A systematic review of opioid conversion ratios used with methadone for the treatment of pain.

OBJECTIVE: Review and analyze the evidence base comprising methadone conversion methods and associated dosing ratios for the treatment of pain. DESIGN: Systematic review. METHODS: Clinical trials and retrospective analyses, case series, and case reports of human subjects published in the English language between January 1966 and June 2006 were included; review articles and reports with incomplete opioid data were excluded. Scatterplots displayed the relationship between previous morphine dose and final methadone dose and dose ratio. Correlation analyses were conducted using Pearson's and Spearman's correlation coefficient with a one-tailed test of significance. RESULTS: Twenty-two clinical studies and 19 case reports or series were reviewed (N = 730 patients). Methadone rotations were most common in cancer patients (N = 625, 88.9%) and those prescribed morphine (N = 259 patients, 41.7% of rotations where prerotation opioid was identified [N = 621]) or hydromorphone (N = 234 patients, 37.7% of rotations). In clinical studies, the most common reason for switching to methadone was a combination of inadequate analgesia and adverse effects (N = 254, 38.6%). Despite various approaches, 46-89% of rotations were successful. Overall, there was a relatively strong, positive correlation between the previous morphine dose and the final methadone dose and dose ratio, but ratios varied widely. CONCLUSIONS: There was no evidence to support the superiority of one method of rotation to methadone over another. Patients may be successfully rotated to methadone despite discrepancies between rotation ratios initially used and those associated with stabilization. Further research is needed to identify patient-level factors that may explain the wide variance in successful methadone rotations.

Actual and potential drug interactions associated with methadone.

OBJECTIVE: To identify and characterize methadone-related drug interactions, as well as factors accounting for the variability in manifesting these interactions clinically. DESIGN: Systematic review of the primary literature. METHODS: Over 200 articles, reports of clinical trials, and case reports were reviewed. Studies and case reports were included if they revealed either quantitative or qualitative methods to identify, evaluate severity of, or compare methadone-related drug interactions. RESULTS OF DATA SYNTHESIS: The evidence base associated with methadone drug interactions is underdeveloped in general, as the majority of references found were case reports or case series. Most of the studies and reports focused on inpatients receiving methadone maintenance treatment (MMT) that were between 20 and 60 years of age, taking 200 mg/day of methadone or less. Evidence supporting the involvement of lesser known cytochrome P450 enzymes such as 2B6 is emerging, which may partially explain the inconsistencies previously found in studies looking specifically at 3A4 in vitro and in vivo. Genetic variability may play a role in the pharmacokinetics and pharmacodynamics of many medications, including methadone. CONCLUSIONS: Drug interactions associated with methadone and their clinical significance are still poorly understood in general. Many tertiary drug information references and review articles report interactions associated with methadone in a general sense, much of which is theoretical and not verified by case reports, much less well-designed clinical trials. The majority of drug interaction reports that do exist were performed in the MMT population, which may differ significantly from chronic pain or cancer pain populations.

Medication inappropriateness for older adults receiving hospice care: a pilot survey.

OBJECTIVE: To test the feasibility and reliability of a tool and methodology for evaluating expert clinicians' perceptions about the application of the Beers criteria in hospice. DESIGN: A pilot survey. SETTING: A national medication therapy management provider specializing in hospice care. PARTICIPANTS: Thirty-five participants from a multidisciplinary panel were invited to complete the survey. They were selected to represent acute, long-term care, and community practice settings with various levels of experience and judgment. INTERVENTION: Respondents were asked to complete the survey by rating their agreement or disagreement with the inappropriateness of the medications or medication classes for hospice patients, using a five-point Likert scale from strongly agree (1) to strongly disagree (5), with the midpoint (3) expressing equivocation. MAIN OUTCOME MEASURES: Feasibility as measured by the percentage of returned and completed surveys. A secondary aim was to measure inter-rater reliability and response. RESULTS: Twenty-four clinicians (69%) completed the survey, including 13 clinical pharmacists, 6 nurses, and 5 physicians. Twenty-nine responses (2%) were furnished by imputation methods. The intraclass correlation for medication inappropriateness for hospice patients was 0.89 (0.81-0.95), indicating "good" inter-rater reliability. Short-acting benzodiazepines, gastrointestinal antispasmodics, anticholinergics, and antihistamines were considered appropriate for use in older hospice patients, but they are considered inappropriate according to the Beers criteria. CONCLUSION: We established a viable methodology for evaluating clinician judgment about medication inappropriateness in older hospice patients. Some medications routinely considered to be inappropriate may be appropriate at end of life; different criteria may be needed to determine medication inappropriateness in hospice care.

Are newer, more expensive pharmacotherapy options associated with superior symptom control compared to less costly agents used in a collaborative practice setting?

Innovative approaches to care may be necessary to provide the most effective symptom management to hospice patients. One approach is prescribing newer pharmacotherapy options with the potential to improve symptom management in hospice. Such therapies are sometimes prescribed outside of Food and Drug Administration indications and are typically more costly than older agents used for the same symptoms. Another approach is the collaborative practice (CP) care model, whereby clinical pharmacists are given prescriptive authority according to evidence-based protocols and algorithms within boundaries approved by a physician. The agents typically included in CP protocols are those with wide therapeutic indices and with substantial evidence to support their use. The purpose of this study was to examine both approaches to management of pain, insomnia, and nausea, comparing symptom scores for those patients who received noncollaborative drug therapies (transdermal fentanyl, zolpidem, and ondansetron) to those who received agents under CP (oral sustained-release opioids, temazepam, and prochlorperazine). The object of the study was to investigate outcomes associated with newer drug therapy options as compared to older agents for the management of pain, insomnia, and nausea. A secondary goal is to compare symptom outcomes for patients receiving pharmaceutical care under CP and non-CP models. The study design was retrospective with a cohort. A total of 50 patients were randomly selected for each cohort of the pain and insomnia study arms. Only 45 patients prescribed oral ondansetron met inclusion criteria for the nausea group; 45 patients prescribed prochlorperazine were randomly selected as the comparator group. Patients were compared on their degree of response to the prescribed therapy. Response was classified as complete, partial, no improvement from baseline, worsened, or unknown. A complete response was defined as the symptom score improving to a 0 of 10, regardless of the previous value documented. A partial response was defined as any improvement in score that did not result in a 0 of 10. No improvement from baseline reflected a lack of overall change in score throughout the series of data points collected. A worsened response was any score found to be higher than the score documented at the time of dispense. The unknown category reflects any set of scores that had an "N/A " documented at the time of medication dispense or when documented for both attempts subsequent to dispensing the medication. A complete response was present in 14 of 50 (28 [corrected] percent) of the patients prescribed oral therapy [corrected] as compared with 12 of 50 (24 [corrected] percent) of those prescribed fentanyl [corrected] (p = .82). Responses defined as partial, no improvement over baseline, worsened, and unknown were also comparable between the two cohorts. A complete response was seen in 26 patients prescribed temazepam (52 percent), whereas only 11 (22 percent) of patients initially prescribed zolpidem achieved the same response (p = .0037). Both groups had a similar distribution of partial, no improvement over baseline, and worsened responses. For the nausea arm of the study, a difference was found in the number of complete responses, favoring prochlorperazine (22 of 45, 48.9 percent for prochlorperazine, 12 of 45, 26.7 percent for ondansetron, p = .0504), as well as an increased number of worse responses seen with ondansetron patients (p = .0513); however, neither difference was statistically significant. Newer pharmacotherapy options for the management of pain, insomnia, and nausea were not found to be superior when compared to older agents prescribed under CP.

Tolerability of the compound ABHR in hospice patients.

BACKGROUND: Compounded formulations comprised of multiple medications may be useful for some patients with refractory nausea and vomiting. The combination of lorazepam, diphenhydramine, haloperidol, and metoclopramide (ABHR) has been used for more than a decade in the management of nausea and vomiting, but the tolerability of this combination in hospice patients has not been examined. OBJECTIVE: Determine the tolerability of the ABHR compound in both younger and elderly hospice patients. DESIGN: Retrospective cohort study. SETTING/SUBJECTS: A total of 11,181 ABHR prescriptions dispensed to 8600 hospice patients in the home care setting were analyzed. RESULTS: A total of 42 ABHR prescriptions were discontinued secondary to adverse drug reactions (ADRs) in 39 patients. Older patients appear to be more sensitive to the effects of ABHR, however, this trend did not achieve statistical significance when looking at extrapyramidal symptoms (EPS) specifically in these patients. The overall incidence of EPS was low, as only 0.1% of all prescriptions discontinued secondary to an ADR were consistent with EPS. CONCLUSIONS: The compound ABHR is generally well tolerated in the majority of hospice patients. More investigation is warranted to determine the efficacy and tolerability of similar pharmaceutical compounds used commonly in the hospice patient population.

