Priority-Setting to Address the Geriatric Pharmacoparadox for Pain Management: A Nursing Home Stakeholder Delphi Study

Abstract

Background:

Evidence to guide clinical decision-making for pain management in nursing home residents is scant.

Objective:

To explore the existence of consensus regarding what analgesic issues should be prioritized for comparative effectiveness studies of beneficial and adverse effects of analgesic regimens in nursing home residents.

Methods:

Two stakeholder panels (nurses only, a mix of clinicians/researchers) were engaged (n=83). During a three-round online modified-Delphi process, participants rated and commented on the need for new evidence on non-opioid analgesic regimens, opioid regimens, short-term adverse effects, long-term adverse effects, short- or longer-term adverse effects, comorbid conditions, and other factors in the nursing home setting (9-point scale; 1=not essential to 9=very essential to obtain new evidence). The quantitative data were analyzed to determine the existence of consensus using an approached from the RAND/UCLA Appropriateness Method’s manual. The qualitative data consisting of participant explanations of their numeric ratings were thematically analyzed by a highly experienced qualitative researcher.

Results:

For nursing home residents, evidence generation was deemed essential for: opioids, gabapentin (alone or with serotonin norepinephrine reuptake inhibitors (SNRIs)), and non-steroid anti-inflammatory medications with SNRIs. Experts prioritized the following outcomes as essential: long-term adverse effects including delirium, cognitive decline, and decline in activities of daily living (ADL). Kidney disease and depression were deemed essential conditions to consider in studies of pain medications. Co-prescribing analgesic regimens with benzodiazepines, sedating medications, and serotonergic medications, non-SNRI antidepressants were noted as essential areas of study. Experts noted that additional study was essential in residents with moderate/severe cognitive impairment and limitations in ADLs.

Conclusions:

Stakeholder priorities for more evidence reflect concerns related to treating medically complex residents with complex drug regimens and included long-term adverse effects, co-prescribing, and sedating medications. Carefully conducted observational studies are needed to address the vast evidence gap for nursing home residents.

1. INTRODUCTION

In nursing homes, many residents experience pain (1), and the prevalence of pain increases near the end of life (2). Despite the availability of clinical practice guidelines, (3) the importance of pain management at the end of life, and the focus on pain management as part of the surveyors inspections, the management of non-malignant pain in nursing homes is sub-optimal (4). This may be (in part) due to the lack of evidence-base to guide sound clinical decision-making for prescribing analgesics regimens to nursing home residents. The clinical complexity of residents and the aging-related alterations in pharmacokinetics and pharmacodynamics (5) pose challenges. Further, inappropriate drug selection reported in nursing home residents (6) can lead to complications in drug therapy, often manifested as adverse drug events. Previously, we have reported that one third of residents in pain received short-acting opioids and one in ten received long-acting opioids (with nearly half of those on opioids also receiving adjuvants), 21% received gabapentinoids, and 6% received non-opioid analgesics with SNRIs (7). The need to understand the potential adverse effects of these analgesic regimens on outcomes germane to nursing home residents (e.g., delirium, changes in cognitive impairment, decline in ADLs, falls and fractures) is underscored by the prevalence of analgesic regimens in this setting.

Findings from randomized clinical trials have limited generalizability to nursing homes because older adults are frequently excluded. When included, the older adult population is highly selected (8). This has been coined the geriatric pharmacoparadox, whereby the persons most likely to be using medications are the least likely to be included in trials. Furthermore, older adults in nursing homes have been systematically excluded from clinical research. This leaves a serious gap in the evidence. While it may be appropriate to apply pain management guidelines to nursing home populations, the reality is that without further study we simply do not know how well they will work and what dangers they may pose. The seminal report entitled “National Priorities for Comparative Effectiveness Research” reinforces the need for studies aimed at improving drug therapy in older populations with polypharmacy and co-morbidities (8). Geriatric experts ranked pharmacologic management as the top condition in need of improvement for older adults (9).

Carefully conducted observational studies of nursing home residents are needed to fill the evidence gap regarding beneficial and adverse effects of commonly used analgesics in this setting. Given the numerous analgesic regimens, potential adverse effects, and comorbid conditions that nursing home residents have, prioritizing the generation of knowledge that would be most useful to clinicians caring for nursing home residents is necessary. The purpose of this modified Delphi process study was to explore the existence of consensus regarding what analgesic issues should be prioritized for comparative effectiveness studies of both beneficial and adverse effects.

2. METHODS

The study protocol for an online only Delphi process was approved by the Institutional Review Board of the University of Massachusetts Medical School and the RAND Corporation.

