Pro Re Nata Prescribing in a Population Receiving Palliative Care: A Prospective Consecutive Case Note Review Bethany J. Russell, MBBS,* Debra Rowett, BPharm,† and David C. Currow, B Med, MPH, PhD‡

OBJECTIVES: To document pro re nata (PRN) prescribing practices and to identify patterns with respect to clinical characteristics and the medications prescribed. DESIGN: Prospective consecutive case note review. SETTING: Two interrelated consultative hospice and palliative care services in regional Victoria, Australia. PARTICIPANTS: Terminally ill inpatients and community-based individuals (N = 203) at the time of referral to a hospice or palliative care service. MEASUREMENTS: Number of medications that the referring physician prescribed on a PRN basis and on a regular basis for symptom control; comorbid disease, performance status, comorbidity burden, disease phase, and survival. RESULTS: Mean number of PRN medications prescribed was 3.0, with significantly higher rates in the last week of life (rate ratio (RR) = 1.30, 95% confidence interval (CI) = 1.07–1.59) and during the terminal phase of disease (RR = 1.36, 95% CI = 1.09–1.68). One-quarter of prescriptions were for medications that met the Beers consensus criteria for potentially inappropriate medication use in elderly persons. CONCLUSION: These descriptive baseline data are new. A mean of three different medications allows responsiveness to a variety of fluctuating symptoms, but there was a large range within the sample, indicating that some individuals and their caregivers have a high burden of administration-related decision-making. J Am Geriatr Soc 62:1736–1740, 2014.

Key words: palliative care; hospice care; physician prescribing patterns; polypharmacy; pro re nata

From the *Centre for Palliative Care, St Vincent’s Hospital, Melbourne, Victoria, Australia; †Drug and Therapeutics Information Service, Repatriation General Hospital, and ‡Discipline, Palliative and Supportive Services, Flinders University, Adelaide, South Australia, Australia. Address correspondence to Dr. Bethany J. Russell, Centre for Palliative Care, PO Box 2900, Fitzroy, Vic., Australia 3065. E-mail: [email protected] DOI: 10.1111/jgs.12981

JAGS 62:1736–1740, 2014 © 2014, Copyright the Authors Journal compilation © 2014, The American Geriatrics Society

T

he “impeccable” treatment of pain and other symptoms to relieve suffering and improve quality of life is one of the core principles of hospice/palliative care (World Health Organization definition).1,2 A variety of medications are commonly prescribed on a pro re nata (PRN) or “as required” basis3 to respond to fluctuations in symptom levels, yet this practice in hospice and palliative care is poorly documented. Some literature exists regarding the PRN use of psychotropic medications in mental health settings4,5 and geriatric care,6 as well as the use of analgesia in the postoperative period.7 Several randomized controlled trials have established the safety, efficacy, and recommended dosage schedules of PRN immediate-release opioids for breakthrough cancer pain and titration of slow-release opioids,8,9 but there are few data regarding how existing evidence is applied to the management of pain or other symptoms in routine practice and specifically in hospice and palliative care populations. One study of European nurses and their approach to breakthrough cancer pain suggested that pharmacological management was inadequate,10 and an audit of a Singapore hospice found that PRN prescribing of morphine was inconsistent and often inappropriate according to clinical guidelines.11 A qualitative study of Australian nurses managing delirium found that their decision-making regarding which drug to use and when varied in different specialty units and often took a “trial and error” approach.12 Individuals receiving palliative care are particularly vulnerable to the unwanted adverse effects of medications because of their altered metabolism, organ dysfunction, and high likelihood of polypharmacy, with subsequent drug–drug and drug–host interactions. Medication-related side effects may be wrongly attributed to disease progression or global deterioration and may trigger a prescribing cascade,13 of which PRN symptom-focused medications may be a precipitant, result, or both. It is therefore important that clinicians strive to prescribe in an informed and rational manner, carefully considering the benefits and risks of regular and PRN prescriptions for each individual. The aim of this prospective study was to provide descriptive data regarding the number of medications being prescribed on a PRN basis to individuals with a

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terminal illness at the time of referral to hospice or palliative care service. Its significance therefore is in providing baseline data that are unique, forming a foundational step toward understanding and potentially improving the use of PRN medications for symptom control in individuals receiving palliative care.

