the prediction of patient survival. We assessed the accuracy of probabilistic clinician prediction of survival (CPS) and temporal CPS for advanced cancer patients admitted to our acute palliative care unit, and identified factors associated with CPS accuracy. Eight physicians and 20 nurses provided their estimation of survival on admission by (a) the temporal approach, "What is the approximate survival for this patient (in days)?" and (b) the probabilistic approach, "What is the approximate probability that this patient will be alive (0%-100%)?" for ≥24 hours, 48 hours, 1 week, 2 weeks, 1 month, 3 months, and 6 months. We also collected patient and clinician demographics. Among 151 patients, the median age was 58 years, 95 (63%) were female, and 138 (81%) had solid tumors. The median overall survival time was 12 days. The median temporal CPS was 14 days for physicians and 20 days for nurses. Physicians were more accurate than nurses. A higher accuracy of temporal physician CPS was associated with older patient age. Probabilistic CPS was significantly more accurate than temporal CPS for both physicians and nurses, although this analysis was limited by the different criteria for determining accuracy. With the probabilistic approach, nurses were significantly more accurate at predicting survival at 24 hours and 48 hours, whereas physicians were significantly more accurate at predicting survival at 6 months. The probabilistic approach was associated with high accuracy and has practical implications.

Background: Recent reports suggest that high doses of methadone may prolong QTc interval and occasionally cause torsades de pointes; however, few of these studies involved the palliative care population. Objective: The purpose of this study was to determine the effect of initiation of methadone on QTc interval in patients with cancer pain seen at the palliative care setting. Methods: We enrolled 100 patients with cancer in this prospective study. Patients were followed clinically and electrocardiographically for QTc changes at baseline, 2, 4, and 8 weeks. Contributing factors for QTc prolongation such as medications, cardiovascular diseases, and electrolytes disturbances were documented. QTc prolongation was defined as greater than 430 ms in males and greater than 450 ms in females, and significant QTc prolongation was defined as QTc interval greater than 25% increase from baseline or 500 ms or more. Results: Electrocardiographic (ECG) assessments were available for 100, 64, 41, and 27 patients at baseline, 2-, 4-, and 8-week follow-up, respectively. At baseline prior to initiation of methadone, 28 (28%) patients had QTc prolongation. Clinically significant increase in QTc occurred in only 1 of 64 (1.6%) patients at week 2, and none at weeks 4 and 8. There was no clinical evidence of torsades de pointes, ventricular fibrillation, or sudden death. QTc prolongation was more frequent among patients with increased baseline QTc interval. Conclusions: Baseline QTc prolongation was common, whereas significant QTc interval 500 ms or more after methadone initiation rarely occurred, with no evidence of clinically significant arrhythmias. This study supports the safety of methadone use for pain control in patients with advanced cancer in the palliative care setting.

Intraspinal opioid therapy has been increasingly used for the management of cancer pain refractory to traditional treatment. However, this approach may present challenges in patients with advanced cancer. Three cases are presented that highlight the challenges associated with using neuraxial analgesia to manage cancer pain that was felt to be “refractory” to conventional treatment. Before an invasive procedure, such as placement of a permanent intrathecal opioid delivery system, a rigorous assessment and treatment of total pain (physical, psychological, spiritual, social, and practical) by an interdisciplinary team would be prudent.

