FormalPara Key Summary Points

Why carry out this study?

In some patients with advanced cancer, pain and anxiety are difficult symptoms to treat properly, both due to insufficient symptom relief and unwanted side effects from parenteral opioids and benzodiazepines.

We present retrospective data on the potential role of additional dexmedetomidine for these patients.

What was learned from the study?

Additional dexmedetomidine decreased opioid consumption and was well tolerated in a small retrospective study.

Symptom relief was reported. Due to study design and limited available data, the results must be interpreted with caution.

Introduction

Pain and anxiety are prevalent symptoms in patients with advanced cancer, and late in the disease trajectory patients also suffer from increased drowsiness [1, 2]. Opioids are the mainstay of analgesic therapy for moderate-to-severe cancer pain and benzodiazepines are used to treat anxiety [3, 4]. Both opioids and benzodiazepines increase the probability for drowsiness, which may limit adequate dose titration and result in suboptimal symptom management [5,6,7]. Consequently, there is a need for novel treatment options to alleviate refractory symptoms late in the course of cancer [8,9,10,11].

Dexmedetomidine is a potent and selective alpha-2 adrenergic receptor agonist, first approved in the US in 1999, and now in clinical use in more than 70 countries [11, 12]. Dexmedetomidine is used as a sedative, anxiolytic, and analgesic-sparing drug [13, 14]. The sedative response is unique and, by reducing central sympathetic activity, makes the patient stay arousable and able to communicate [15,16,17]. The anxiolytic and analgesic-sparing qualities are mediated through adrenoreceptors located in the central nervous system [13, 16]. With reduced doses of opioids and benzodiazepines, dexmedetomidine might contribute to less therapy-induced drowsiness and a decreased delirium occurrence [5, 6, 18]. In addition, dexmedetomidine’s presumed neuroprotective and anti-inflammatory attributes can represent a potential for delirium management [16, 17, 19]. Moreover, while opioids and benzodiazepines may reduce respiratory rates, dexmedetomidine does not exert this respiratory depressant effect [20].

Evidence from randomized controlled trials and a Cochrane review showed that extended use of dexmedetomidine is feasible and beneficial in intensive care, with reduced duration of mechanical ventilation and length of stay [16, 21, 22]. The short onset of action (15 min after IV administration) and the short terminal half-life (2–2.5 h) make the drug easy to monitor and titrate [23]. Dexmedetomidine is also rapidly absorbed after subcutaneous administration and usually well tolerated, with bradycardia and fever as the most relevant potential adverse effects [11, 23,24,25].

A decade ago, a review article outlined the possibilities for the use of dexmedetomidine in palliative care patients [23]. However, the evidence base for its use in this group of patients is still limited [26]. For adults, case reports described symptom relief in patients with severe cancer pain and anxiety, and anecdotal papers reported positive effects on various symptoms like delirium, dyspnea, vomiting, and depression [8,9,10, 27,28,29,30,31]. In terminally ill children, a recent systematic review, based on retrospective evidence, found dexmedetomidine for pain control to be significantly associated with improved quality of life [32].

For more than 20 years, dexmedetomidine has proven useful in anesthesia. For patients with advanced cancer and complex symptomatology, the drug may constitute a novel pharmacological approach for improved palliative care. With the aim of describing effects, safety, and tolerability, we reviewed the charts of adult cancer patients consecutively treated with dexmedetomidine in an acute palliative care unit (APCU). We addressed the following research questions:

  1. 1.

    Which indications were decisive for initiating dexmedetomidine treatment?

  2. 2.

    What effects and side effects were registered and when?

  3. 3.

    For how long was dexmedetomidine used, and was it continued after hospital discharge?

Methods

Study Design

The APCU, Cancer Clinic, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway, has 12 beds and approximately 600 admissions a year, and is an ESMO designated center of integrated oncology and palliative care. The admitted patients consist of adult cancer patients with incurable disease and symptom burden warranting hospitalization. Previous research demonstrated that mean symptom scores at admission for worst pain intensity, anxiety, and drowsiness were 5.2, 3.0, and 5.2 (numeric rating scale (NRS) 0–10), respectively [33]. Patients with hematological, gynecological, and pulmonary cancer are only admitted to the APCU when in need of neuraxial pain management. The current study is an in-house cohort study including all patients consecutively treated with continuous administration of dexmedetomidine between January 1, 2019 and January 1, 2021. Treatment was initiated if insufficient symptom relief, and/or unacceptable side effects with the use of standard interventions. Dexmedetomidine treatment was started and monitored by anesthesiologists. The study participants were identified retrospectively.