Development of guidelines for palliative care pharmacotherapy.

Despite limited evidence to support their use, hospice and palliative care programs commonly employ protocols and/or algorithms for symptom management. The use of these tools may assist in the standardization of care and help manage pharmacotherapy-related costs. The process used by one national palliative care pharmacy company to create palliative care guidelines and algorithms is described along with some of the challenges in validating such tools.

Toward evidence-based prescribing at end of life: a comparative review of temazepam and zolpidem for the treatment of insomnia.

A comparative review of temazepam and zolpidem use in managing insomnia in the hospice patient was undertaken to determine whether treatment with temazepam is a more cost-effective approach for this patient population. A MEDLINE search was conducted to identify pertinent literature, including clinical trials and reviews that involved temazepam or zolpidem. Published data was used as background information and provided in the discussion. This retrospective analysis, conducted from June 2002 through November 2002, focused on the prescribing patterns of temazepam and zolpidem in our hospice practice setting. We examined the reasons for discontinuation of each agent, along with the frequency of therapeutic change from temazepam to zolpidem. The top 10 ICD-9 codes associated with each treatment modality were investigated to determine any prescribing patterns. A total of 4,752 participants were prescribed either temazepam or zolpidem during this six-month period. Of the 4,065 patients prescribed temazepam 9.9 percent had the agent discontinued, whereas, 13.0 percent of those taking zolpidem (n = 687) terminated therapy. Reasons for discontinuation included change in dose, incomplete efficacy, change in patient status, adverse drug reaction, cultural/social issues and "other." Analyses of prescribing patterns and the reasons for termination of each drug therapy were completed and compared with results found in the primary literature. Due to the limited financial resources available for hospice care, our goal is to provide the most clinically appropriate and cost-effective agents for hospice patients. With the lack of data pertaining to the hospice patient, physicians often are faced with challenges in deciding the most appropriate therapy. They may prefer one agent over another based on current medical opinion rather than sound clinical evidence. After review of the primary literature and the prescribing patterns in our setting, there is currently no evidence in our patient population to support that zolpidem is superior to benzodiazepines for the treatment of insomnia.

Acetylcholinesterase inhibitor and N-methyl-D-aspartic acid receptor antagonist use among hospice enrollees with a primary diagnosis of dementia.

OBJECTIVES: To describe acetylcholinesterase inhibitor (AChEI) and memantine use among persons over the age of 65 admitted to hospice with a primary diagnosis of dementia and identify patient and hospice program characteristics associated with the use of these agents. DESIGN: Retrospective, cross-sectional study. SETTING: Administrative database of a national hospice pharmacy provider. PARTICIPANTS: A total of 10,065 persons with end-stage dementia admitted to one of 441 U.S. hospices in 2004. MEASUREMENTS: The frequency of AChEI and memantine use was determined and utilized as the unit of analysis for bivariate and multivariate comparisons with patient and hospice program characteristics. RESULTS: Twenty-one percent (2148/10,065) of patients were prescribed AChEI and/or memantine therapy at the time of hospice enrollment. Of these, 49.5% were prescribed donepezil. Odds of receiving AChEI and/or memantine therapy were less likely if the patient was female, (odds ratio [OR] 0.68, 0.62-0.76), died while enrolled in hospice (OR 0.75, 0.67-0.85), received care at home (0.80, 0.71-0.89), or had a hospice length of stay (LOS) less than 7 days (0.53, 0.45-0.62). Patients who had a LOS of at least 60 days were significantly more likely to have received such therapies (OR 1.41 [1.24-1.60] for 61-180 days and 1.33 [1.15-1.54] for over 180 days). CONCLUSION: A notable number of hospice enrollees with a primary diagnosis of dementia were prescribed AChEI and/or NMDA receptor antagonist therapy. Studies are needed to better define the role of these agents as well as the impact of medication discontinuation in persons with end-stage dementia.

Initial Selection of Antiemetics in End-of-Life Care: A Retrospecitve Analysis.