2.1. Sample

We used a purposive quota sampling strategy (9) to assemble a diverse sample of participants. To recruit eligible experts and clinicians, we created a short online survey asking potential participants to express their interest in participation and to provide answers to basic demographic questions including gender, age, race/ethnicity, state of residence, degree, and professional role (e.g., registered nurse (RN), nurse practitioner (NP), nursing home administrator, primary care physician, geriatric pain specialist, geriatric psychiatrist, geriatric clinical pharmacist, consultant pharmacist, or academic researcher). In August 2019, screening survey links were sent to participants either directly or through professional societies. The professional societies (or, in some cases, a member of that professional society) assisting our recruitment efforts included the American Geriatric Society (state affiliates), The Society for Post-Acute and Long-Term Care Medicine, Gerontological Advanced Practice Nurses Association, American Association of Colleges of Pharmacy, Society of Pain and Palliative Care Pharmacists, AcademyHealth, Gerontological Society of America, and the Hospice and Palliative Nurses Association.

With 83 qualified participants recruited, we exceeded our target of including 4 participants from each professional role group and met our objective to engage a geographically diverse group of participants. We assigned each participant into one of two panels because previous research suggests that the optimal size of online panels is 40–60 participants (10). We assigned participants into either a homogeneous panel (n=38) that included only nurses (RN or NP) or a mixed panel (n=45) that included all professional roles. The first panel consisted of 31 RNs and 7 NPs and the second panel included 11 geriatricians, 9 researchers, 7 RNs, 7 pain specialists, 6 nursing home administrators, and 5 pharmacists. While nurses were randomly assigned to one of the two panels, all other types of participants were assigned to the mixed panel.

2.2. Data Collection via ExpertLens™

Participants shared their perspectives on priorities for future research focusing on potential adverse effects of commonly used pain treatment regimens in older adults and the need for more information drugs used for pain among nursing home residents. Each panel engaged in a 3-round online modified-Delphi panel (see Appendix). We conducted the online panels using ExpertLens, a previously evaluated online modified-Delphi platform for expert elicitation and stakeholder engagement (10, 11). This platform has been successfully used in more than two dozen studies, (12–14) including a research study focused on nursing homes (15). Within ExpertLens, participants answer questions and explain their responses; discuss their responses with other participants; and revise their original responses if needed. Instead of requiring participants to reach consensus, ExpertLens automatically determines the existence of consensus after each rating round using the RAND/UCLA Appropriateness Method’s approach to measuring consensus (16) and displays this information to participants in subsequent rounds. Briefly, based on responses from 9-point Likert scales, scores from 7–9 indicate strong agreement, scores in the 1–3 range are considered evidence of strong disagreement, and scores in the range of 4–6 indicate uncertainty. Consistent with previous research, consensus is defined as panelist agreement of at least two thirds. Increased consensus is consistent with reductions in deviations with analyses derived from the last survey round

Each panel completed a 3-round ExpertLens process using identical protocols. Participants were assigned to either Panel A or Panel B and could only see ratings and comments from their own panel. In Round One, participants rated the need for new evidence on 50 research topics, including adverse effects, comorbid conditions, and concomitant medication/resident characteristics in the nursing home setting using a 9-point scale, ranging from 1=not essential to obtain new evidence to 9=very essential to obtain new evidence. Participants explained their numeric ratings using open text boxes provided after each rating question (see Supplemental Figure 1). The items participants rated were grouped into six categories, including non-opioid analgesic regimens, opioids, short-term adverse effects, long-term adverse effects, short- or longer-term adverse effects, comorbid conditions, and other factors. Round One was open between October 7 and October 16, 2019. Moderators (AL, JT, JP) were tasked to generate discussion amongst participants and prompt further explanations for highlighted comments from expert panelists.

In Round Two, participants saw how their own responses compared to those of other participants in their panel. Data were presented for each rating question including medians, inter-quartile ranges, and color-coded statements describing whether the panelists reached consensus and considered the need for new evidence to be essential, uncertain, or non-essential. Participants also had the opportunity to review the summaries of explanations participants provided in Round One and to discuss Round One results using an asynchronous, anonymous, moderated online discussion board (see Supplemental Figure 2). Participants could read others’ comments and respond to them if desired. Round Two was open between October 23 and November 1, 2019. In Round Three, participants could revise their Round One responses if they felt that seeing other participants’ responses and comments affected their perspectives (see Supplemental Figure 3). Round Three was open between November 1 and November 19, 2019.

2.3. Data Analysis

To identify priorities for future research, we combined the two panels and analyzed the ratings. The final rating for each question was determined by applying the RAND/UCLA appropriateness method techniques (see Supplemental Figure 4) to the analytic sample of responses, which consisted of Round Three responses of those participants who provided them and Round One responses of those participants who decided not to change their original responses. This approach has been used in previous panels (12–14). We considered responses of 7 through 9 as essential.

We conducted a qualitative analysis to deepen our understanding of the results of the quantitative data. We thematically analyzed qualitative data of free-text responses collected. The coding and qualitative analysis was conducted by one of the authors (CD, an Associate Professor at UMass Medical School with extensive experience in qualitative research and who teaches the Qualitative Methods course in the Graduate School of Biomedical Sciences). Numerous comments were generated during modified-Delphi process. They were downloaded and organized into 50 tables corresponding to each drug regimen. The comments were reviewed in their entirety and were coded by type of regimen and by respondent type. We thematically analyzed the comments to identify the most salient themes and sub-themes (17). As a result of this analyses, we focused our qualitative analysis on opioid regimens. Nine comment tables for opioid regimens were loaded as source documents into NVivo (QSR NVivo. QSR International Pty Ltd., Melbourne, Australia, 2000) for qualitative analysis (see Supplemental Tables 1 and 2) representing a total of 262 comments (range = 21–36 comments per drug regimen, mean = 29 comments).

