Opioid stewardship in multimorbidity demands clinical sophistication beyond guideline adherence. It requires individualized risk-benefit analysis, mastery of pharmacokinetic principles, commitment to functional rather than purely pain-focused goals, and most critically, interprofessional collaboration. Those caring for complex patients must become comfortable with uncertainty, recognizing that "the right answer" emerges from team-based deliberation rather than algorithmic prescribing. As healthcare systems transition toward value-based care, managing multimorbid patients effectively becomes both a quality imperative and a professional responsibility. Safe opioid prescribing in this population is not about withholding analgesia. It is about providing comprehensive, coordinated pain management that honors patient complexity while minimizing harm.
- INTRODUCTION
- UNDERSTANDING THE MULTIMORBIDITY CHALLENGE
- CRITICAL DRUG-DRUG INTERACTIONS IN OPIOID THERAPY
- ALTERNATIVES TO OPIOIDS IN MULTIMORBID PATIENTS
- WHEN FUNCTION, NOT PAIN ELIMINATION, IS THE GOAL
- INTERPROFESSIONAL COORDINATION: THE KEY TO SAFE PRESCRIBING
- CASE APPLICATION: BRINGING CONCEPTS TOGETHER
- CONCLUSION
- Works Cited
This course is designed for physicians, PAs, and nurses involved in the care of patients with multiple chronic conditions and comorbid pain.
The purpose of this course is to provide physicians, PAs, and nurses with evidence-based strategies for safe opioid prescribing in patients with multiple chronic conditions and complex medication regimens, improving interprofessional care and patient outcomes.
Upon completion of this course, you should be able to:
- Identify critical drug-drug interactions between opioids and commonly prescribed medications in multimorbid patients.
- Describe evidence-based alternatives to opioids for chronic pain management.
- Implement risk mitigation strategies when opioid therapy is necessary in patients with polypharmacy.
- Articulate the roles of pharmacists and behavioral health professionals in interprofessional opioid stewardship.
Mary Franks, MSN, APRN, FNP-C, is a board-certified Family Nurse Practitioner and NetCE Nurse Planner. She works as a Nurse Division Planner for NetCE and a per diem nurse practitioner in urgent care in Central Illinois. Mary graduated with her Associate’s degree in nursing from Carl Sandburg College, her BSN from OSF Saint Francis Medical Center College of Nursing in 2013, and her MSN with a focus on nursing education from Chamberlain University in 2017. She received a second master's degree in nursing as a Family Nurse Practitioner from Chamberlain University in 2019. She is an adjunct faculty member for a local university in Central Illinois in the MSN FNP program. Her previous nursing experience includes emergency/trauma nursing, critical care nursing, surgery, pediatrics, and urgent care. As a nurse practitioner, she has practiced as a primary care provider for long-term care facilities and school-based health services. She enjoys caring for minor illnesses and injuries, prevention of disease processes, health, and wellness. In her spare time, she stays busy with her two children and husband, coaching baseball, staying active with her own personal fitness journey, and cooking. She is a member of the American Association of Nurse Practitioners and the Illinois Society of Advanced Practice Nursing, for which she is a member of the bylaws committee.
John M. Leonard, MD, Professor of Medicine Emeritus, Vanderbilt University School of Medicine, completed his post-graduate clinical training at the Yale and Vanderbilt University Medical Centers before joining the Vanderbilt faculty in 1974. He is a clinician-educator and for many years served as director of residency training and student educational programs for the Vanderbilt University Department of Medicine. Over a career span of 40 years, Dr. Leonard conducted an active practice of general internal medicine and an inpatient consulting practice of infectious diseases.
Contributing faculty, Mary Franks, MSN, APRN, FNP-C, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
Contributing faculty, John M. Leonard, MD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
Margo A. Halm, RN, PhD, NEA-BC, FAAN
Alice Yick Flanagan, PhD, MSW
The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
Sarah Campbell
The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.
Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.
It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.
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The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.
Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.
#95060: Opioid Stewardship in Multimorbidity: Balancing Pain, Function, and Polypharmacy
Managing pain in patients with multiple chronic conditions presents unique challenges that extend far beyond traditional analgesia. As healthcare providers, we encounter an increasingly complex patient population—older adults juggling cardiovascular disease, diabetes, chronic kidney disease, and psychiatric comorbidities, often taking 10 or more medications daily. In this landscape, opioid prescribing becomes a high-stakes clinical decision requiring sophisticated risk-benefit analysis, interprofessional collaboration, and a fundamental shift in therapeutic goals.