INTRODUCTION:Methadone (ME) is a highly effective opioid agonist used for difficult pain syndromes. However, in the management of cancer pain with strong opioids, rotation to a different opioid (opioid rotation) may be required because of side effects or poor pain control. Rotation from methadone to another opioid has received limited study and therefore may be difficult because of the absence of a uniformly accepted dose conversion ratio.METHODS:Retrospectively reviewed consecutive medical records of patients undergoing an opioid rotation from methadone to an alternative opioid were evaluated. For inclusion, patients were required to have received methadone for at least 3 days and have reached stable dose of the alternative opioid(s) during the 7 days following. Stable dose was defined as a 30% or less change in opioid dose from one day to the next.RESULTS:Records of 39 patients met inclusion criteria. Excluded from analysis were 5 patients who were restarted on methadone within 7 days, 2 with irregular opioid use resulting in negligible regular opioid doses post-switch, and 3 due to concerns about reliability of multiple routes used for fentanyl. Data from 29 patients, 10 female, mean age 48 +/- 14.4 years, were evaluable. The mean dose ratio for oral methadone to oral morphine equivalent daily dose (MEDD) was 1:4.7 (95% confidence interval [CI], 3.0-6.5; n = 16), and for intravenous (IV) methadone to MEDD was 1:13.5 (95% CI, 6.6-20.5; n = 13), p = 0.06. Methadone dose was significantly correlated to stable MEDD after switching opioids for both methadone IV and oral (Spearman = 0.86, p = 0.0001 and Spearman = 0.72, p = 0.0024), respectively. Mean day of achieving stable dose was day 2.5 +/- 0.2 for IV methadone and day 2.6 +/- 0.3 for oral methadone.CONCLUSION:These dose ratios are new findings that may assist in switching patients more safely to alternative opioids when side effects or pain problems occur when patients are receiving methadone. An important difference in analgesic potency appears to exist between IV and oral ME. Future research with prospective studies is required.

Patients in severe pain, on high opioid doses, and exhibiting cognitive failure, are some of the most challenging patients to manage. Often there is uncertainty about the underlying cause of the pain, such as the role of physical vs. psychosocial factors and the role of opioid tolerance or substance abuse. Multiple medications are often administered in the attempt to improve the patient's situation by affecting multiple pain pathways. Clinicians rightfully become nervous when dealing with opioid doses that have become markedly escalated. Often there are few resources to turn to for guidance as the situation falls out of the norm from which the guidelines for opioid use have been determined. Sufentanil, a piperadine-derived mu agonist opioid, is a more potent congener of fentanyl that was approved for clinical use by the U.S. Food and Drug Administration in 1984.1Gauthier M.E. Fine P.G. The emerging role of the fentanyl series in the treatment of chronic cancer pain.in: Portenoy R.K. Bruera E. Topics in palliative care. Oxford University Press, New York1997: 177-194Google Scholar It has been used extensively for surgical anesthesia and also as a neuraxial analgesic for acute pain.2Reynolds L. Rauck R. Webster L. et al.Relative analgesic potency of fentanyl and sufentanil during intermediate-term infusions in patients after long-term opioid treatment for chronic pain.Pain. 2004; 110: 182-188Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 3Kampe S. Randerbrock G. Kiencke P. et al.Comparison of continuous epidural infusion of ropivacaine and sufentanil with intravenous patient-controlled analgesia after total hip replacement.Anaesthesia. 2001; 52: 1189-1193Google Scholar, 4Nelson K.E. Rauch T. Terebub V. et al.A comparison of intrathecal fentanyl and sufentanil for labor analgesia.Anesthesiology. 