Comments were reviewed to identify emerging themes and then coded by theme. During this process, additional themes emerged and were added to the coding scheme. Some comments were coded into multiple categories. The final list of codes is shown in Supplemental Table 1. The most frequent three codes (i.e., more information needed, adverse effects, and challenges) were subject to further analysis. For each of the 3 codes, a sub-analysis was conducted using the code report generated by NVivo as the source document. We identified subthemes within each code report. Subthemes were identified and coded by CD and additional subthemes emerged during this phase of the analysis. Code reports were generated for each subtheme and for each drug regimen within each of these 3 major themes (1 - More info Needed; 2 - Adverse Effects; 3- Challenges). Results were not provided to participants for feedback.

3. Results

3.1. Sample Characteristics

Of the 83 invited participants, 48 (58%) participated in at least one round of this panel. Of these 48 participants, 42 (88%) participated in Round One, 28 (58%) participated in Round Two, and 17 (35%) participated in Round Three. Most study participants were White women (79%) (Table 1). Close to three-fifths of participants were between 50 and 64 years of age. Thirty-eight percent were nurses.

Table 1:

Participant characteristics (n=48)

Demographic characteristics	n (%)
Sex
Female	38 (79.2)
Male	9 (18.8)
Other Nonbinary	1 (2.1)
Race
White	38 (79.2)
Asian	1 (2.1)
American Indian/Alaska Native	2 (4.2)
Black/African American	3 (6.3)
Other	4 (8.3)
Degrees
Associates Degree	11 (22.9)
Bachelors Degree	25 (52.1)
Masters Degree	19 (39.6)
LPN	5 (10.4)
RN	17 (35.4)
MSN	8 (16.7)
DNP	3 (6.3)
PharmD	7 (14.6)
MD	6 (12.5)
DO	1 (2.1)
PhD	15 (31.3)
Other Doctoral Degree	1 (2.1)
Age
18–34 years	3 (6.3)
35–49 years	12 (25)
50–64 years	28 (58.3)
65+ years	5 (10.4)
Participant Type
Geriatrician	6 (12.5)
Nursing home administrator	4 (8.3)
Nurse practitioner	6 (12.5)
Nurse	18 (37.5)
Pain specialist	5 (10.4)
Pharmacist	3 (6.3)
Researcher	6 (12.5)

3.2. ExpertLens Overall Quantitative Findings

Participating experts agreed that new evidence is essential to obtain for 33 out of 50 research topics, including all topics covering opioids, long-term adverse effects, and other factors, as well 4 out of 6 topics covering non-opioid analgesic regimens, 4 out of 7 topics focusing on short-term adverse effects, 5 out of 7 topics covering short- or longer-term adverse effects, and 2 out of 12 topics about comorbid conditions (Table 2). The 6 research areas with the highest median value were: 1) use of gabapentin with SNRI antidepressant (median: 8), 2) short term adverse effects -delirium (median: 8); 3) longer term adverse effects, ADL decline (median: 8); 4) longer term adverse effect-cognitive decline (median: 8); 5) short term/longer term adverse effects - falls and fractures (median: 8); and 6) other factors to consider-moderate/severe cognitive impairment (median: 8). Experts disagreed on the extent to which new evidence is needed about short term adverse effects on constipation. They considered the need for new evidence for the remaining 16 topics to be uncertain, meaning that new evidence may be helpful, but is not essential.

Table 2:

Final ratings regarding evidence needs for pain medication management in nursing home residents

