Primary Care Clinical Office Practice in Diagnosis and Treatment of Osteoarthritis

Recommendations

These recommendations are structured into three key areas for your consideration in primary care clinical office practice:

Determining when to initiate or continue opioid prescriptions for chronic pain in osteoarthritis patients.
Opioid selection, dosage, duration, follow-up strategies, and discontinuation protocols.
Risk assessment and management of harms associated with opioid use in the context of osteoarthritis treatment.

These guidelines consist of 12 specific recommendations (Box 1). Each recommendation is followed by a rationale, providing context and justification, along with practical considerations for implementation in your primary care clinical office practice. In line with the ACIP GRADE process, these recommendations from the CDC are grounded in a comprehensive evaluation of clinical evidence, contextual factors (including the balance of benefits and harms, patient values and preferences, and resource allocation), and expert clinical judgment. For each recommendation, the category (A or B) and the evidence type (1, 2, 3, or 4) are clearly indicated (Box 2). Expert insights, gathered from the Core Expert Group and the Opioid Guideline Workgroup, are integrated into the rationale for each recommendation. While formal consensus was not sought, these experts expressed broad support for the recommendations. Areas where expert opinions diverged regarding specific clinical actions or implementation are noted within the supporting rationale statements.

Category A recommendations suggest that the recommended action is appropriate for most patients. Category B recommendations indicate that clinical decision-making should be tailored to individual patients, requiring clinicians to engage patients in shared decision-making that aligns with their values, preferences, and specific clinical circumstances. Consistent with the ACIP (47) and GRADE process (48), Category A recommendations were established even with type 3 and 4 evidence when there was strong agreement that the advantages of a clinical action significantly outweighed the disadvantages, considering benefits, harms, patient values, preferences, and resource implications. Category B recommendations were issued when advantages and disadvantages were more balanced, yet the advantages were still substantial enough to warrant a recommendation. All recommendations are Category A, except for recommendation 10, which is Category B. The evidence supporting these recommendations ranges from type 2 to type 4.

In summary, the categorization of these recommendations is based on the following critical assessments relevant to primary care clinical office practice in diagnosis and treatment of osteoarthritis:

There is no robust evidence demonstrating the long-term benefit of opioids on pain and function compared to non-opioid strategies for chronic pain, when outcomes are assessed at least one year later. Most placebo-controlled randomized trials are limited to ≤6 weeks.
Extensive evidence highlights the significant potential harms of opioid use, including opioid use disorder, overdose, and increased risk of motor vehicle accidents.
Substantial evidence supports the benefits of nonpharmacologic and nonopioid pharmacologic treatments compared to long-term opioid therapy, with a considerably lower risk profile.

Determining When to Initiate or Continue Opioids for Chronic Pain in Osteoarthritis within Primary Care Clinical Office Practice

1. Nonpharmacologic therapy and nonopioid pharmacologic therapy are the preferred first-line approaches for managing chronic pain associated with osteoarthritis. Clinicians in primary care clinical office practice should only consider opioid therapy if the anticipated benefits for both pain relief and functional improvement are expected to outweigh the risks for the individual patient. If opioids are deemed necessary, they should be used in conjunction with nonpharmacologic and nonopioid pharmacologic therapies, as clinically appropriate (recommendation category: A, evidence type: 3).

In primary care clinical office practice, prioritize treatments for osteoarthritis pain that offer the greatest benefit relative to risk. Evidence indicates that numerous nonpharmacologic therapies, including physical therapy, weight management for knee osteoarthritis, cognitive behavioral therapy (CBT), and specific interventional procedures, can effectively alleviate chronic pain. High-quality evidence demonstrates that exercise therapy, a cornerstone of physical therapy, reduces pain and improves function in hip (100) and knee (99) osteoarthritis immediately post-treatment, with sustained improvements for at least 2–6 months. Prior guidelines advocate for aerobic, aquatic, and resistance exercises for osteoarthritis of the knee or hip (176). Exercise therapy is also beneficial for low back pain and can enhance overall well-being and physical function in fibromyalgia (98,101). Multimodal and multidisciplinary biopsychosocial rehabilitation approaches, integrating psychological therapies with exercise, can lead to greater long-term pain reduction and functional improvement compared to usual care or exercise alone. However, the availability and insurance coverage for multimodal therapies can be inconsistent, and they may be time-intensive and costly for patients. Interventional approaches like arthrocentesis and intraarticular glucocorticoid injections for osteoarthritis (118) can provide short-term pain and function improvement. The long-term safety of repeated glucocorticoid injections, particularly regarding articular cartilage changes and sepsis (118), remains uncertain. Serious adverse events from epidural injections are rare but have been reported (120).