The opioid crisis has prompted essential reflection on prescribing practices, but it has also revealed a critical gap: most clinical guidelines address opioid use in relatively healthy populations, leaving providers uncertain when treating multimorbid patients with complex medication regimens. This course addresses that gap, providing evidence-based strategies for safe opioid stewardship when polypharmacy, drug-drug interactions, and functional rather than pain-focused goals dominate the clinical picture.
Multimorbidity—the coexistence of two or more chronic conditions—affects approximately 67% of adults 65 years of age and older in the United States [1]. These patients frequently experience chronic pain from osteoarthritis, neuropathy, or other conditions, while simultaneously managing medications for hypertension, heart failure, depression, and other diseases. The average Medicare beneficiary with five or more chronic conditions takes 14 different prescription medications [2].
This clinical scenario creates a perfect storm for adverse drug events. Opioids, even when appropriately prescribed, interact with numerous medication classes commonly used in multimorbid patients. The Centers for Disease Control and Prevention (CDC) Clinical Practice Guideline for Prescribing Opioids emphasizes that patients with complex medical regimens require enhanced monitoring and individualized treatment planning [3]. Yet traditional pain management approaches often fail to account for the pharmacokinetic and pharmacodynamic changes that occur in older adults with multiple organ system impairments.
The concurrent use of opioids with gabapentin or pregabalin has emerged as a significant safety concern. A 2019 FDA safety communication warned that combining these agents increases the risk of respiratory depression and sedation [4]. Population-based studies demonstrate that patients taking both opioids and gabapentinoids face a 49% increased risk of opioid-related death compared to opioids alone [5].
The mechanism involves additive central nervous system depression. Gabapentinoids enhance GABA activity and reduce excitatory neurotransmitter release, while opioids suppress brainstem respiratory centers. In multimorbid patients with compromised renal function—common with diabetes or heart failure—gabapentinoid accumulation further amplifies toxicity risk, as these drugs are renally excreted [6].
Screen all patients receiving opioids for concurrent gabapentinoid use.
When combination therapy is necessary, use the lowest effective doses and titrate slowly.
Monitor for confusion, dizziness, and difficulty breathing—particularly in patients older than 65 years of age.
Adjust gabapentinoid dosing based on creatinine clearance.
Educate patients about signs of respiratory depression and when to seek emergency care.
The co-prescribing of opioids and benzodiazepines represents one of the most dangerous yet common polypharmacy patterns. Data from the National Institute on Drug Abuse reveal that 16% of opioid overdose deaths involve benzodiazepines [7]. Both drug classes depress central respiratory drive through distinct mechanisms—opioids via mu-receptor activation in the medullary respiratory center, benzodiazepines through GABA-A receptor potentiation [8].
For patients with anxiety disorders, insomnia, or alcohol use disorder (conditions frequently comorbid with chronic pain) the temptation to prescribe benzodiazepines alongside opioids is substantial. However, research consistently demonstrates that this combination increases overdose risk by 3- to 5-fold [9].
Avoid initiating benzodiazepines in patients on chronic opioid therapy when possible.
For existing combinations, implement gradual benzodiazepine tapers using evidence-based protocols [10].
Consider safer alternatives: buspirone for anxiety, trazodone or doxepin for insomnia, cognitive-behavioral therapy for both conditions.
When tapering is not feasible, maximize harm reduction: prescribe naloxone, reduce opioid doses, increase monitoring frequency.
Document informed consent discussions about overdose risk.
The interaction between opioids and serotonergic antidepressants involves multiple pathways. Most clinically significant is serotonin syndrome risk, particularly with tramadol, meperidine, and methadone, which have serotonergic properties [11]. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) increase synaptic serotonin, and when combined with serotonergic opioids, can precipitate a potentially life-threatening syndrome characterized by altered mental status, autonomic instability, and neuromuscular abnormalities [12].
Additionally, many SSRIs and SNRIs inhibit cytochrome P450 enzymes (particularly CYP2D6 and CYP3A4) affecting opioid metabolism. For prodrug opioids like codeine and tramadol, which require CYP2D6 conversion to active metabolites, SSRI co-administration may reduce analgesic efficacy [13]. Conversely, CYP3A4 inhibition can increase levels of fentanyl, oxycodone, and methadone, raising toxicity risk [14].
Assess depression and anxiety in all patients with chronic pain, as these conditions are highly comorbid.
