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].

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.

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].

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.

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.

Clinical pharmacists uniquely positioned to optimize medication regimens in multimorbid patients can:

Integrated behavioral health models that embed psychologists, social workers, or psychiatric nurse practitioners in primary care enable: