ethics in cardiopulmonary medicine Narcotic and Benzodiazepine Use After Withdrawal of Life Support*

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1 ethics in cardiopulmonary medicine Narcotic and Benzodiazepine Use After Withdrawal of Life Support* Association With Time to Death? Jeannie D. Chan, PharmD, MPH; Patsy D. Treece, RN, MN; Ruth A. Engelberg, PhD; Lauren Crowley, BA; Gordon D. Rubenfeld, MD, MSc, FCCP; Kenneth P. Steinberg, MD, FCCP; and J. Randall Curtis, MD, MPH, FCCP Objective: To determine whether the dose of narcotics and benzodiazepines is associated with length of time from mechanical ventilation withdrawal to death in the setting of withdrawal of life-sustaining treatment in the ICU. Design: Retrospective chart review. Setting: University-affiliated, level I trauma center. Patients: Consecutive critically ill patients who had mechanical ventilation withdrawn and subsequently died in the ICU during two study time periods. Results: There were 75 eligible patients with a mean age of 59 years. The primary ICU admission diagnoses included intracranial hemorrhage (37%), trauma (27%), acute respiratory failure (27%), and acute renal failure (20%). Patients died during a median of 35 min (range, 1 to 890 min) after ventilator withdrawal. On average, 16.2 mg/h opiates in morphine equivalents and 7.5 mg/h benzodiazepine in lorazepam equivalents were administered during the time period starting 1 h before ventilator withdrawal and ending at death. There was no statistically significant relationship between the average hourly narcotic and benzodiazepine use during the 1-h period prior to ventilator withdrawal until death, and the time from ventilator withdrawal to death. The restriction of medication assessment in the last 2 h of life showed an inverse association between the use of benzodiazepines and time to death. For every 1 mg/h increase in benzodiazepine use, time to death was increased by 13 min (p 0.015). There was no relationship between narcotic dose and time to death during the last 2hoflife (p 0.11). Conclusions: We found no evidence that the use of narcotics or benzodiazepines to treat discomfort after the withdrawal of life support hastens death in critically ill patients at our center. Clinicians should strive to control patient symptoms in this setting and should document the rationale for escalating drug doses. (CHEST 2004; 126: ) Key words: benzodiazepines; death; end-of-life care; ICU; mechanical ventilation; narcotics; withdrawing life support Abbreviations: APACHE acute physiology and chronic health evaluation; GCS Glasgow coma scale Despite remarkable advances in critical care technology and treatment, the mortality of patients in the ICU remains high. A large proportion of *From the Department of Epidemiology (Dr. Chan), School of Public Health and Community Medicine, University of Washington, Seattle; and Harborview Medical Center (Mss. Treece and Crowley, and Drs. Engelberg, Rubenfeld, Steinberg, and Curtis), Division of Pulmonary and Critical Care, Seattle, WA. This project was funded by a grant from the Greenwall Foundation and the National Institute of Nursing Research (grant No. R01NR/AG ). Manuscript received August 11, 2003; revision accepted February 23, deaths in the ICU occurs in the context of withholding or withdrawing life-sustaining treatments. 1,2 The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments 3 showed that, according to seriously ill hospitalized patients and Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( permissions@chestnet.org). Correspondence to: Jeannie D. Chan, PharmD, MPH, Harborview Medical Center, 325 Ninth Ave, Room GEH-74, Department of Pharmacy, Box , Seattle, WA 98104; jdchan@ u.washington.edu 286 Ethics in Cardiopulmonary Medicine

2 their proxies, approximately 50% of patients were in moderate or severe pain during the last 3 days of life. The study also suggested that patients with critical illness and those cared for by intensivists had equal or worse symptom control than other seriously ill hospitalized patients. 4 The problem of symptom assessment in the ICU can be particularly challenging, because many patients have impaired cognition and communication. A cohort study 5 of cancer patients suggested that between 55% and 75% of critically ill patients who could describe their symptoms reported experiencing moderate-to-severe levels of pain, discomfort, anxiety, sleep disturbance, unsatisfied hunger, or thirst while in the ICU. In one study 6 of trauma patients receiving intensive care, 95% of physicians and 81% of nurses reported that their patients had received adequate analgesia, whereas 74% of these patients rated their pain as moderate or severe. These studies suggested that ICU patients commonly experience distressing symptoms at levels of severity that are substantial and may be underestimated by caregivers. However, despite the need to incorporate the principles of palliative care into practices in the ICU to provide better symptom control and end-of-life care, there is limited research to guide clinicians in understanding and improving practice in this area In addition to these documented shortcomings in symptom assessment and management, there are considerable discrepancies and variations among health-care professionals in the way that life-sustaining therapy is withheld or withdrawn. 