METHODS Study Setting and Participants The complete methodology for this study was described in an earlier publication.14 A prospective consecutive case note audit was performed of 203 individuals newly referred to either of two hospices and palliative care services in regional Victoria between August 2011 and February 2012. These two government-funded services provide specialist inpatient and community-based care over a 48,000 square kilometers region for individuals with incurable, life-limiting illnesses whose family physician or other specialist has referred. Early referral for symptom control, psychosocial support, and care coordination is encouraged, so individuals may receive hospice and palliative care services in parallel with active therapies for their primary disease. Inclusion criteria were aged 18 and older with a recent referral to hospice or palliative care. The Australian healthcare system requires the ongoing involvement of family physicians, and the individuals referred in this study had already been recognized as having a life-limiting diagnosis and complexity of need requiring specialized input.

Data Collection Age, sex, primary diagnosis, adverse drug reactions, and a complete medication list were recorded for each individual at the time of first hospice or palliative care consultation, before any medication changes instituted during that consultation. The audit could be augmented by direct contact with an individual’s family physician or other treating doctor. Medications were classified into those prescribed regularly for treatment of comorbid illness, those prescribed regularly for symptom control, and those prescribed on a PRN basis. (Regular prescriptions are discussed in a separate article.)14 Functional status was assessed using the Australian Modified Karnofsky Performance Scale (AKPS),15 place in disease trajectory using the Palliative Care Outcomes Collaboration (PCOC) Phase tool (stable, unstable, deteriorating, terminal),16 and comorbidities using the Charlson Comorbidity Index weighted against their prognostic importance.17 Medications were also coded using the Beers consensus criteria of potentially inappropriate medication use in elderly adults.18 Number of days between first clinical contact and death or study completion was also recorded. All data were de-identified.

Analysis Data were entered into Excel version 14.3.1 (Microsoft Corp., Redmond, WA), and statistical analysis was performed using Stata version 12.1 (Stata Corp., College Station, TX) using a negative binomial model.

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Ethics The local hospital human ethics and research committee granted ethics approval in accordance with the Australian National Health and Medical Research Council requirements. This study complies with the ethical rules for human experimentation stated in the Declaration of Helsinki.19 Reporting the study complies with the Strengthening the Reporting of Observational Studies in Epidemiology consensus statement on reporting observational studies.20

RESULTS Population Characteristics Two hundred three individuals (mean age 73, 59% male) (Table 1) were included in this consecutive cohort study.

Table 1. Population Characteristics Characteristic

Value

Age, mean  SD (range) median 72.9  12.6 Male 119 Died, n (%) 165 Days from admission to death, mean 92.9 (range) Censored, n (%) 40 Alive at November 16, 2012, n (%) 31 Lost to follow-up, n (%) 9 Days from admission to censoring, mean 220.2 (range) Primary disease Malignant, n (%) 138 Colon, n (%) 25 Lung, n (%) 22 Upper gastrointestinal, n (%) 19 Prostate, n (%) 19 Hematological, n (%) 13 Breast, n (%) 8 Gynecological, n (%) 4 Central nervous system, n (%) 4 Other, n (%) 24 Nonmalignant, n (%) 65 Respiratory failure, n (%) 20 Cardiac failure, n (%) 10 Renal failure, n (%) 7 Neurodegenerative, n (%) 6 Hepatic failure, n (%) 3 Other, n (%) 19 Australian-Modified Karnofsky Performance Status Mean  SD (range) 48.2  19.1 ≥80, n (%) 12 50–70, n (%) 109 ≤40, n (%) 82 Palliative Care Outcomes Collaborative phase, n (%) 1 (stable), n (%) 67 2 (unstable), n (%) 90 3 (deteriorating), n (%) 30 4 (terminal), n (%) 16 Charlson Comorbidity Index, mean  SD 8.4  2.8 (range) median SD = standard deviation.

(37–98) 75 (58.6) (80.3) (0–424) (19.7) (14.8) (4.4) (0–452)

(68.0) (12.3) (10.8) (9.4) (9.4) (6.4) (3.9) (2.0) (1.97) (11.8) (32.0) (9.85) (4.9) (3.5) (3.0) (1.5) (9.4) (10–90) 50 (5.9) (53.7) (40.4) (33.0) (44.3) (14.8) (7.9) (2–20) 8.0

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Table 2. Medication Class Frequencies

Medication

Opioid Antiemetic Benzodiazepine Laxative Acetaminophen Other Total

Participants Prescribed at Least One Medication in This Class

Total Prescriptions

n (%)

n (%)

142 91 72 60 55

(70.0) (44.8) (35.5) (29.6) (27.1)

203 (100)

178 112 99 82 56 79 606

(29.4) (18.5) (16.3) (13.5) (9.2) (13.0)

phase of their disease were prescribed significantly more PRN medications than those in any other disease phase (rate ratio = 1.36 PCOC 4 vs PCOC 1–3, 95% CI = 1.09– 1.68; Figure 1), and those who died within 1 week of admission were prescribed significantly more PRN medications than those who survived longer (rate ratio = 1.30, 95% CI = 1.07–1.59). Variation in Charlson Comorbidity Index score was not associated with any significant difference in PRN medication prescriptions according to quartile.