TOPICS	Final Ratings
	Median	Decision	# of Ratings
Non-opioid pain medication regimens
1. Celecoxib or meloxicam alone (monotherapy for pain)	6	u	44
2. Ibuprofen, naproxen, or diclofenac alone (monotherapy for pain)	6	u	41
3. Celecoxib or meloxicam with serotonin norepinephrine reuptake inhibitors (SNRI)	7	+	39
4.Ibuprofen, naproxen, or diclofenac with SNRI antidepressant	7	+	39
5. Gabapentin alone (monotherapy for pain)	7	+	40
6. Gabapentin with SNRI antidepressant	8	+	38
Opioid pain medication regimens
1. Short acting opioid alone (monotherapy for pain)	7	+	41
2. Short acting opioid with gabapentin	7	+	41
3. Short acting opioid with SNRI antidepressant	7	+	40
4. Long acting opioid alone (monotherapy for pain)	7	+	38
5. Long and short acting opioid	7	+	38
6. Long acting opioid with gabapentin	7	+	36
7. Long-acting opioid with SNRI antidepressant	7	+	38
8. Long and short acting opioids with gabapentin	7	+	36
9. Long and short acting opioids with SNRI antidepressant	7	+	36
Short-term adverse effects
1. Short term - heart failure	7	+	37
2. Short term - hypertension	6	u	37
3. Short term - impaired renal function	7	+	37
4. Short term - delirium	8	+	39
5. Short term - hallucinations	7	+	36
6. Short term - urinary retention	6	u	35
7. Short term - constipation	5	d	36
Long-term adverse effects
1. Longer term - cognitive decline	8	+	37
2. Longer term – activities of daily living (ADL) decline	8	+	36
3. Longer term - serotonin syndrome	7	+	37
Short- or longer-term adverse effects
1. Short/longer term – gastrointestinal bleeding events	7	+	36
2. Short/longer term – falls and fractures	8	+	35
3. Short/longer term – cognitive impairment	7	+	34
4. Short/longer term – sleep disorders	7	+	34
5. Short/longer term – stroke	6	u	34
6. Short/longer term – myocardial infarction	6	u	35
7. Short/longer term – pulmonary	7	+	35
Comorbid conditions
1. Comorbid cardiovascular disease	6	u	35
2. Comorbid chronic kidney disease	7	+	33
3. Comorbid heart failure	6	u	32
4. Comorbid hypertension	6	u	34
5. Comorbid osteoporosis	5	u	35
6. Comorbid seizure history	6	u	33
7. Comorbid compromised pulmonary function	6	u	33
8. Comorbid atrial fibrillation	5	u	33
9. Comorbid depression	7	+	32
10. Comorbid obesity	6	u	33
11. Comorbid insomnia	6	u	33
12. Comorbid sleep apnea	6	u	33
Other factors
1. Benzodiazepine	7	+	34
2. Sedating medications	7	+	33
3. Non-SNRI Antidepressants	7	+	33
4. Serotonergic medications	7	+	33
5. Moderate/severe cognitive impairment	8	+	31
6. ADL limitations	7	+	33

Notes: highlighted in grey are cells are those with positive decision. “+”: essential, “u”: uncertain, “d”: participants disagreed with each other.

3.3. Need for More Data: Opioid Regimens in Nursing Home Residents

Qualitative findings for opioid regimens are summarized in Table 3. In all opioid regimens, there were 99 comments that were in support of needing more data on the adverse effects of opioids. The number of comments for each drug or drug combination ranged from 9–14. The most comments addressed combination therapy with long-acting and short-acting opioids, and gabapentin. The fewest comments addressed long-acting opioids with SNRIs and for short-acting opioids with SNRIs. Comments are summarized below for the three combinations with the most comments: long- and short-acting opioids (17 comments), long- and short-acting opioids with gabapentin (17 comments), and short-acting opioids 24/7 (13 comments).

Table 3.

Summary of qualitative analysis of comments related to evidence needs for opioid pain medication regimens in nursing home residents