2002; 96: 1070-1073Crossref PubMed Scopus (86) Google Scholar However, experience with its use as a systemic analgesic for chronic pain is limited.2Reynolds L. Rauck R. Webster L. et al.Relative analgesic potency of fentanyl and sufentanil during intermediate-term infusions in patients after long-term opioid treatment for chronic pain.Pain. 2004; 110: 182-188Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar We report a challenging case of a patient receiving high doses of intravenous (IV) sufentanil. A 24-year-old Hispanic female, on active duty in the Army, had been diagnosed with Hodgkin's disease three years earlier. She was married and had a two-year-old daughter but there was history of a strain in her relationship with her husband. No history of substance abuse was apparent. She had undergone multiple chemotherapies, and mediastinal radiotherapy, with only partial response. Approximately three months before presentation, she had developed progressive left-sided pelvic pain, for which she commenced palliative radiotherapy. She was able to receive only two out of 20 fractions of radiation to her pelvis as she developed transfusion-dependent anemia and thrombocytopenia. At the time she was admitted to the hospital, her pain was rated 10/10 on a numeric rating scale and was described as a constant ache in the left lower abdomen and pelvis, aggravated by movement and radiating down to the lower thigh area. She had limited ability to ambulate. On examination, she was found to have a left lower quadrant abdominal mass, left lower extremity swelling but no objective weakness or sensory changes. Imaging studies had earlier shown sclerosis of the left ischium, acetabulum, and inferior pubic ramus, as well as a soft tissue mass involving the left obturator muscle and marked adenopathy of the left groin. Abdominal plain films showed no evidence of constipation, obstruction, ileus, or perforation. She was on a combination of multiple opioids, including hydromorphone, methadone, and oral transmucosal fentanyl citrate. All of these opioids were initially prescribed on an as needed basis. The patient was also taking lorazepam for anxiety. The hydromorphone was switched to IV via patient-controlled analgesia (PCA) and methadone was discontinued. She continued to report intractable pain, and after a few days on escalating doses of hydromorphone, she underwent an opioid rotation to sufentanil via PCA together with transdermal fentanyl. After 10 days, the patient continued doing poorly and the palliative care team was consulted. After initial assessment, she was transferred to the Palliative Care Unit (PCU). At this time, she appeared drowsy but arousable, with poor concentration and disorientation to time. Her Mini-Mental State Examination score was 5/30, indicating profound cognitive impairment. Due to the patient's cognitive decline, pain was rated by the nurse, with a resulting score of 7/10 on the Edmonton Symptom Assessment System. She was receiving sufentanil PCA with a basal rate of 100 mcg/h, a self-administered demand dose of 50 mcg every 10 minutes and a nursing bolus of 20 mcg/h as needed. She was also receiving a total of 250 mcg/h of transdermal fentanyl via patches, which were changed every 72 hours. Other medications included a lorazepam infusion of 0.5 mg/h, clonazepam 0.5 mg orally twice daily, dronabinol 12.5 mg orally twice daily, and dexamethasone 4 mg daily. Her cognitive impairment was attributed to opioid toxicity secondary to opioid escalation together with multiple centrally, acting drugs. A strong element of anxiety was evident based on the history. The team learned that the patient had recent communication of the bad news that her disease was refractory to treatment. This had caused further stress to the patient and her family. Her primary service had then discussed and documented her DNR status at that time. Her drug-induced delirium was deemed the more pressing clinical problem. The palliative care team was in agreement on stopping her dronabinol and both benzodiazepines. We then looked to the more challenging task of safely rotating her to an alternative opioid. The patient's opioid doses were extremely high. We decided to rotate sufentanil and transdermal fentanyl to methadone as the patient's sole opioid, based on the patient's previously tolerating this drug well and the significant potency of methadone seen with rotation from high doses of morphine, as reported by Ripamonti et al.5Ripamonti C. Groff L. Brunelli C. et al.Switching from morphine to oral methadone in treating cancer pain: what is the equianalgesic dose ratio?.J Clin Oncol. 