The Intervention

Dexmedetomidine was used as an add-on to regular medication for management of refractory symptoms. The starting dose depended on clinical judgement and patient weight, but set no lower than 240 µg/24 h (equivalent to 0.2 µg/kg/h for a patient weighing 50 kg). Evaluations were conducted every 8 h for the first 24 h, thereafter daily. Dexmedetomidine dose adjustments and dose adjustments of the regular medication for symptom management were made based on patient reports and physician-evaluated symptom relief and side effects.

Data Collection and Assessments

Data on patient demographics, metastatic status, Eastern Cooperative Oncology Group (ECOG) performance status, comorbidities, and pre-intervention symptom management were collected by chart review [34]. Physician-reported information on dexmedetomidine indications, dosing, effects and side effects, and treatment length were also collected from the patients’ medical records. Opioid dose at the introduction of dexmedetomidine was defined as 100% and further opioid doses calculated as percentages of that dose. Vital parameters, including blood pressure, heart rate, and oxygen saturation were measured every 8 h for the first 24 h, then daily until day seven of treatment. After that, follow-up was performed as in routine care. Body temperature was measured if hyperthermia was suspected. Tolerability and safety were assessed in accordance with the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 [35].

Statistical Analysis

Descriptive analyses were used to summarize clinical quantitative data. Means or medians were used as descriptors of central tendencies, and range as descriptor of dispersion. Statistical analysis was performed using SPSS statistical software (Version 27.0).

Ethics

The retrospective chart review was approved by the Regional Committee for Medical and Health Research Ethics (reference number 2021/258166). The study was conducted in accordance with the Declaration of Helsinki [36].

Results

Patient Demographics

During the 2-year study period, nine patients used dexmedetomidine as an add-on to the regular medical management of refractory symptoms provided at the APCU. Six were men and mean age was 54 years (range, 42–66 years). All had metastatic disease (one patient with lymph node metastases only) and median ECOG performance status was III (range, I–IV). Further information on patient demographics is shown in Table 1.

Table 1 Patient demographics
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Pre-intervention Symptom Management

Prior to the introduction of dexmedetomidine, all patients were administered continuous parenteral opioid infusions via syringe drivers. Three patients received opioids intravenously, the remaining six subcutaneously. Maximum parenteral opioid dose was hydromorphone 850 mg/24 h, and two patients used more than one opioid. Additionally, one patient already underwent neuraxial pain management. Two patients experienced severe anxiety despite parenteral midazolam (68 and 13 mg/24 h, respectively), when dexmedetomidine was introduced. Details on pre-dexmedetomidine symptom management are delineated in Table 2.

Table 2 Pre-intervention symptom management
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Indications for Use

For seven patients, pain was decisive for the introduction of dexmedetomidine and for two, anxiety. The two patients with difficult-to-treat anxiety also suffered from pain and depression, respectively. Four patients experienced unacceptable side effects from pre-dexmedetomidine symptom management, of which drowsiness was the most common.

Dexmedetomidine Administration and Dosing

All patients had continuous infusions of dexmedetomidine. Starting doses ranged from 240 to 1344 µg/24 h, and continued doses ranged from 240 to 2440 µg/24 h. Mean maintenance dose at day 7 was 977 µg/24 h. The specifics are described in Table 3 and illustrated in Fig. 1. The two patients with severe anxiety received the drug intravenously. In line with expressed wishes, for one patient the infusion rate was decreased when suitable or increased for comfort care. The other seven patients were given dexmedetomidine subcutaneously.