Avoid tramadol, meperidine, and tapentadol in patients on SSRIs or SNRIs.
When serotonergic agents are necessary, choose opioids without serotonergic activity (e.g., morphine, hydromorphone, oxycodone).
Monitor for serotonin syndrome symptoms (e.g., agitation, confusion, rapid heart rate, dilated pupils, tremor, muscle rigidity)
Educate patients about over-the-counter medications with serotonergic properties (e.g., dextromethorphan, St. John's wort)
The American Geriatrics Society Beers Criteria recommend avoiding opioids when non-opioid alternatives can provide adequate pain control in older adults [15]. For multimorbid patients, this guidance becomes even more critical, as alternatives often address multiple conditions simultaneously.
Acetaminophen remains a first-line analgesic for musculoskeletal pain, with good safety profiles in most multimorbid patients. Maximum daily dosing should be reduced to 3 grams (rather than 4 grams) in older adults, those with hepatic impairment, or chronic alcohol use [16]. For patients on multiple medications, verify that acetaminophen is not duplicated in combination products.
Topical NSAIDs such as diclofenac gel and lidocaine patches offer localized pain relief with minimal systemic absorption, making them ideal for patients with cardiovascular or renal disease where oral NSAIDs pose risks [17]. Topical agents avoid most drug-drug interactions while providing efficacy comparable to oral analgesics for focal joint pain.
Duloxetine, an SNRI approved for diabetic neuropathy, fibromyalgia, and musculoskeletal pain, simultaneously treats chronic pain and comorbid depression or anxiety [18]. This dual mechanism makes duloxetine particularly valuable in multimorbidity, addressing multiple conditions with a single agent. Monitor for serotonin syndrome when initiating in patients on other serotonergic medications.
Anticonvulsants like gabapentin and pregabalin effectively treat neuropathic pain but require careful dose titration and renal dose adjustment. While safer than opioid monotherapy, their sedation profile necessitates caution in older adults at fall risk [19].
Evidence increasingly supports multimodal approaches incorporating physical therapy, cognitive behavioral therapy, exercise, acupuncture, and mindfulness-based stress reduction [20]. For multimorbid patients, these interventions offer pain relief without adding to polypharmacy burdens. Physical therapy improves both pain and function—a dual benefit particularly relevant when functional goals supersede pain elimination. Cognitive-behavioral therapy for pain reduces pain catastrophizing and improves coping strategies, with effects sustained long-term [21].
Integrated pain management programs combining physical rehabilitation, psychological support, and judicious pharmacotherapy demonstrate superior outcomes compared to medication-only approaches in complex chronic pain patients [22].
A paradigm shift in chronic pain management recognizes that complete pain elimination may be unrealistic or achievable only with unacceptable risk in multimorbid patients. Instead, functional restoration becomes the primary therapeutic target. Can the patient walk to the mailbox? Prepare meals? Engage in valued activities? These functional metrics often matter more to quality of life than numeric pain scores.
The CDC guideline explicitly states that opioid therapy should be considered only when benefits for pain and function outweigh risks [3]. For patients with multiple comorbidities, this calculation frequently tilts toward non-opioid strategies. When opioid therapy is pursued, establishing functional goals—rather than pain score targets—provides clearer metrics for assessing effectiveness.
Validated instruments like the Opioid Risk Tool (ORT) or the SOAPP-R (Screener and Opioid Assessment for Patients with Pain-Revised) help stratify patients by risk for opioid misuse [23]. However, these tools were developed in relatively healthy populations; multimorbid patients with cognitive impairment, polypharmacy, or multiple prescribers may be systematically underestimated.
Check state PDMPs before prescribing and regularly during therapy to identify multiple providers or overlapping prescriptions [24]. For multimorbid patients seeing multiple specialists, this coordination is essential.
Current guidelines recommend offering naloxone to any patient on chronic opioid therapy, particularly those on doses ≥50 morphine milligram equivalents (MME) daily, with concurrent benzodiazepine or gabapentinoid use, or with substance use history [25]. For multimorbid patients, this threshold should be lower given enhanced respiratory depression risk.
Implement baseline and periodic urine drug screening, not as punitive surveillance but as a safety tool ensuring prescribed medications are taken and non-prescribed substances are absent [26]. Interpret results carefully, understanding metabolism variations in patients with hepatic or renal impairment.