1998; 16: 3216-3221PubMed Google Scholar We chose to rotate the sufentanil dose of the basal rate alone and not factor into the calculations contributions from demand and nursing boluses of sufentanil, as these, we believed, were heavily influenced by the patient's anxiety. The demand doses were discontinued due to the patient's impaired cognition. Due to the very large doses of opioids involved, we chose to gradually decrease the sufentanil PCA and fentanyl patches and introduce the oral methadone over three days (Table 1).Table 1Sufentanil/Fentanyl Rotation to MethadoneDaySufentanyl/FentanylMethadone (Oral)1Reduce sufentanil basal rate by 1/3 from 100 mcg/h to 60 mcg/hStart at 1/3 target dose 50 mg q8 hourReduce fentanyl patch by 1/3 from 250 mcg/h to 150 mcg/h q72 hour2Reduce sufentanil basal rate by 1/3 from 60 mcg/h to 30 mcg/hIncrease dose by further 1/3 to 100 mg q8 hourReduce fentanyl patch by further 1/3 from 150 mcg/h to 75 mcg/h q72 hour3Stop sufentanil PCA and fentanyl patchIncrease to target dose of 150 mg q8 hour Open table in a new tab The day following these changes, the patient had noticeable improvement in her functional status and cognition, with her Mini-Mental State Examination score improving to 23/30. By the eighth day on the PCU, she exhibited normal cognition, with a Mini-Mental State Examination of 26/30. She was able to receive other modalities to improve her pain, such as expressive-supportive counseling and visits from the chaplain as well as a family meeting. She voiced some of her significant fears that appeared to be contributing to her anxiety and expression of pain, including fear of what was going to happen to her two-year-old daughter, and her concern about tension between her husband and her mother and sister. She remained on the PCU for a total of 13 days, during which time it was possible to gradually reduce her methadone dose. During the last four days on the PCU, she rated her pain as a 1, 4, 4, and 1, respectively, on the 0–10 scale, but complained of anorexia, poor overall well-being, and insomnia. She was discharged home to hospice, ambulatory with minimal assistance, on oral methadone 30 mg every eight hours and 10 mg every two hours as needed for breakthrough pain. Two main points emerge from this case. The first concern we faced was extremely high doses of an opioid we use rarely, sufentanil via PCA. Although other strong opioids could have been used to rotate the patient off of sufentanil, methadone can be a particularly helpful drug in this setting as more manageable opioid doses result with the benefit of less future risk of opioid toxicity. For the purposes of illustration, we include the rationale we used in calculating the opioid rotation. A review of the literature shows few studies that address the relative potency of systemically administered sufentanil in patients receiving opioids chronically. Older literature reports sufentanil as being 10 times more potent than fentanyl.1Gauthier M.E. Fine P.G. The emerging role of the fentanyl series in the treatment of chronic cancer pain.in: Portenoy R.K. Bruera E. Topics in palliative care. Oxford University Press, New York1997: 177-194Google Scholar, 6Janssen P.A.J. Opioids in analgesia.in: Estafanous F.G. The development of new synthetic narcotics. Butterworth, Boston, MA1984: 40Google Scholar, 7Bailey P.L. Stanley T.H. Narcotic intravenous anesthetics.in: Miller R.D. Anesthesia. 3rd ed. Churchill Livingstone, New York1990Google Scholar Paix et al. reported a series of 11 cancer patients who were rotated from morphine continuous subcutaneous infusion (CSCI) to fentanyl CSCI due to unacceptable opioid side effects. The findings resulted in a recommendation that 150–200 mcg of fentanyl is equivalent to 10 mg morphine in nonopioid-naive chronic cancer patients. Two of the patients in this series required fentanyl CSCI to be changed to sufentanil CSCI due to the volume being too large for the portable syringe driver. The clinically derived sufentanil to fentanyl potencies were 24:1 and 16:1 in these two patients.8Paix A, Coleman A, Lees J, et al. Subcutaneous fentanyl and sufentanil infusion substitution for morphine intolerance in cancer pain management. Pain 63:263–269.Google Scholar However, Reynolds et al. investigated the relative analgesic