Major domain	Sub theme	# of mentions	Representative quotes and/or summary
Need more data	Lack of research on drug use among nursing home patients	27	“Overall more research is needed in the nursing home population of patients who are frail and often have numerous comorbidities.” (NP 05)
	Adverse effects are unknown or unverified	22	Opioids combined with gabapentin had the most mentions. “The risk of additive toxicity makes the need for adverse event data in this population necessary” (Pharmacist 01).
	Lack of information on combination therapies	19	“Too little is known about risks of adverse effects when these combinations are used in nursing home settings” (Researcher 06).
	Need more information to inform clinical decisions (including effectiveness data, comparative studies, and dosing)	18	Focused primarily on drug combinations and short-acting opioids used around the clock. “Data about combination effects/side effects would be helpful for all patients but particularly for the patients most likely to experience side effects (nursing home residents among them), but it would require individual combination studies and comparison among them to be meaningful in practice” (Geriatrician 05). “I feel it is imperative to have sufficient evidence to support the use of these medication combinations to ensure safety” (Nurse 07). “We don’t know about long term use of short-acting opioids as to outcomes that would support switching to long-acting agents” (Nurse 20)
	The drug or combination is commonly used or standard of care	10	Common use was for long- and short-acting opioids used in combination, the “standard of practice” (Pharmacist 04). “I am uncertain about the frequency with which this combination [long-acting opioid with gabapentin] is used in nursing homes but if it is relatively high we need to learn more about risks of adverse events” (Researcher 06).
	More information needed to individualize therapy	8	“How they [drugs] interact with each individual sometimes is trial and error to find the best management” (Nurse 10) “Further evidence is required as well as individualization” (Nurse 22) One nurse practitioner mentioned, “[re: long-acting opioids with gabapentin] I see altered mental status with gabapentin and there appears to be a lot of variation in its effectiveness” (NP 06)
	Need more information about dependence or addiction potential	5	“Finding the true addition potential would be useful. [long- and short-acting opioids together] Most patients will be physically dependent, but true addiction is not well defined” (Pain Specialist 04). “I personally believe that we have created a lot of drug dependence in our elderly and would be interested in seeing if this is backed up by evidence” (Nurse 08B).
Adverse Events	Central nervous system effects	23	Nurse 08 “risk of sedation is so high” (3 drug combinations); Nurse 26 “confusion that presents with multipharma can be confused with dementia” (2 triple drug combinations); and Pain Specialist 04 “additive central nervous system effects” (5 drug combinations). Both NP 06 and Nurse 04 expressed concern about the mind-altering effects of gabapentin, and NP 05 noted observing frequent side effects with gabapentin in the nursing home population including sedation and myoclonic jerks. Nurse 08B noted “Anecdotally see too much sedation with this combination [short-acting opioid with gabapentin], would be very interesting to see if this is backed up by research.”
	High risk for nursing home residents	13	Several respondents indicated that the risk of sedation and other adverse effects in the nursing home population may be too high. Concerns were expressed for combination therapy (opioids with gabapentin or serotonin norepinephrine reuptake inhibitors (SNRI)) and for long-acting opioids alone, particularly in “frail elderly patients with impaired renal/hepatic function” (NP05). Researcher 09 noted “Long-acting opioids have a variable and long elimination half-life. For me this was more of a concern in terms of adverse drug events and level of drug accumulation for the older adult.”
	Falls and gait	12	Concerns about falls and gait stability were raised for combination therapy including long-acting and/or short-acting opioids and gabapentin or SNRIs. Regarding long-acting opioids with SNRIs Pharmacist 04 noted “The anticholinergic effects of many of the SNRIs combined with the sedative and depressive effects of LA OAs concern me re the increased risk for dizziness, anxiety etc., which in turn increase the risk for falls and trauma.”
	Adverse drug events unclear or unknown	8	One respondent (Pain Specialist 04) made the same comment for 5 different drug combinations (opioids combined with gabapentin or SNRIs) stressing that, with the exception of central nervous system effects, “other adverse drug effects not clear.” Researcher 06 indicated the need to learn more about adverse drug event risk with long-acting opioids and SNRIs.
	Drug interactions or additive effects	8	Comments here focused on potential synergistic effects when combining long-acting and short-acting opioids (Researcher 09). Three respondents noted that drug-drug interactions were a concern when combining long-acting opioids and gabapentin, and two respondents raised this same concern with short-acting opioids with gabapentin. Nurse 04 expressed concern about SNRI side effects when combined with short acting opioids.
Challenges	Drugs used in combination	13	Geriatrician 06 noted repeatedly that “combinations are problematic.” For combinations including gabapentin, respondents focused on challenges including sorting out the side-effects and efficacy of the opioid versus the gabapentin, and the potential for multiple comorbidities. Where gabapentin is combined with both short- and long-acting opioids, concerns about polypharmacy were expressed. For long-acting opioids and SNRIs, Researcher 09 noted “This combination has a more complex effect on both the nociceptive processing and pain perception. I think it is probably effective, but for the older population we should be aware of serotonin syndrome and how to recognize it in our NH residents.”
	Side effects	9	Challenges from side effects mentioned included increased risks for negative effects independent of treatment regimen, and the need for risk profiles. Constipation was also identified as a challenge in nursing home patients (Nurse 27). Researcher 09 noted “Long-acting opioids have a variable and long elimination half-life. For me this was more of a concern in terms of adverse drug events and level of drug accumulation for the older adult, not to mention possible other co-morbidities (renal disease, diabetes, etc.) adding to the risk.”
	Opioid crisis	7	Addiction, diversion, and reluctance of providers to prescribe opioids were identified as challenges. Nurse 27 noted “While in theory we don’t feel that addiction is a problem, this population is very vulnerable to the potential for addiction.” “Seems like risk of adverse effects too high for this population, and potential of misuse/theft to great in this setting” (Researcher 08). “I don’t want to prescribe an opioid (because of legal red tape, not because of any concerns of addiction or abuse in this population)” (NP 05).
	Gabapentin	7	Gabapentin is described as a “wild card” with multiple issues when used alone (NP 06). Researcher 09 noted “I would worry about half-life and renal clearance of the drugs, but feel that gabapentin is more of a risk with this combination [long-acting and short-acting opioids together] than SNRIs.”
	Serotonin and norepinephrine inhibitors	6	“SNRI dosing is not well established and there appears to be questions of efficacy that may be masked by opioid” (NP 06). SNRIs and opioids are “currently used together frequently for depression and pain. Any positive effect of the SNRI on pain would have been an added benefit as it would not have been the MDs conscious decision” (Nurse 01 B). Other comments mentioned challenges with SNRI dosing (NP 06) and the potential to impact Centers for Medicare & Medicaid Services ratings (Nurse 01).

Long- and Short-Acting Opioids (17 Comments) –

Several participants commented that a combination of long- and short-acting opioids is commonly used in nursing homes, and characterized this combination as a “mainstay of therapy” (Geriatrician 06) or “somewhat the standard of practice” (Pharmacist 04). Most comments for this drug combination mentioned the lack of research on older adults in the nursing home setting: “This is the combination recommended in pain literature. However, we have few controlled data in older adults” (Pharmacist 01). Others noted that there was “little evidence of effectiveness and safety in long term care population” (Pharmacist 04). Researcher 06 commented: “To my knowledge we have insufficient evidence of risks of adverse effects of combining use of short-acting and long-acting opioids to treat pain in nursing home settings.”