The CDC recommends caution with doses ≥50 MME/day and avoiding or carefully justifying doses ≥90 MME/day [3]. For multimorbid older adults, even lower thresholds may be appropriate given altered pharmacokinetics and enhanced sensitivity.
Complex patients require complex care teams. No single provider can manage all aspects of opioid stewardship in multimorbidity. Effective interprofessional collaboration, particularly with pharmacists and behavioral health specialists, transforms opioid management from a prescription into a comprehensive care strategy.
Clinical pharmacists uniquely positioned to optimize medication regimens in multimorbid patients can:
Conduct comprehensive medication reviews, identifying all potential drug-drug interactions, not just opioid-related ones
Recommend dose adjustments based on renal and hepatic function, preventing accumulation toxicity
Suggest therapeutic alternatives when interaction risks are excessive
Coordinate deprescribing strategies, safely discontinuing medications no longer necessary
Provide patient education about proper medication use, storage, and disposal
Studies demonstrate that pharmacist-involved pain management services reduce opioid doses, improve pain control, and decrease adverse events [27]. For multimorbid patients, pharmacist collaboration is essential, not optional. Structured medication therapy management programs, increasingly common in integrated health systems, provide frameworks for this collaboration [28].
Chronic pain is inseparable from psychological well-being. Depression, anxiety, and post-traumatic stress disorder (PTSD) amplify pain perception while increasing opioid misuse risk [29]. Conversely, uncontrolled pain exacerbates psychiatric conditions, creating bidirectional causation that medication alone cannot address.
Integrated behavioral health models that embed psychologists, social workers, or psychiatric nurse practitioners in primary care enable:
Screening and treatment of comorbid mental health conditions
Cognitive-behavioral therapy for chronic pain, addressing maladaptive pain beliefs
Motivational interviewing for patients resistant to tapering or non-opioid alternatives
Substance use disorder assessment and treatment when opioid misuse emerges
Sleep hygiene counseling, as insomnia worsens both pain and mental health
The biopsychosocial model of pain posits that biological, psychological, and social factors interactively determine pain experience [30]. Multimorbid patients exemplify this complexity; their pain influenced by inflammatory arthritis (biological), depression (psychological), and social isolation (social). Addressing all three domains requires interprofessional coordination extending beyond traditional medical care.
Consider Patient M, a 72-year-old woman with type 2 diabetes, chronic kidney disease (stage 3b), hypertension, heart failure, depression, and osteoarthritis. Her current medications include metformin, lisinopril, carvedilol, furosemide, sertraline, and as-needed tramadol for knee pain. She reports her pain level is 6/10, limiting her ability to grocery shop independently.
Patient M faces multiple interaction risks—tramadol with sertraline (serotonin syndrome), tramadol with renal impairment (accumulation), polypharmacy burden (nine medications), and functional limitations. Her depression increases opioid misuse risk, while her age and renal disease heighten adverse effect susceptibility.
The patient's healthcare team creates a collaborative care plan that includes:
Pharmacist consultation: Reviews medication list, identifies tramadol- sertraline interaction, notes inadequate renal dose adjustment for several medications, recommends alternatives
Tramadol discontinuation: Switch to scheduled acetaminophen 650 mg three times per day and topical diclofenac gel to knee twice per day
Physical therapy referral: Focus on quadriceps strengthening and gait training to improve grocery shopping capacity (functional goal)
Optimize depression treatment: Ensure sertraline is at therapeutic dose; consider referral to embedded behavioral health clinician
Follow-up plan: Reassess pain and function in two weeks; if inadequate, consider duloxetine (addresses both pain and depression), with pharmacist involved in sertraline-to-duloxetine transition to prevent serotonin syndrome
This plan prioritizes Patient M's functional goal (independent grocery shopping), minimizes polypharmacy and interaction risks, and leverages interprofessional expertise to optimize outcomes.
Opioid stewardship in multimorbidity demands clinical sophistication beyond guideline adherence. It requires individualized risk-benefit analysis, mastery of pharmacokinetic principles, commitment to functional rather than purely pain-focused goals, and—most critically—interprofessional collaboration. Nurses and physicians caring for complex patients must become comfortable with uncertainty, recognizing that "the right answer" emerges from team-based deliberation rather than algorithmic prescribing.
As healthcare systems transition toward value-based care, managing multimorbid patients effectively becomes both a quality imperative and a professional responsibility. Safe opioid prescribing in this population is not about withholding analgesia. It is about providing comprehensive, coordinated pain management that honors patient complexity while minimizing harm.
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