potency of fentanyl and sufentanil IV in 41 patients on long-term opioid management for chronic pain and found sufentanil to be approximately 7.5 times as potent as fentanyl.2Reynolds L. Rauck R. Webster L. et al.Relative analgesic potency of fentanyl and sufentanil during intermediate-term infusions in patients after long-term opioid treatment for chronic pain.Pain. 2004; 110: 182-188Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar In performing the calculations for the opioid rotation, we elected to err on the side of underdosing rather than overdosing with the new opioid, and, therefore, used the findings of Paix et al. to convert the 2,400 mcg of IV sufentanil a day that the patient was receiving in the PCA basal rate to an equivalent dose of fentanyl by multiplying by a factor of 20 (i.e., between 24:1 and 16:1). The result was a calculated equivalent dose of IV fentanyl of 48,000 mcg per day. We then calculated an equivalent dose of IV morphine based on the established conversion ratios reported at www.palliative.org/PC/ClinicalInfo/AssesmentTools/, as we have had prior experience using this ratio (i.e., fentanyl 100 mcg IV=morphine 10 mg IV), rather than using the recommendation of Paix et al. for converting between fentanyl and morphine. This resulted in an equivalent dosage of 4,800 mg of IV morphine. This number was multiplied by 2.5 to achieve an oral morphine equivalent daily dose (MEDD) of 12,000 mg based on IV morphine being approximately 2.5 times more potent than oral morphine. We elected not to add in the contributions of the fentanyl patches as they were relatively small by comparison (250 mcg fentanyl patch=500 mg oral morphine). Based on this extremely high MEDD and the data extrapolated from the study of Ripmonti et al., we divided the MEDD by a factor of 20 (methadone being approximately 20 times more potent than morphine at this high MEDD) and then further reduced the dose by 25% to be cautious.5Ripamonti C. Groff L. Brunelli C. et al.Switching from morphine to oral methadone in treating cancer pain: what is the equianalgesic dose ratio?.J Clin Oncol. 1998; 16: 3216-3221PubMed Google Scholar This resulted in an equivalent oral daily dose of methadone of 450 mg. The second point is that psychosocial distress can be expressed as pain and may not be effectively managed with medications. Escalation of opioids and sedatives can exacerbate the situation by causing sedation and delirium. Opioid rotation and reduction of the dose, together with discontinuing the centrally acting agents, resulted in a return to normal cognition and patient then being able to engage in psychosocial interventions. The resulting reduction of the patient's opioid dose and pain complaint confirmed the initial clinical suspicion that a significant component of “total pain” or suffering was driving the patient's distress.

Journal of Palliative MedicineVol. 10, No. 2 Case Discussions in Palliative MedicinePalliative Sedation: When the Family and Consulting Service See No AlternativeEgidio Del Fabbro, Shantan G. Reddy, Paul Walker, and Eduardo BrueraEgidio Del FabbroSearch for more papers by this author, Shantan G. ReddySearch for more papers by this author, Paul WalkerSearch for more papers by this author, and Eduardo BrueraSearch for more papers by this authorPublished Online:1 May 2007https://doi.org/10.1089/jpm.2006.9974AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byManagement of Physical Symptoms in Patients with Advanced Cancer during the Last Weeks and Days of LifeCancer Research and Treatment, Vol. 54, No. 3Pain Management in the Era of the Opioid CrisisAmerican Society of Clinical Oncology Educational Book, Vol. 51, No. 38The Use of Ultrasound in Palliative Care and Hospice11 January 2016 | American Journal of Hospice and Palliative Medicine®, Vol. 34, No. 4Cancer-associated malnutrition, cachexia and sarcopenia: the skeleton in the hospital closet 40 years later20 January 2016 | Proceedings of the Nutrition Society, Vol. 75, No. 2Musculoskeletal pain in older adults at the end-of-life: a systematic search and critical review of the literature with priorities for future research25 July 2013 | BMC Palliative Care, Vol. 12, No. 1Delirium in Palliative Medicine: A ReviewJournal of Pain and Symptom Management, Vol. 44, No. 