Long- and Short-Acting Opioids with Gabapentin (17 Comments) –

Some participants commented on the need for additional evidence about adverse events and side effects of long- and short-acting opioids in combination with gabapentin. “I would anticipate that the risk of serious adverse events would be substantially increased with the combination, but am unaware of any data to support that hypothesis” (Pain Specialist 06). The combination was described as “very high risk” (Researcher 03) with a substantial potential for toxicity, “We have essentially no information about the combination” (Pharmacist 01). Nurse 10 also noted a degree of uncertainty when administering this combination: “How they interact with each individual sometimes is trial and error to find the best management.”

Short-Acting Opioid 24–7 (13 Comments) –

Comments spanned several topic areas including lack of information on adverse events, the need for research among nursing home patients, and the need for better information to guide clinical decision-making. Two participants (Nurse 08B, Nurse 27) commented on the need to better understand addiction or dependency potential in the nursing home setting.

Sub-analysis: More Evidence Needed –

We show the results of the sub-analysis of the comments coded in this category (Table 3). Themes identified were: 1) lack of research on drug use among nursing home residents; 2) Adverse effects are unknown or unverified; 3) Lack of information on combination therapies; 4) Need more information to inform clinical decisions (including effectiveness data, comparative studies, and dosing); 5) The drug or combination is commonly used or standard of care; 6) More information needed to individualize therapy; and 7) Need more information about dependence or addiction potential.

3.4. Adverse Effects: Opioid Regimens in Nursing Home Residents

There were 76 comments mentioning adverse effects (range = 4–16 comments per drug combination). Most comments were for long-acting opioids combined with gabapentin (16 comments). Several participants had concerns about risk of adverse drug events in the nursing home population: “Seems like the risk of adverse effects too high for this population” (Researcher 08); “Risk of sedation is so high… Perhaps too high a risk for nursing home residents?” (Nurse 08B). Specific risks included sedation, somnolence, and additive central nervous system effects; increased fall risk; and potential drug accumulation in older patients. Interactions of these drugs was also identified as a concern: “I believe that there [are] side effects in the elderly population is well documented with these meds alone. How they interact with each individual sometimes is trial and error” (Nurse 10); “Setting up frail older adults with double dependency? Side effects and drug-drug interaction also a concern” (Pharmacist 04). Pain Specialist 05 commented, “…my concern people in this target group may have an increased risk for some of the potential negative effects and may therefore have higher likelihood to experience them. Further, some of these negative effects could subsequently result in decreased quality of life without clearly recognizing the accurate etiology.” There were also concerns were expressed about central nervous system effects of short acting opioids used with gabapentin (10 comments) including myoclonic jerks, gait stability and fall risk, and worsening renal function. Nurse 04 expressed concern about dosing: “Dosing is often difficult to manage pain control in the elderly” and Pharmacist 01 noted “Additive adverse effects warrant investigation of these combination[s].” Ten comments related to short-acting opioids used with SNRIs. Nurse 01B felt that adverse effects for this combination “have been established adequately and is frequently used together for depression and pain” while Geriatrician 05 pointed out that “not all SNRIs are the same to begin with, all of them fraught with increased central nervous system side effects (sedation, falls, change of mental status, in some cases increase seizure risk).” Pain Specialist 06 indicated a preferred combination of opioid + SNRI that would avoid drug interactions: “Venlafaxine and desvenlafaxine do not affect CYP metabolism of opioids and would be preferred.” Researcher 09 stressed the importance of close monitoring older adult patients for serotonin syndrome which could lead to negative consequences. The combination of long-acting opioids with SNRIs (9 comments) was seen as high risk, with sedation, fall risk and trauma, dizziness, anxiety, and potential hospitalization due to misdiagnosis of negative effects noted as concerns. Researcher 06 stressed “Because of the high prevalence of pain and depression among nursing home residents it is very important that we learn more about the risks of adverse effects of using this combination of medications.”

We conducted a sub-analysis to identify the adverse events mentioned most frequently (Table 3). We found 18 adverse event categories, 6 of which only had one mention each (renal function, long-term effects, constipation, respiratory depression, age-related pharmacodynamics and pharmacokinetics, sleep disturbance) and 5 had only 2 mentions (opioid naïve, behavioral issues, eating/loss of appetite, reduction in quality of life, drug accumulation). Comments about serotonin/serotonin syndrome had 3 mentions and comments about ADEs needing continual review had 5 mentions.