2,11,12 Although variation does not necessarily indicate poor quality of care, large degrees of variation suggest a lack of consensus in clinicians approaches to dying patients. Furthermore, critical care nurses report frustration with the end-of-life care provided by physicians and cite as an example their impression that some physicians are reluctant to use sedation for fear of hastening death. 13,14 This impression is reinforced by surveys of physicians that reflect concern about hastening death with the use of sedation in the setting of withdrawing life-sustaining treatments. 15,16 These studies raise the possibility that well-intentioned but unskilled cessation of life-sustaining treatment may cause distressing symptoms, leading to significant and unnecessary suffering in the final hours of life. Given the lack of consistency in the delivery of end-of-life care and reports from critical care nurses implying that some nurses may be using narcotics or benzodiazepines to hasten death, concerns about hastening death by oversedating patients are understandable. We therefore conducted a retrospective study to determine whether the use of narcotics or benzodiazepines is associated with the length of time between the removal of mechanical ventilation and death among ICU patients for whom life-sustaining treatments were being withdrawn. Materials and Methods The data were collected as part of a hospital-wide quality improvement project. A total of 2,250 patients were admitted to the ICU of Harborview Medical Center over an 8-month period including June to August 2000 and July to November All patients (178 patients) who died in the ICU during this 8-month time period were screened for eligibility for participation in the study. Eligible patients included those who had received mechanical ventilation within 1 week before death and had mechanical ventilation discontinued prior to death (137 patients). We excluded patients who received cardiopulmonary resuscitation immediately prior to death (22 patients) and those who had no documentation of life support withdrawal (2 patients). We also attempted to exclude patients for whom the use of benzodiazepines or narcotics after withdrawal of mechanical ventilation would be unnecessary, such as those who were brain dead (29 patients) and those who had a Glasgow coma scale (GCS) score of 3 and died within 24 h of ICU admission (9 patients). A total of 75 patients were included in the analysis. The institutional review board reviewed this study and determined it to be exempt from requirements for written consent, because anonymous data were obtained from the previous hospital-wide quality improvement project such that patients and clinicians could not be identified. Basic demographic characteristics (ie, age, gender, and race) and clinical information (ie, ICU diagnoses, GCS score, ICU length of stay, and IV narcotic and sedative drugs used 24 h prior to death) had been abstracted previously from electronic chart review as part of a quality improvement project. Based on a relative potency scale for benzodiazepines and opiates used by a previous study, 17 doses of opiates (ie, fentanyl and morphine) were compared according to a dose-equivalent conversion factor of 15 g fentanyl to 1 mg morphine. Lorazepam and midazolam were compared based on a dose-equivalent conversion factor of 2.5 mg midazolam to 1 mg lorazepam. The cumulative amounts of benzodiazepines and narcotics used were calculated during the following three stages of life support withdrawal: (1) the 24-h period before death; (2) the time period from 1 h prior to ventilation withdrawal until the time of death; and (3) the 2-h period prior to death. In response to comments from reviewers, we also examined the 4-h and the 8-h periods prior to death. Cumulative medication use during these different time intervals was divided by the total amount of time in the interval and was expressed as an average number of milligrams per hour administered over these time periods. We used multivariate linear regression modeling with robust variance estimates (a conservative approach that does not assume equal variances of parameters in the model) to determine whether the use of narcotics and sedatives during these time periods was associated with the length of time from the withdrawal of mechanical ventilation to death. Our primary analysis was to test for an association between the predictor variables of the narcotic and benzodiazepine doses used during the time period from 1 h prior to ventilator withdrawal until death and the outcome variable of length of time from ventilator withdrawal to death. As secondary analyses, we also examined the predictor variables of the doses of narcotics and benzodiazepines used during the last 2 h, 4 h, and8hoflife in association with the same outcome variable. Hypothesis-driven linear regression models were constructed by placing a priori defined potential confoundwww.chestjournal.org CHEST / 126 / 1/ JULY,