4Palliative Sedation26 November 2011 | Clinical Journal of Oncology Nursing, Vol. 15, No. 6Assessing the role of hydration in delirium at the end of lifeCurrent Opinion in Supportive & Palliative Care, Vol. 5, No. 2Efficacy and safety of deep, continuous palliative sedation at home: a retrospective, single-institution study3 April 2009 | Supportive Care in Cancer, Vol. 18, No. 1Use of palliative sedation for intractable symptoms in the palliative care unit of a comprehensive cancer center7 May 2008 | Supportive Care in Cancer, Vol. 17, No. 1 Volume 10Issue 2Apr 2007 InformationMary Ann Liebert, Inc.To cite this article:Egidio Del Fabbro, Shantan G. Reddy, Paul Walker, and Eduardo Bruera.Palliative Sedation: When the Family and Consulting Service See No Alternative.Journal of Palliative Medicine.Apr 2007.488-492.http://doi.org/10.1089/jpm.2006.9974Published in Volume: 10 Issue 2: May 1, 2007PDF download

8617 Background: Methadone (ME) is a highly effective opioid agonist used for difficult pain syndromes. However, the rotation from ME to another opioid may be difficult because of the absence of a uniformly accepted conversion ratio. Methods: We retrospectively reviewed consecutive medical records of Pts undergoing an opioid rotation from ME to an alternative opioid. For inclusion, Pts were required to have received ME for at least 3 days prior to the switch and reach a stable dose of the alternative opioid(s) during 7 days following. Stable dose was defined as a 30% or less change in opioid dose from one day to the next. For purposes of analysis, on the day before the switch, doses, were divided into ME doses and the oral morphine equivalent daily dose (MEDD), based on medication and route of all other opioids taken on that day, using standard equinalgesic tables. All doses after the switch were converted to the MEDD. For Pts receiving ME and a second opioid prior to the switch, the MEDD of the second opioid was subtracted from the MEDD calculated for the day when stable dose was reached. The remainder was used to calculate the equianalgesic raio with the previous ME dose. Results: Records on 39 Pts met inclusion criteria. Excluded from analysis were 5 Pts who were restarted on ME in < 8 days, 2 whose opioid dose markedly decreased of post switch, and 3 due to concerns about reliability of multiple routes used for fentanyl. Data from 29 Pts, 10 female, mean age 48 ±14.4 were evaluable. The ratio for: oral ME to MEDD was 1:4.7 (CL 3.0–6.5)(n=16), IV ME to MEDD was 1:13.5 (CL6.6–20.5)(n=13), p=0.06. ME dose is significantly correlated to stable MEDD after switching opioids for both ME IV and oral (Spearman=0.86,p=0.0001 and Spearman=0.72, p=0.0024, respectively. Mean day of achieving stable dose was on day 2.5 ±0.2 for IV ME and day 2.6±0.3 for oral ME. Conclusions: These dose ratios are new findings that will assist in switching Pts more safely to alternative opioids, when side effects or pain problems occur.An important difference in analgesic potency appears to exist between IV and oral ME. Further research with prospective studies is required. No significant financial relationships to disclose.

Patients with advanced cancer frequently experience intractable pain without sufficient response to a conventional pharmacological approach. One reason for refractory pain at the end of life can be the bidirectional nature of pain and suffering. Three terminally ill patients were assessed using a multidimensional palliative pain concept, including sensory, affective, cognitive, and existential components. In these patients, resistant pain did not equal insufficient eradication of the nociceptive input, but also suffering. Unrelieved emotions, depressive or anxious symptoms, delirium, difficulties communicating, or chemical coping influenced the expression of pain, illuminating the phenomenon of somatization. Palliative pain treatment integrated analgesic treatments, psychological, rehabilitative, and existential interventions, in consideration of individual expectations and outcomes. With the disciplined assessment and alternative multidisciplinary palliative approach, the quality of life of three terminally ill cancer patients with intractable pain could be enhanced, and unnecessary interventions and escalation of medications avoided.

