What is the recommended standard multimodal regimen for managing chronic pain, including non‑opioid medications and criteria for adding opioids?

Standard Multimodal Regimen for Chronic Pain Management

Non-opioid pharmacologic therapy combined with non-pharmacologic interventions should be the foundation of chronic pain management, with opioids reserved only as a last resort after documented failure of safer alternatives. 1, 2

First-Line Pharmacological Approach

For Musculoskeletal Pain

• Start with acetaminophen 1000 mg every 4-6 hours (maximum 4 g/day in patients with normal liver function; reduce dose in liver disease) as the safest initial option with fewest side effects. 1, 2
• Add or substitute an NSAID (ibuprofen 600 mg four times daily, naproxen 500 mg twice daily, or diclofenac 75 mg twice daily) for inflammatory or bone pain, particularly when acetaminophen alone is insufficient. 1, 2
• The combination of acetaminophen 500 mg plus ibuprofen 200 mg provides superior analgesia to opioid-based regimens and should be prioritized. 3, 4
• Consider COX-2 selective NSAIDs (celecoxib) to reduce gastrointestinal bleeding risk, but recognize increased cardiovascular risk compared to traditional NSAIDs. 1, 2
• Prescribe proton pump inhibitors for gastroprotection when using traditional NSAIDs long-term. 1

For Neuropathic Pain

• Initiate gabapentin as first-line therapy, titrating to 2400 mg/day in three divided doses (typically 800 mg three times daily). 2, 5
• Alternatively, use pregabalin 100-600 mg/day divided in 2-3 doses, particularly in patients with liver impairment where duloxetine is contraindicated. 2
• Apply capsaicin 8% dermal patch topically, with a single 30-minute application providing relief for up to 12 weeks. 2, 5

Second-Line Pharmacological Options

• Add duloxetine or venlafaxine (SNRIs) for inadequate response to first-line treatments, particularly when neuropathic components are present. 2, 5
• Consider tramadol 37.5-400 mg/day in divided doses for up to 3 months for osteoarthritis pain, recognizing it carries lower addiction risk than traditional opioids but requires monitoring for opioid-like side effects. 1, 2
• Reserve tricyclic antidepressants as alternatives to SNRIs, acknowledging their greater side effect burden. 5

Essential Non-Pharmacological Interventions

These must be integrated into every chronic pain regimen, not offered as optional adjuncts: 1, 2

• Cognitive Behavioral Therapy (CBT) is strongly recommended to promote adaptive behaviors and address maladaptive pain responses such as fear-avoidance. 2, 5
• Physical and occupational therapy to improve muscle strength, function, and reduce pain interference in daily activities. 2, 5
• Yoga specifically for chronic neck/back pain, headache, rheumatoid arthritis, and musculoskeletal pain. 2, 5
• Medical exercise programs to improve muscular strength and sensorimotor function. 2, 5
• Hypnosis particularly for neuropathic pain components. 2, 5
• Acupuncture may be trialed though evidence is limited. 2

Opioid Therapy: Strict Last-Resort Protocol

Opioids should only be considered after documented failure of all first-line and second-line therapies in patients reporting moderate-to-severe pain with functional impairment, and only when potential benefits clearly outweigh risks of addiction, respiratory depression, and death. 1, 2

Pre-Initiation Requirements

• Check state Prescription Drug Monitoring Program (PDMP) to identify concurrent prescriptions or doctor-shopping. 1, 2
• Obtain baseline urine drug testing to detect undisclosed substance use. 1, 2
• Assess all patients for risk factors including history of substance use disorder, mental health conditions, concurrent benzodiazepine use, and sleep apnea. 1, 2
• Establish written opioid patient-provider agreement (PPA) covering informed consent, treatment goals, and plan of care before prescribing. 1, 2

Initiation Protocol

• Start with immediate-release opioids (not extended-release formulations) at the lowest effective dose—never exceed 50 morphine milligram equivalents (MME)/day initially. 1, 2
• For neuropathic pain, consider combining morphine with gabapentin for additive effects and lower individual doses required. 1
• For musculoskeletal pain, combine short- and long-acting opioids starting with the smallest effective dose. 1

Dose Thresholds and Monitoring

• Carefully reassess benefits versus risks when approaching 50 MME/day. 1, 2
• Avoid increasing to 90 MME/day or carefully justify any decision to exceed this threshold, as mortality risk rises substantially. 1, 2
• Evaluate benefits and harms within 1-4 weeks of starting therapy or dose escalation, then every 3 months minimum. 1, 2
• Review PDMP data at every visit, ranging from every prescription to every 3 months. 1, 2
• Perform urine drug testing at least annually to assess for prescribed medications and detect illicit drugs. 1, 2

Absolute Contraindications

• Never prescribe opioids concurrently with benzodiazepines due to severe respiratory depression and overdose risk. 1, 6

Discontinuation Criteria

• Discontinue opioids if there is no clinically meaningful improvement in both pain AND function after 3 months, or if evidence of misuse, diversion, or opioid use disorder emerges. 1, 2
• Optimize other therapies and work with patients to taper opioids to lower dosages or discontinue entirely when benefits do not outweigh harms. 1, 2

Mandatory Monitoring and Reassessment

• Screen all patients for depression using two questions: "During the past 2 weeks have you been bothered by feeling down, depressed, or hopeless?" and "During the past 2 weeks have you been bothered by little interest or pleasure in doing things?" 2
• Assess baseline mental health for modifiable factors: self-esteem, coping skills, recent loss/grief, substance use, violence/safety concerns, mood disorders, and suicidal ideation. 2
• Regularly document pain intensity using numerical rating scales (0-10), functional improvement in specific activities, and medication side effects at every visit. 1, 2

Common Pitfalls to Avoid

• Never start with extended-release opioids—this dramatically increases overdose risk. 1, 2
• Never continue opioids based on pain reduction alone without documented functional improvement. 1, 2
• Never prescribe opioids without first checking PDMP to identify dangerous concurrent prescriptions. 1, 2
• Never use lamotrigine for neuropathic pain due to rash risk and limited efficacy. 1
• Never combine two sustained-release opioids or two products of the same pharmacological class with the same kinetics. 1
• Never ignore constipation prophylaxis—prescribe stimulant laxatives (senna or bisacodyl) routinely when initiating opioids. 1