Table 3 Mean daily dexmedetomidine (DEX), opioid, and midazolam doses during the first week
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Fig. 1
figure 1

Dosages during the first week of concomitant dexmedetomidine and opioid treatment. For opioids, indicated as percentages of the dose when dexmedetomidine was introduced. For patient No. 6, additional fentanyl and methadone dose reductions (Table 3) are not displayed

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Registered Effects

With no systematic NRS registrations available, effect evaluations are based on chart reviews. The two patients with severe anxiety experienced symptom relief with acceptable side effects, but also midazolam doses were increased during the first week of dexmedetomidine treatment (Table 3). They were able to communicate with both staff and next of kin. Among the seven other patients started on dexmedetomidine, pain relief was observed in five. For two patients, initiating neuraxial pain management was necessary to achieve sufficient pain relief during the primary hospital stay. One of these patients required additional propofol sedation, and for the other, dexmedetomidine was withdrawn due to pain relief from intrathecal pain management.

At day 2 of dexmedetomidine treatment, the opioid consumption was reduced in six out of nine patients (Table 3). One patient died at day 4 and one was discharged at day 6, but for the four remaining patients the systemic opioid dose at day 7 was lower than at the introduction of dexmedetomidine. For the seven patients with available data after 1 week of dexmedetomidine treatment, mean systemic opioid consumption was reduced by 26% (Fig. 1). When excluding the two patients started on neuraxial pain management during the first week of dexmedetomidine treatment, mean systemic opioid consumption was reduced by 20% (Fig. 1). When also excluding the one patient with severe anxiety, the corresponding number was 35% (Fig. 1). For one patient started on neuraxial pain management, the systemic opioid dose was increased approximately by 5% the following day, and for the other, decreased by 9% (Table 3).

Safety and Tolerability

Two patients experienced hypotension at day 1 of dexmedetomidine administration. One patient had a temporary drop in blood pressure from 94/60 to 70/46 mmHg and intravascular fluid replenishment was indicated. The incident was classified as CTCAE grade 3. One patient had a temporary drop in blood pressure from systolic 100–110 to 92/56 mmHg, classified as a grade 2 reaction. For both patients, dexmedetomidine administration was continued without further hypotension. No incidents of drug-related hyperthermia, bradycardia, hypertension, respiratory depression, or agitation were reported. In addition, no treatment-related drug withdrawals occurred. The observed sedative responses did not limit continued use, even though the two patients with severe anxiety experienced drowsiness. For the patient who died after 4 days of dexmedetomidine use, imminent cancer-related death was expected prior to the administration of the drug.

Treatment Length and Place of Care

Mean treatment period was 40 days (range, 4–114 days). Cumulative treatment observation period was 361 days. All but one patient continued dexmedetomidine until death. In the one exception, dexmedetomidine was discontinued after 18 days of treatment. For the patients who continued dexmedetomidine until death, three died during the primary hospital stay, two were discharged to nursing homes, and three to home care.

Discussion

Statement of Principal Findings

The study reports accumulated treatment experiences from the use of dexmedetomidine in palliative cancer care. We present results from all consecutively treated patients during a two-year period and provide cumulative data from almost one year of treatment. Both symptom management and reduced opioid doses were documented in the reviewed charts. Two patients experienced initial hypotension, but administered in close collaboration with anesthesiologists dexmedetomidine use was safe. No side effect-related drug withdrawals were registered. However, due to study design and sample size, no firm conclusions can be drawn.

Appraisal of Methods

Retrospective studies have several inherent limitations [37]. The collected data were retrieved from charts not designed for the research purpose and biases may affect the results. The treatment was started at a university hospital with immediate access to both anesthesiology and palliative care expertise. Hence, the findings may not be generalizable to other settings. In addition, the large systemic doses of medications for symptom management, even in patients with intrathecal infusions, indicate that the studied patients were highly selected. Furthermore, patient-reported outcome measures (PROMs) are advocated in palliative care research [38]. The current study did not provide systematic and standardized PROMs, which implies that the results should be interpreted with even more caution. Finally, in clinical practice, efforts are made to best balance positive responses and side effects. This fact may have influenced both dexmedetomidine and opioid dosing, and the choice to initiate neuraxial pain management in two patients.

On the other hand, the current paper describes the largest consecutive series of adult patients with advanced cancer and refractory pain and anxiety treated with dexmedetomidine. The findings may serve as a basis for hypotheses in future better-designed studies.