3.5. Challenges Opioid Regimens in Nursing Home Residents

There were 66 comments about the challenges associated with different drugs and drug combinations (range = 3–13 comments per drug combination). The most challenges were identified for short-acting opioids combined with gabapentin and the least were for long- and short-acting opioids with gabapentin. Several respondents expressed concerns about short-acting opioids, gabapentin, and both used in combination (13 comments). Nurse 01 noted “Any short-acting medication that is [used] ‘as needed’ in the nursing home setting is underused. Residents do not ask for medication, numerous risks associated with use of drugs on the Beers list as they should be avoided in older adults.” Gabapentin use was described as “on the rise” in the general population (Nurse 01B) and increasingly prescribed post operatively for pain (Geriatrician 10). The combination of the 2 drugs elicited the following challenges: “Gabapentin is a wild card alone so in combination is an even greater problem” (NP 06); “Both have adverse reactions and difficult to decide which is causing” (Nurse 09); and “It is hard to tell which is eliciting the relief – the opioid alone or the combination” (Nurse 22).

With respect to short-acting opioids (12 comments), the main challenge noted was medication monitoring in the nursing home. “Monitoring effects/side effects in nursing homes is challenging due to time constraints of nursing staff, staff-resident ratios, and also lack of training/understanding of nursing staff about on-set of action of medication/vigilance to side effects… Scheduled application in opioid-naïve frail older adults may quite easily lead to unnecessary side effects” (Geriatrician 05). The need for frequent administration was also seen as challenging as well as the potential for addiction, diversion, and constipation. Potential inadequate treatment was also mentioned as a challenge as “most residents are unable to ask for medication, are not assessed frequently enough, and therefore, not adequately treated” (Nurse 22). Nurse 22 also noted: “Short-acting opioids alone often put the LTC resident on the roller coaster of short-term relief followed by escalating pain.”

With respect to monotherapy with long-acting opioids (11 comments), the need for individualization of therapy was seen as challenging by several respondents. Finding the best management for an individual was described as “trial and error” (Nurse 10) and Pain Specialist 06 noted “I think there is much to be done in developing risk profiles to inform the appropriate prescribing of this class of medications.” Other challenges included how to handle opioid naïve patients and patients with renal insufficiency. Behavioral issues may also be challenging as noted by Nurse 09 “One issue I have is how to keep them from removing a topical patch.”

Lastly, for long- and short-acting opioids used together (8 Comments), there were a variety of sometimes conflicting statements. Nurses 01 and 09 and Researcher 08 characterized this combination as too risky for the nursing home population, requiring further study, and introducing the potential for diversion. Pharmacists 01 and 04 and Researcher 01 described a role for these drugs used together, with short-acting opioids used for breakthrough pain. However non-communicative patients were seen as challenging when using this approach “Processes need to be in place for pain assessment in non-verbal older persons who cannot communicate their needs or pain” (Pharmacist 04).

We conducted a sub-analysis to identify challenges mentioned most frequently (Table 3). We found 54 different challenges, 10 of which had 3 or fewer mentions each (lack of staff training, nurses too busy, impaired renal function, monitoring opioid effectiveness and side effects, patients’ behavioral issues, unique aspects of the nursing home population, treating opioid naïve patients, need for Individualized therapy, the “roller coaster of pain”, and inadequate treatment). Challenges with 5 mentions included issues related to dosing and the difficulty treating patients who are unable to communicate. Categories with 6 or more mentions are summarized on Table 3. Regulations in response to the opioid epidemic served as barriers for prescribing opioids in nursing homes.

4. Discussion

This study identified numerous evidence gaps relating to analgesic regimens for older nursing home residents. Although most areas were rated highly as in need of evidence, experts deemed that knowledge generation was essential regarding opioids, gabapentin, and opioids with SNRIs, gabapentin with SNRIs, and non-steroid anti-inflammatory medications with SNRIs. Of particular concern was use of analgesics concomitantly with psychotropic medications such as benzodiazepines. Understanding the impact of these medications on fractures, delirium, changes in cognitive function, ADL decline, and the development of serotonin syndrome was prioritized. Depression and chronic kidney disease were identified as comorbid conditions in need of consideration in studies of analgesics in nursing home residents. Experts noted that evidence regarding the beneficial and adverse effects of analgesic regimens in those with moderate to severe cognitive impairment and/or limitations in ADLs is of high priority.

4.1. Pain medications prioritized for research

The experts reached consensus on the need to generate more evidence for nursing home residents for opioids, gabapentin, and SNRIs used with opioids, gabapentin, or non-steroidal anti-inflammatory medications. These regimens are common in the nursing home settings (7). Fifteen percent of nursing home residents use opioids long term (18), but duration of gabapentin use and multidrug pain regimens is unknown. Previously, our group has found that risks of falls/fractures is not similar across short acting oral opioids commonly used in nursing homes (19) which reinforces the need to explore within and between class differences in the potential adverse effects of pain regimens. From our qualitative analysis, we learned that regulations to curb the opioid epidemic have served as barriers for prescribing opioids in nursing homes. Given that undertreatment of pain in nursing homes has been well documented (7, 20), the extent to which such regulations had the unintended effect of impacting the management of pain in nursing home residents warrants further exploration. Our qualitative analyses also revealed that gabapentin used alone or in combination with opioids was viewed as a “wild card” by experts. Off-label use of gabapentin in nursing homes is common (21) which underscores the need for information regarding its safety in this medically complex population.