3 ers between medication use and time to death into the models followed by the predictor variables of interest. These potential confounders included age (years), gender, hospital admission diagnosis of an intracranial hemorrhage (yes or no), worst GCS score in the 24 h prior to death as indicator for neurologic status, and ICU length of stay (days) as a surrogate marker for disease severity. Comparisons between average hourly medication dosages at different stages of life support withdrawal were analyzed using the Student t test without equal variance assumption. Differences were considered to be statistically significant for a two-sided p value of Data analyses were performed using a statistical software package (STATA, version 7.0; Stata Corporation; College Station, TX). Results The mean age of the study population was 59 years (age range, 16 to 91 years). The majority of the patients were non-hispanic whites. Intracranial hemorrhage was the most common primary ICU admission diagnosis (37%), and neurologic status was poor in this study population, with a mean worst GCS score of 4 in the 24 h prior to death. The other frequent ICU admission diagnoses were trauma (27%), acute respiratory failure (27%), and acute renal failure (20%). The median length of ICU stay in this study sample was 4 days. Once the process of ventilator withdrawal was initiated, patients died within a median of 35 min (25th percentile to 75th percentile, 16 to 146 min) [Table 1]. Medications were administered by both bolus and continuous infusion during life support withdrawal. A progressive increase in narcotic dosage was observed starting 8 h prior to death, with the most evident increase in dosage occurring during the last 4 h of life. Similarly, there was a steady increase in benzodiazepine dosage noted throughout the last 8 h of life (Fig 1). However, justifications for medication dosage increase were not consistently documented using sedation or pain scores, and we therefore were not able to report patient comfort or sedation levels. Overall, five patients did not receive any opiate or benzodiazepine during the 24-h period preceding death. Narcotic medications were commonly used during the two time periods (ie, 1 h before ventilator withdrawal until death and the last2hoflife) in 84% of patients (63 patients). Users and nonusers of opiates were similar in demographic characteristics and neurologic status as assessed by worst GCS score. However, those who received opiates were less likely to have trauma as a primary admission diagnosis (p 0.020) and tended to have longer ICU lengths of stay (mean length of stay, 9.4 vs 3.7 days, respectively; p 0.012) than did those who did not receive opiates. Benzodiazepine use was less frequent, with only 40% of the patients (30 patients) receiving these sedatives during the time periods from 1 h before ventilator withdrawal until death and Table 1 Characteristics of Study Subjects* Characteristics Values Age, yr (16 91) Male gender, % 53 Race, % Non-Hispanic white 77 African American 5 Asian 3 Hispanic 3 Uncoded 8 Mean worst GCS score 24 h prior to death 4(3 10) Median ICU length of stay, d 4 (1 82) Median time to death from ventilator 35 (1 890) withdrawal, min ICU admission diagnosis, % Intracranial hemorrhage 37 Respiratory arrest/failure 27 Trauma 27 Acute renal failure 20 Myocardial infarction 12 Pneumonia 12 ARDS 9 Sepsis/septic shock 9 Coagulopathy 8 Anoxic brain injury 7 Congestive heart failure 7 Stroke 7 GI bleed 5 Neoplasm 5 Other 18 *Values in parentheses are ranges; n 75. Values given as mean SD. Data available in 74 subjects. during the last 2 h of life. There was no statistically significant difference by demographic characteristics, primary ICU admission diagnosis, and ICU length of stay between users and nonusers of benzodiazepines, although users tended to have a marginally higher GCS score (median GCS score, 5 vs 4, respectively; p 0.054). Among patients who received these medications, morphine (90%) and lorazepam (80%) were the primary agents used compared to other opiates and benzodiazepines, respectively. In this study population, an average of 4 mg/h narcotic (in morphine equivalents), and 1.6 mg/h benzodiazepines (in lorazepam equivalents) were administered during the last 24 h of life. Medication dosages were escalated when the initiation of lifesustaining therapy withdrawal was anticipated. During the time interval from 1 h prior to ventilator withdrawal until death, average doses of 16.2 mg/h narcotics and 7.5 mg/h benzodiazepines were administered. These drug dosages represented marked increases compared to the average hourly dosages of opiates and benzodiazepines used during the time interval from the 24th h before death to 1 h prior to 288 Ethics in Cardiopulmonary Medicine