DISCUSSION

Sixty-eight percent had a malignancy as their primary lifelimiting illness.

Prescribing of PRN Medications The mean number of PRN medications that the referring physician had prescribed was 3.0  2.0 (median 3.0, range 0–9). One in four (25.9%) prescriptions were for medications that met the Beers consensus criteria for potentially inappropriate medication use in elderly adults. The most common classes of medications prescribed were opioids, antiemetics, and benzodiazepines (Table 2). There was no significant correlation between number of PRN medications and total number of regular medications (7.2  3.7) or number of regular medications prescribed for treatment of comorbid illness (5.3  3.5). There was a significant but only weakly positive correlation between number of PRN medications and total number of regular medications prescribed for symptom control (1.9  2.0, correlation coefficient = 0.194, P = .006). There was no significant difference in the number of medications prescribed for individuals with a nonmalignant or malignant primary diagnosis (mean 2.9 vs 3.0; relative risk = 1.04, 95% confidence interval (CI) = 0.84–1.28). Individuals with poorer performance status tended to be taking more medications (mean 3.4 in AKPS 0–40 vs 2.2 in AKPS 80–100; rate ratio = 1.57, 95% CI = 0.98–2.50; Figure 1). Participants in the terminal

Data regarding the scale and patterns of PRN prescribing in individuals receiving palliative care have not previously been published. These data reflect the prescribing practices of nonhospice and nonpalliative care physicians at the time of referring an individual to a specialist palliative care service. A mean of three different medications prescribed regardless of primary diagnosis or comorbidity burden seems appropriate to allow responsiveness to a variety of fluctuating symptoms, including pain, nausea, and dyspnea, and is consistent with internationally recognized end-of-life care plans.21 The most commonly prescribed medication classes—opioids, antiemetics, and benzodiazepines—correspond to these symptoms, with opioids being used in the management of pain and breathlessness and benzodiazepines often being used to treat anxiety-related dyspnea. A significant but weak correlation between number of PRN medications prescribed and number of regular medications prescribed for symptom control may reflect the appropriate use of regular medications for symptom control paired with an immediate-release preparation of the same class. More PRN medication prescriptions in individuals with poorer performance status may be appropriate, because higher symptom burden often accompanies clinical deterioration (Figure 1). Likewise, the prescribing increase noted with global deterioration as participants entered the terminal phase of disease (Figure 1) further reflects that these medications are for symptom control rather than comorbid conditions. These findings suggest that changes in the clinical status of the individual appropriately prompt PRN prescribing.

Number of medications taken PRN vs AKPS

Number of medications taken PRN vs PCOC 8 number of medications taken PRN (mean ± 1 std dev)

8 number of medications taken PRN (mean ± 1 std dev)

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7 6 5 4 3 2 1 0

7 6 5 4 3 2 1 0

90

80

70 60 50 40 30 20 Australia-modified Karnofsky Performance Status

nonmalignant disease

malignant disease

10

overall

0

1

2 3 Palliative Care Outcomes Collaboration phase nonmalignant disease

malignant disease

4 overall

Figure 1. Pro re nata (PRN) prescribing plotted against Australia-modified Karnofsky Performance Status (AKPS) and Palliative Care Outcomes Collaborative (PCOC) Phase of Disease.

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A previous Australian study of delirium management found that PRN medication selection was challenging for nurses working in an inpatient setting and was often done on a “trial and error” basis.12 Family members, aged care workers, or the individuals themselves administer medications prescribed on a PRN basis outside of hospital settings, which means that the least-trained people involved in care are required to make decisions regarding which drug to give, what dose to administer, when to give or repeat the dose, and by which route of administration if multiple formulations are prescribed—a situation prone to confusion and error.22 This is a daunting task when up to nine different medications are prescribed, the range found in this study. Documentation of usage and dose, as well as recognition of effectiveness and adverse events may be less than optimal in community and hospital settings. Education and support may be beneficial, particularly for lay caregivers,23 and explicitly stating the indication, minimum dosage interval, and maximum daily dosage on the prescription has been recommended.24 Prescription of medications meeting the Beers consensus criteria of potentially inappropriate medication use in elderly adults increases as death approaches.25 This study found that one-quarter of prescriptions fulfilled the criteria, although many of these medications are recommended and indeed necessary for symptom control. This unavoidable exposure to potential drug toxicities further highlights the need to minimize harm by careful clinical evaluation, clear reasons to administer or not administer these medications (especially those for inactive comorbid disease that are not adding value to clinical care), and ensuring that the correct dose is given.