The purpose of this study was to compare the relative severity of nausea and vomiting scores before and after initiation of treatnment regimens in end-of-life cancer patients, and secondarily to evaluate the efficacy of a combination antiemetic preparation (ABHR; lorazepam [Ativan], diphenhydramine [Benadryl], haloperidol [Haldol], and metoclopramide [Reglan] in this patient population. A retrospective analysis of antiemetic use was performed through a systematic chart review of patients with an end-of-life diagnosis of lung, pancreatic, or colorectal cancer whose medications were provided through Hospice Pharmacia. Information collected included patient age and sex; terminal diagnosis; pre- and post-antiemetic nausea and vomiting scores; and initial antiemetic choice. A total of 584 patient records were examined, and the most widely used antiemetics used were prochlorperazine, metoclopramide, and ABHR. The most prevalent diagnosis was lung cancer. All of the agents and preparations were determined to be effective as intial therapy for the management of nausea and vomiting in the end-of-life cancer patient; therefore use of these agents as first-line therapy options in this population appears to be justified. ABHR appears to be at least as efficacious as other first-line monotherapy options investigated. Despite a lack of information on the absolute bioavailability of alternative ABHR dosage forms such as suppositories and topical gels, these also appear to be efficacious and therefore are viable options in the treatment of nausea and vomiting in end-of-life cancer patients.

Toward evidence-based prescribing at end of life: a comparative analysis of sustained-release morphine, oxycodone, and transdermal fentanyl, with pain, constipation, and caregiver interaction outcomes in hospice patients.

OBJECTIVE: The primary goal of this investigation was to examine selected outcomes in hospice patients who are prescribed one of three sustained-release opioid preparations. The outcomes examined include: pain score, constipation severity, and ability of the patient to communicate with caregivers. PATIENTS AND SETTINGS: This study included 12,000 terminally ill patients consecutively admitted to hospices and receiving pharmaceutical care services between the period of July 1 and December 31, 2002. DESIGN: We retrospectively examined prescribing patterns of sustained-release morphine, oxycodone, and transdermal fentanyl. We compared individual opioids on the aforementioned outcome markers, as well as patient gender, terminal diagnosis, and median length of stay. RESULTS: Patients prescribed a sustained-release opioid had similar average ratings of pain and constipation severity, regardless of the agent chosen. Patients prescribed transdermal fentanyl were reported to have more difficulty communicating with friends and family when compared with patients prescribed either morphine or oxycodone. On average, patients prescribed transdermal fentanyl had a shorter length of stay on hospice as compared with those receiving morphine or oxycodone. CONCLUSION: There was no difference in observed pain or constipation severity among patients prescribed sustained-release opioid preparations. Patients receiving fentanyl were likely to have been prescribed the medication due to advanced illness and associated dysphagia. Diminished ability to communicate with caregivers and a shorter hospice course would be consistent with this profile. Further investigation is warranted to examine the correlation between a patient's ability to interact with caregivers and pain control achieved.

Methadone and the hospice patient: prescribing trends in the home-care setting.

OBJECTIVE: To identify frequency and utilization patterns of methadone by hospice patients in the home-care setting. PATIENTS AND SETTING: All hospice patients admitted to a North American palliative care specialty pharmacy and dispensed methadone from November 1, 2001 to October 31, 2002 were analyzed. We also analyzed all hospice patients dispensed long-acting opioids during that same time period. DESIGN: A retrospective analysis of the pharmacy database was performed for patients dispensed methadone. Data was compared to the long acting opioid cohort to be able to identify any difference in terminal diagnoses present, and the presence of neuropathic pain in both groups. Methadone daily dosage was also analyzed during this study. RESULTS: Four hundred sixteen hospice patients were dispensed methadone over a twelve-month period of time. For comparison, 21,219 patients were prescribed a long-acting opioid preparation (sustained-release morphine, sustained-release oxycodone, or transdermal fentanyl). The most common terminal diagnosis for both groups was lung carcinoma. The distribution of terminal diagnoses was similar in both groups. The group prescribed methadone was found to have a higher incidence of neuropathic pain (30.5% of patients) when compared to the long-acting opioid group (16.9%). Most patients (61.3%) were prescribed daily methadone doses of 100 mg or less. CONCLUSIONS: Despite its potential clinical and economic benefits, methadone is not commonly prescribed for the hospice patient in the home-care setting. Clinicians may be more aware of the usefulness of methadone in the treatment of neuropathic pain.