4 Figure 1. Mean dose of narcotic and sedative medication administered to study subjects over the final 24 h of life. For each patient receiving a narcotic or sedative drug corresponding to the particular hour of time to death, the cumulative amount was calculated, and the average hourly dose was tabulated based on the number of patients receiving a narcotic or sedative drug at that particular hour. ventilator withdrawal, respectively (p for both opiates and benzodiazepines). During the last 2 h of life, average doses of 18.1 mg/h narcotics and 9.2 mg/h benzodiazepines were administered (Table 2). These medication dosages were significantly higher than the average hourly dosages of opiates and benzodiazepines used during the 22 h before death after excluding the final 2 h of life, respectively (p for both opiates and benzodiazepines). Multivariate linear regression models examining the association between narcotic and benzodiazepine medication used (expressed in milligrams per hour, the predictor variable) and the time from ventilator withdrawal to death (the outcome variable) are presented in Tables 3 and 4. Age, gender, and neurologic status did not appear to be predictive of time to death after adjustment for the other covariates, but ICU length of stay was inversely associated with time to death. Every 1-day increase in ICU stay corresponded to an approximate 2.5-min reduction from the time of ventilator withdrawal to death (p 0.03). Adjustment for baseline medication use (defined as a narcotic or benzodiazepine received in the 24th h before death), extubation prior to death, and time periods of data collection (June to August 2000 and July to November 2001) did not change these estimates appreciably (data not presented). Our results demonstrated no statistically significant relationship between either benzodiazepine or narcotic dose during the time interval from 1 h prior to ventilator withdrawal until death and the outcome of time to death from ventilator discontinuation (Table 3). However, there was a significant dose effect of hourly medication use in the last 2 h of life that was associated with the time from ventilator withdrawal to death (Table 4). On average, every 1 mg/h increase in benzodiazepine use corresponded to a statistically significant 13-min increase in the duration of time between ventilator withdrawal and death (p 0.015). On the contrary, for every 1 mg/h increase in narcotic use, there was a 2-min reduction in the time from ventilator withdrawal to death, although statistical significance was not achieved (p 0.11). Further analyses with the average hourly amount of medication used in the last 4 and 8hof life as the predictors of interest yielded similar results, with no statistical association seen between narcotic use and time to death but with a trend toward increased benzodiazepine use being associated with an increased time to death (Table 4). Discussion The principle of double effect states that it is acceptable for medications to be used that may have the potential to hasten death in the setting of terminal illness, provided that the purpose of the medications is to relieve suffering. Although there is some debate about the philosophy of this principle, it is generally well-accepted in the practice of palliative medicine. 18 Nonetheless, surveys of physicians show that a substantial minority of physicians withhold or CHEST / 126 / 1/ JULY,

5 Table 2 Administration of Narcotic and Benzodiazepine Medications* Variables Cumulative Amount Hourly Amount Average medication usage 24 h before death Morphine, mg 81.4 (2 1,052) 3.4 (0.1 44) Fentanyl, g (50 14,400) 94.5 (2 600) Total narcotic in morphine equivalents, mg 97.0 (2 1,052) 4.0 (0.1 44) Lorazepam, mg 39.3 (1 379) 1.6 ( ) Midazolam, mg 34.3 (3 214) 1.4 (0.1 9) Total benzodiazepine in lorazepam equivalents, mg 37.3 (1 379) 1.6 ( ) Average medication usage 1 h before ventilator withdrawal to death Morphine, mg 52.9 (2 399) 15.6 (1 106) Fentanyl, g (25 3,054) ( ) Total narcotic in morphine equivalents, mg 51.7 (2 399) 16.2 (1 106) Lorazepam, mg 37.3 ( ) 8.6 (0.1 35) Midazolam, mg 12.8 (2 28) 8.2 ( ) Total benzodiazepine in lorazepam equivalents, mg 30.9 ( ) 7.5 (0.1 35) Average medication usage 2 h before death Morphine, mg 35.1 (2 286) 17.6 (1 143) Fentanyl, g (25 2,554) (13 1,277) Total narcotic in morphine equivalents, mg 36.2 (2 286) 18.1 (1 143) Lorazepam, mg 20.7 (1 72) 10.3 (0.5 36) Midazolam, mg 14.8 (2 30) 7.4 (1 15) Total benzodiazepine in lorazepam equivalents, mg 18.5 (1 72) 9.2 (0.4 36) *Values in parentheses are ranges. Narcotic use is calculated based on the combined amount of morphine and fentanyl (fentanyl, 15 g; morphine, 1 mg). Benzodiazepine use is calculated based on the combined amount of lorazepam and midazolam (midazolam, 2.5 mg; lorazepam, 1 mg). Calculation based on 70 patients. Calculation based on 42 patients. Calculation based on 63 patients. Calculation based on 30 patients. limit narcotics and benzodiazepines at the end of life out of fear that they will be perceived to be hastening death. 