Comparison with Previous Work

Published 20 years ago, the first report on the use of dexmedetomidine in palliative care depicted its applicability in dying cancer patients with pain, anxiety, and symptoms compatible with side effects from the ongoing symptom management [27]. A decade later, a case report described the drug as a safe adjuvant agent for analgesia in patients with intractable cancer pain [8]. In addition to dexmedetomidine’s positive effects on pain and anxiety, its analgesic sparing properties are reported [9, 28, 39]. Recently, a narrative review on the use of dexmedetomidine in palliative care highlighted cancer pain and neuropsychiatric symptoms as potential relevant indications [25]. This is supported by our study, which also indicated beneficial treatment effects.

Already the first report concerning dexmedetomidine for symptom relief late in the palliative care trajectory described the use of continuous infusions [27]. While intravenous administration previously was preferred, the proven rapid and efficient absorption of subcutaneously administered dexmedetomidine made subcutaneous drug delivery a feasible alternative [8, 10, 11, 17]. In addition, dexmedetomidine is demonstrated visually compatible in admixtures with drugs like morphine, hydromorphone, haloperidol, and hyoscine butylbromide, and the drug is stable in bags intended for subcutaneous infusions [40, 41].

Many clinicians refrain from loading doses and start with a rather low dose such as dexmedetomidine 0.3 µg/kg/h [25]. Maintenance doses ranging from 0.2 to 1.0 µg/kg/h are suggested, even though the use of higher doses is described in specialized units [10, 25, 39]. In our study, the lowest dexmedetomidine starting dose was approximately 0.2 µg/kg/h and the highest maintenance dose 2.0 µg/kg/h (Table 3). For compliance with common palliative care prescription standards, the doses were described as milligrams per 24 h [3, 25].

In the literature, the symptom relief of adjuvant dexmedetomidine are both described by physician-reported observations and PROMs [8,9,10, 27,28,29, 39]. In case reports where PROMs were registered, treatment results for cancer pain varied widely [8, 9]. With pain scores of NRS 8 before dexmedetomidine treatment, the corresponding scores after treatment ranged from 0 to 6 (0–10) [8, 9]. These findings are consistent with our results, where five out of seven patients with severe cancer pain described pain relief. In a case report on successful treatment of cancer pain and depression with intrathecal administration of dexmedetomidine and morphine, also significantly reduced symptom scores for anxiety and drowsiness were reported [29]. These data are congruent with our observations of reduced anxiety and acceptable side effects. However, in our study, the effects of increased midazolam doses must be considered and may even cause the observed effect.

The use of dexmedetomidine is restricted and its application in palliative care is off label [25]. The treatment in our study was initiated and monitored by anesthesiologists. Previous papers have described the safe use of dexmedetomidine in palliative care patients [9, 29, 39]. However, potential safety issues include the risk for bradycardia, arrhythmias, and both hyper- and hypotension [25]. Initial ECG monitoring for selected patients, dose reductions in case of hepatic dysfunction, and avoiding loading doses may reduce the risk for safety problems [25]. Besides, in patients with advanced cancer and refractory symptoms, some risks for adverse effects might be acceptable. In the current study, two patients had temporary hypotension, but there were no dexmedetomidine-related treatment withdrawals.

Several papers describe the prolonged use of dexmedetomidine in palliative care [29, 30, 39, 42]. One case report described continuous intravenous dexmedetomidine infusion for 76 days, and another intrathecal administration that was still ongoing when the report was written [29, 39]. In pediatric palliative care, treatment lengths up to 111 days are described, and one adolescent palliative care patients used continuous dexmedetomidine in a home care setting for nearly 3 years [30, 42]. One of our patients received dexmedetomidine for little less than 4 months, and we report almost 1 year of accumulated treatment experiences. Altogether, the published literature so far supports the potential for long-term use of dexmedetomidine in palliative care.

Implications and Further Work

Based on previous and current findings, dexmedetomidine may have potential for more widespread use in palliative cancer care, both regarding indications and length of treatment. However, its use in palliative care is only supported by weak evidence. To ensure patient safety and to establish a better body of knowledge, larger studies with improved design are needed. Future studies may also address the potential for utilization of dexmedetomidine earlier during palliative care.

Conclusions

No firm conclusions can be drawn from the current study. Still, in a retrospective study of nine palliative cancer patients, the introduction of adjuvant dexmedetomidine by anesthesiologists in an APCU was safe and resulted in reduced opioid consumption for patients late in the disease trajectory.