4.2. Outcomes prioritized for research

In our study, the most highly ranked outcomes in need of study included fractures, delirium, changes in cognitive impairment, and ADL decline. These findings coincide with a landmark study on adverse drug events revealed that fractures and delirium were two of the most common preventable adverse drug events in nursing homes (22). Delirium is associated with a high risk of adverse outcomes in nursing home residents (23), with medications among the most common precipitating factors (24). For nursing home residents, the 2-year risk of hip fracture is 3% among long-stay residents (25), which leads to functional decline (26) and increased risk of death (27). Research to evaluate the effect of analgesic regimens on these high priority outcomes is possible in the United States. By federal mandate, the Minimum Data Set, a comprehensive geriatric assessment, is conducted at on virtually all nursing home residents at admission, quarterly, and when significant change occurs. Measures of falls/fractures, and scales to evaluate delirium (23), ADLs, (18) and cognitive impairment, (28) are embedded within the Minimum Data Set. As such, comparative safety studies focusing on these outcomes is possible. Responses from participants also identified the need for additional research into serotonin syndrome in the nursing home population taking opioids, gabapentin and other concomitant drugs. This syndrome may present as agitation, restlessness, confusion and headache among other symptoms and might be easily overlooked or attributed to aging-related changes. Given that many additional serotonergic drugs including tramadol, SNRI, SSRI, tricyclic antidepressants, metoclopramide, ondansetron and some anticonvulsants may also be prescribed to these patients, additional research is essential.

4.3. Co-morbid conditions prioritized for research

Experts were most concerned about depression and chronic kidney disease as comorbid conditions in need of consideration in studies of analgesic regimens for nursing home residents. Given that nursing home residents with depression may have the highest reported prevalence of pain, (29, 30) the established bi-directional links between depression and pain intensity, (31, 32) and the role of pain, ADLs, and recovery from depression, (33, 34) this finding was not surprising. Concerns about comorbid kidney disease align with the literature. An estimated 48% of nursing home residents have moderate renal insufficiency and 15% have severe renal insufficiency, with one in five with renal insufficiency on medications contraindicated or requiring dose adjustments (35). Given the high prevalence of polypharmacy in nursing homes (36), studying the role of chronic kidney disease when evaluating potential adverse effects of analgesics and/or adjuvants is necessary. We were a bit surprised that insomnia was not prioritized as essential for research. Pain is a leading cause of sleep disturbance among older adults (37, 38), the prevalence of sleep disturbance increases with pain severity (39), and pain predicts sleep quality (40). It is possible that among the list of potential comorbid conditions to consider, more emphasis was placed on highly prevalent comorbid conditions.

4.5. Strengths and Limitations

This study is (to our knowledge) the first to engage a researchers and clinicians in a modified-Delphi process to prioritize gaps in evidence needed to inform clinical decision making for pain management in a population often neglected by the evidence- nursing home residents. Conducted in accordance with best practices for Delphi panels (40), we used purposive sampling. Doing so assured representation from key stakeholder groups (41) which is a strength of the current study. The number of participants included in our panels was large relative to previous nursing-home based modified-Delphi panels. The diverse experiences shared by the participants represents a strength of the study. Limitations of our study must also be considered. Participants provided input on 50 different items and the length may have contributed to attrition through the panel rounds. While attrition is common in Delphi panels (42), we recognize that it may have biased our results. Because we began with a purposeful sample and had attrition through panel rounds, these findings must not be considered as generalizable.

5. Conclusions

Experts included in this study prioritized information needs to expand the evidence-base related to pain management for nursing home residents. The information needs identified were many. Many nursing home residents are dependent in ADLs and/or have severe cognitive impairment and as such the needs of understanding how analgesics impact these residents is a priority. Opioids and gabapentin were ranked highly with respect to needing information to guide decision making, as were non-opioids and opioids used concomitantly with SNRIs. Because methodological advances in the conduct of observational studies in clinically complex nursing home residents allow for robust evidence to be generated from existing data resources such as the Minimum Data Set and Medicare claims, achieving the information needs prioritized in this study is possible.

Key Points:

• The evidence-base to guide sound clinical decision-making for prescribing analgesics to nursing home residents is scant.

• Given the numerous analgesic regimens, potential adverse effects, and comorbid conditions among nursing home residents, prioritizing the generation of new knowledge that would be most useful to clinicians caring for nursing home residents is warranted.

• To our knowledge, no study has tried to prioritize knowledge generation related to pain medications for nursing home residents.

• Evidence on opioids, gabapentin, and all analgesics used in combination with serotonin norepinephrine reuptake inhibitors was deemed essential.

• Potential adverse effects in need of additional study were delirium, cognitive decline, and decline in activities of daily living.

• Evidence on risks/benefits in residents with moderate/severe cognitive impairment and limitations in activities of daily living were deemed essential, as was evidence on the risks/benefits of analgesic regimens used with other psychotropic medications.