15 In this context, it is useful to know whether narcotics and benzodiazepines are being used in a way that hastens death. Our study suggested that in our ICU, after the withdrawal of mechanical ventilation, narcotics and Table 3 Dose-Response Relationship Between Average Hourly Narcotic and Sedative Medication Use 1 h Prior to Ventilator Withdrawal and Time From Ventilator Withdrawal to Death* Variables Time to Death, min 95% CI p Value Hourly narcotic dose, mg/h Hourly benzodiazepine dose, mg/h Age, yr Sex Worst GCS score Intracranial hemorrhage ICU length of stay, d *CI confidence interval. Estimate for hourly narcotic adjusted for benzodiazepine use, age, sex, GCS, intracranial hemorrhage, and ICU length of stay. Estimate for hourly benzodiazepine adjusted for narcotic use, age, sex, GCS, intracranial hemorrhage, and ICU length of stay. benzodiazepines are not being used in ways that significantly hasten death. This is consistent with the results of a previous report 19 stating that survival duration was unrelated to morphine dosage in patients undergoing mechanical ventilation withdrawal as part of end-of-life care. Other non-icu studies also have documented the lack of relationship between opiate and sedative use during end-oflife care and time to death. In a prospective study of 120 patients with terminal cancer assisted by a home care team, there was no detectable survival difference between sedated and nonsedated patients. 20 There was also no significant difference found in another study 21 examining survival time between the 30 sedated patients and the 85 nonsedated patients in a hospice inpatient unit. In a retrospective study of 238 patients receiving palliative care during the last week of life, patients who received a marked increase in opiate dosage did not have a shorter survival time compared to those who received no increases. 22 Finally, among the 227 patients with terminal cancer who were admitted to a hospice unit in Taiwan, 23 there was no statistically significant difference in survival time between sedated and nonsedated patients. All but one of these studies was performed in the hospice setting, and medication assessment was completed over a much longer spectrum of time 290 Ethics in Cardiopulmonary Medicine

6 Table 4 Dose-Response Relationship Between Average Hourly Narcotic and Sedative Medication Use and Time From Ventilator Withdrawal to Death* Variables Time to Death, min 95% CI p Value Medication use 2 h before death Hourly narcotic dose, mg/h Hourly benzodiazepine dose, mg/h Age, yr Sex Worst GCS score Intracranial hemorrhage ICU length of stay, d Medication use 4 h before death Hourly narcotic dose, mg/h Hourly benzodiazepine dose, mg/h Age, yr Sex Worst GCS score Intracranial hemorrhage ICU length of stay, d Medication use 8 h before death Hourly narcotic dose, mg/h Hourly benzodiazepine dose, mg/h Age, yr Sex Worst GCS score Intracranial hemorrhage ICU length of stay, d *See Table 3 for abbreviations not used in text. Estimate for hourly narcotic adjusted for benzodiazepine use, age, sex, GCS, intracranial hemorrhage, and ICU length of stay. Estimate for hourly benzodiazepine adjusted for narcotic use, age, sex, GCS, intracranial hemorrhage, and ICU length of stay. prior to death, but, nonetheless, our results are consistent with these prior findings that opiate and sedative use is not associated with the hastening of death. Our results demonstrate no statistically significant dose-response relationship between either benzodiazepine or narcotic use during the time interval from 1 h prior to ventilator withdrawal until death and the outcome of time to death after ventilator withdrawal. However, we found a statistically significant association between increased benzodiazepine dose during thelast2hoflife and increased time from ventilator withdrawal to death. Perhaps the most likely explanation for this finding is that those patients who survived longer developed tolerance to benzodiazepines and therefore required a higher dose to maintain comfort. Alternatively, symptom distress may hasten death in the setting of withdrawal of life-sustaining treatment. Physiologic stress from unrelieved pain and anxiety may increase oxygen consumption and coagulability, may promote protein catabolism and proinflammatory cytokine expression, and thus may trigger the systemic inflammatory response The anxiolytic property of the benzodiazepines may have achieved a calming effect in these dying patients without the compromise of hastening death. It is, however, important to emphasize that the positive association between benzodiazepine use and increasing time to death from mechanical ventilation withdrawal in this study can only be considered as being hypothesis-generating