Bisphosphonates have become standard treatment in management of malignancy-induced hypercalcemia and malignant bone pain. One obstacle to the routine use of bisphosphonates in palliative patients is that oral bisphosphonates have low bioavailability and a degree of gastrointestinal toxicity that may explain poor compliance. Intravenous administration can be cumbersome in patients admitted to long-term care settings or at home. We have developed and tested a new way of administering clodronate via subcutaneous infusion. This retrospective cohort study evaluated 150 patients admitted to a tertiary palliative care unit from May 1996 to May 2000 who received 254 subcutaneous infusions of clodronate for hypercalcemia or bony complications. Data were collected by chart review and specifically evaluated site toxicity and biochemistry. There was minimal local toxicity and only 2 infusions needed to be discontinued because of pain at the subcutaneous site. Clodronate showed efficacy in normalizing the serum calcium within 5 days post-infusion in 32 of 43 infusions given for hypercalcemia. This study shows that subcutaneous clodronate is safe and can lower serum calcium levels in malignant hypercalcemia.

Three patients who developed torsades de pointes while receiving high dosages of oral methadone (>600mg/day) are presented. In all of the cases, drug interactions involving methadone and CYP3A4 isoenzyme system were possible. Two cases involve some previous cardiac impairment. The potential for toxic doses of methadone to cause ventricular arrhythmia is raised by these cases. Until further evidence is available it may be prudent to be vigilant for arrhythmias when high dosages of methadone (>600mg/day) are used, especially in patients on other drugs that interact with the CYP3A4 isoenzyme system, or with conditions that predispose to torsades de pointes.

Cocaine addiction is characterized by long-lasting vulnerability to relapse arising because neutral environmental stimuli become associated with drug use and then act as cues that induce relapse. It is not known how cues elicit cocaine seeking, and why cocaine seeking is more difficult to regulate than seeking a natural reward. We found that cocaine-associated cues initiate cocaine seeking by inducing a rapid, transient increase in dendritic spine size and synaptic strength in the nucleus accumbens. These changes required neural activity in the prefrontal cortex. This is not the case when identical cues were associated with obtaining sucrose, which did not elicit changes in spine size or synaptic strength. The marked cue-induced synaptic changes in the accumbens were correlated with the intensity of cocaine, but not sucrose seeking, and may explain the difficulty addicts experience in managing relapse to cocaine use.

Institution-based palliative care continues to change rapidly thanks to the commitment of research in the field of palliative medicine. Home hospice care in the United States, however, still struggles to incorporate evidence-based medicine into its medical practice. Multiple reasons exist, including lack of physician leadership due to busy private practices, minimal available full-time opportunities for physicians in hospice care, poor support from hospices in the training and retention of qualified physicians, and a lack of teaching of hospice nursing staff by their team physicians.

Oxycodone is a strong opioid that has been available for at least 70 years. At present, commercially prepared parenteral oxycodone is only available in Finland. We report in this paper our experience of administering oxycodone s.c. From 21 October 1996 to 31 July 1998, 63 advanced cancer patients received intermittent s.c. injections of oxycodone via the Edmonton Injector, a simple, low-cost mechanical device. Local tolerance and systemic toxicity were followed prospectively. Only 2 patients developed s.c. injection site intolerance, and in both cases doses of 50 mg/ml or more were being administered. Most of the patients in this study were rotated to oxycodone because of opioid toxicity, and in 34% of those patients their delirium subsided. A subgroup of 19 patients who underwent rotation to oxycodone SC from morphine and hydromorphone were studied for equivalent analgesia with oxycodone. We found a ratio (mean +/- SD) of 1.2+/-0.4 for morphine s.c. to oxycodone s.c. and a mean ratio of 0.5+/-0.4 for hydromorphone s.c. to oxycodone s.c. When hydromorphone s.c. was converted to a morphine s.c. equivalent dose and the results for these patients were added to those for the morphine s.c. group, the mean and median overall ratios of morphine s.c. equivalent dose to oxycodone were 1.9+/-1.5 and 1.4, respectively. The cost of the oxycodone s.c. was also evaluated and was found to be comparable to that of morphine s.c. and lower than that of hydromorphone s.c. We conclude that s.c. oxycodone can be an effective, safe and inexpensive alternative opioid agonist.