Limitations Limitations of this study include that data were collected from case note review, although this was done contemporaneously so that referring practitioners could clarify data. The medications prescribed may not all have been used, but the evaluation was of how physicians prescribe. The dose and frequency of each prescription were not studied. Likewise, multiple prescriptions of the same drug with different formulations were not recorded, so the burden of decision-making as to which form of the drug to use has not been fully explored. This study was cross-sectional rather than longitudinal; future work should follow participants over time to evaluate changes in PRN prescribing. Some subgroups in this study were small. There were only 12 participants with an AKPS of 80 or greater and 16 participants in the terminal phase of their disease. Larger studies are needed to replicate these findings.

Generalizability This study cohort broadly reflects the age, sex, diagnoses, and settings of care of the hospice and palliative care population.

Clinical and Research Implications Given the variable patterns of care in referral-based hospice and palliative care, longitudinal prospective data from a

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number of inpatient and community services are required to more fully understand the nature, magnitude, risks, and benefits of PRN prescriptions in the setting of terminal illness. Questions remain regarding which specific medications are prescribed, the ratio of regular to PRN prescriptions, the relationship between those regular medications and the choice of associated PRN medication, and the burden of administration, with particular emphasis on decision-making processes and the training or information provided to those who take on such a role. Further research is warranted to investigate the experience of administering PRN medications from the individual and family caregiver point of view, as well as the potential benefit of pharmacist reviews, which are known to reduce PRN medication prescription and use in the aged care setting.26

CONCLUSION This prospective study provides important baseline data documenting the patterns of PRN prescribing in individuals receiving palliative care for the first time. As clinical status worsens, the trends of increasing numbers of PRN prescriptions reflect the flexibility in prescribing required to respond quickly to changing clinical circumstances or symptoms. A large range was noted in the sample, indicating that some participants and their caregivers had a high burden of administration-related decision-making.

ACKNOWLEDGMENTS Emeritus Professor Philip Ryan provided assistance with statistical analysis. Conflict of Interest: The authors have no financial, personal, or potential conflict of interest to declare. Author Contributions: Russell: study design, acquisition, analysis and interpretation of data, drafting the article, final approval of this version for publication. Rowett, Currow: study conception and design, analysis and interpretation of data, revising the article, final approval of this version for publication. Sponsor’s Role: This project did not receive any sponsorship.

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9. Zeppetella G, Davies A, Eijgelshoven I et al. A network meta-analysis of the efficacy of opioid analgesics for the management of breakthrough cancer pain episodes. J Pain Symptom Manage 2014;47:772–785.e5. 10. Rustøen T, Geerling JI, Pappa T et al. A European survey of oncology nurse breakthrough cancer pain practices. Eur J Oncol Nurs 2013;17:95–100. 11. Neo SH, Loh EC, Koo WH. An audit of morphine prescribing in a hospice. Singapore Med J 2001;42:417–419. 12. Agar M, Draper B, Phillips PA et al. Making decisions about delirium: A qualitative comparison of decision making between nurses working in palliative care, aged care, aged care psychiatry, and oncology. Palliat Med 2012;26:887–896. 13. Rochon PA, Gurwitz JH. Optimising drug treatment for elderly people: The prescribing cascade. BMJ 1997;315:1096–1099. 14. Russell BJ, Rowett D, Abernethy AP et al. Prescribing for comorbid disease in a palliative population: Focus on the use of lipid-lowering medications. Intern Med J 2014;44:177–184. 15. Abernethy AP, Shelby-James T, Fazekas BS et al. The Australia-modified Karnofsky Performance Status (AKPS) scale: A revised scale for contemporary palliative care clinical practice. BMC Palliat Care 2005;4:7. 16. Eagar K, Green J, Gordon R. An Australian casemix classification for palliative care: Technical development and results. Palliat Med 2004;18:217–226. 17. Charlson ME, Pompei P, Ales KL et al. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 1987;40:373–383.

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Pro re nata prescribing in a population receiving palliative care: a prospective consecutive case note review.

To document pro re nata (PRN) prescribing practices and to identify patterns with respect to clinical characteristics and the medications prescribed...
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