until these results can be confirmed with a larger study population. The use of an average hourly amount of narcotics and benzodiazepines from 1 h prior to the withdrawal of mechanical ventilation until death as the marker of exposure to these medications is an arbitrary time period. We, however, believe that the 1-h window prior to the withdrawal of mechanical ventilation allowed us to capture the possibility of anticipatory dosing before withdrawal and that it is a reasonable proxy for the true effect of these medications preceding death. Furthermore, we postulated that medication use during the last 2hoflife is the most clinically sensitive measure to detect an association with hastening of death, as patients would be more susceptible to this effect of opiates and benzodiazepines during the time immediately preceding death. We documented an increase in medication use during the last 4 to 8 h of life, which was consistent with that reported by others. Hall and Rocker 11 showed that the increase in morphine administration was most evident in the final 4 h before death, a time frame that is consistent with the average time from the withdrawal of life support to death in their study. Although the medication dosages that we reported are similar to the findings from earlier studies, 17,28 there is tremendous variability in the range of these medications. This variability is likely due to the fact that symptom burden is highly unpredictable, the assessment of symptoms can be difficult in the dying critically ill population, and tolerance to narcotics and benzodiazepines is common, leading to large variations in medication administration. Our study has several important limitations. First, the study was limited by a small sample size and may not have sufficient power to detect small differences. As this is an anonymous database obtained for quality improvement purposes, we are unable to add to the sample size. The confirmation of our results with a larger population would be useful. In addition, we were unable to collect additional data such as acute physiology and chronic health evaluation (APACHE) CHEST / 126 / 1/ JULY,

7 scores because of the anonymous nature of the data. However, it is not clear that severity of illness, independent of neurologic status, would be associated with opiate or benzodiazepine use and therefore would contribute as a confounder. Second, the restriction to medication use during the last 2 h prior to death may be a more clinically sensitive measure for detecting an association with hastening of death, but it is problematic for the subset of patients (25% of the study population) who took longer than 2 h to die after ventilator withdrawal. This is because the assessment of exposure (drug use in the last 2hoflife) occurs after the initiation of the outcome measurement (ie, time from ventilator withdrawal to death) in these patients. Since an important criterion for a causal relationship is that the exposure must precede the outcome, inferences of causality cannot be definitively made. Third, an observational study cannot dismiss the possibility of residual confounding despite analytic efforts through the adjustment of potential confounders. However, an observational study is the only ethical approach to this study question. Fourth, patient comfort or sedation level was not routinely recorded, and therefore we were not able to assess whether the levels of sedation and analgesia were appropriate. Finally, our findings may have limited generalizability to other ICUs as the study population consisted of a substantial number of intracranial hemorrhage and trauma patients. Stratification by diagnosis of intracranial hemorrhage was considered, but our sample size was too small to explore effect modification by neurologic status. Concerns about hastening death by oversedating patients are understandable, and the judicious use of narcotics and benzodiazepines is necessary. Nevertheless, clinicians should be aware of the difficulties of assessing discomfort in critically ill patients and should understand that many patients develop tolerance to sedative and opiate medications. When death is imminent, these medications should be given in a way that alleviates suffering and achieves optimal patient comfort. The principle of double effect, along with our data suggesting that increasing doses of narcotics and benzodiazepines were not associated with hastened death, should reassure critical care clinicians that they need not limit pain and symptom management in the setting of discomfort during the withdrawal of life-sustaining treatments. However, when narcotic and benzodiazepine medications are used to manage symptoms during end-of-life care, it is important for clinicians to record the reasons for the escalating doses in order to document that these drugs are being used for the purpose of controlling symptoms. 9,29 References 1 Prendergast TJ, Luce JM. 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