Several nonopioid pharmacologic therapies are effective for chronic pain management in osteoarthritis, including acetaminophen, NSAIDs, and certain antidepressants and anticonvulsants. Acetaminophen and NSAIDs are particularly useful for osteoarthritis and low back pain. Anticonvulsants like pregabalin and gabapentin can improve pain in diabetic neuropathy and post-herpetic neuralgia. Pregabalin, gabapentin, and carbamazepine are FDA-approved for neuropathic pain, and pregabalin is approved for fibromyalgia. Tricyclic antidepressants and SNRIs are effective analgesics for neuropathic pain, including diabetic neuropathy and post-herpetic neuralgia, even at lower doses than used for depression. They can also alleviate fibromyalgia symptoms. Duloxetine, an SNRI, is FDA-approved for diabetic neuropathy and fibromyalgia. Given the frequent co-occurrence of depression in chronic pain patients (144), and depression’s potential to exacerbate pain (177), antidepressants can be particularly beneficial for patients with both conditions (see Recommendation 8). Nonopioid pharmacologic therapies generally do not carry the risk of substance use disorder, and associated fatal overdoses are significantly fewer compared to opioids. For instance, in 2010, acetaminophen, NSAIDs, and opioid pain medications were linked to 881, 228, and 16,651 pharmaceutical overdose deaths in the U.S. (178). However, nonopioid pharmacologic therapies also have risks, especially for older patients, pregnant women, and those with cardiovascular, renal, gastrointestinal, or liver diseases. For example, acetaminophen can be hepatotoxic at doses exceeding 3-4 grams/day, and at lower doses in individuals with chronic alcohol use or liver disease (109). NSAID use is associated with gastritis, peptic ulcer disease, cardiovascular events (111,112), and fluid retention, and most NSAIDs (except choline magnesium trilisate and selective COX-2 inhibitors) interfere with platelet aggregation (179). Always review FDA-approved labeling, including boxed warnings, before initiating any pharmacologic therapy.

While opioids can provide short-term pain relief, evidence is lacking to confirm sustained pain relief or functional/quality of life improvements with long-term opioid therapy for osteoarthritis (KQ1). Conversely, the risks of long-term opioid use are well-documented and significant. Long-term opioid use is linked to increased risks of opioid use disorder, overdose, myocardial infarction, and motor vehicle injuries (KQ2). Over 165,000 opioid pain medication-related overdose deaths have occurred in the U.S. since 1999.

Effective pain management requires a coordinated approach addressing medical, psychological, and social aspects of care, involving primary care, mental health services, and specialist referrals as needed (180). Nonpharmacologic physical and psychological treatments like exercise and CBT actively engage patients in their care, address the broader impact of pain, and can yield lasting improvements in pain and function with minimal risks. Despite these advantages, insurance coverage, access, and cost can be barriers. Even with limited specialty care access, elements of these approaches can be incorporated. Prior guidelines strongly recommend aerobic, aquatic, and resistance exercises for knee or hip osteoarthritis (176) and maintaining activity for low back pain (110). A randomized trial showed no significant difference in chronic low back pain reduction between low-cost group aerobics, individual physiotherapy, or muscle reconditioning (181). Low-cost exercise options include brisk walking or public recreation facilities. CBT addresses psychosocial factors in pain and improves function (97). Primary care clinicians can integrate CBT principles by encouraging active patient participation, supporting engagement in beneficial activities like exercise (179), and providing relaxation and coping strategies education. Community-based programs often offer free or low-cost patient support and education for stress reduction and mental health benefits. Patients with significant anxiety, fear related to pain, or psychological distress should be referred for specialized mental health therapy. Multimodal therapies should be considered for patients not responding to single-modality approaches, tailored to individual needs, cost, and convenience.

To guide therapy selection, a thorough patient evaluation is crucial to establish or confirm the diagnosis of osteoarthritis. While detailed diagnostic recommendations are available in other guidelines (110,179), evaluation should include a focused history of pain characteristics and contributing factors (function, psychosocial stressors, sleep), and physical examination. Imaging or diagnostic testing should be used selectively (e.g., for severe neurologic deficits or suspected serious underlying conditions) (110,179). For complex pain syndromes, pain specialty consultation can aid in diagnosis and management. Diagnosis can identify disease-specific interventions to reverse or alleviate pain, such as glucose control for diabetic neuropathy, immune-modulating agents for rheumatoid arthritis, physical therapy for musculoskeletal pain, or surgical intervention for mechanical/compressive pain (179). Pain syndromes are broadly categorized as neuropathic (e.g., diabetic neuropathy, fibromyalgia) or nociceptive (e.g., osteoarthritis, back pain). The pain diagnosis and pathophysiology inform symptomatic medication treatment. Evidence is limited for long-term opioid effectiveness in common chronic pain conditions like low back pain (182), headache (183), and fibromyalgia (184). While NSAIDs can manage nociceptive pain exacerbations, neuropathic pain often requires tricyclics, anticonvulsants, or topical lidocaine. Neuropathic pain improvement may take weeks after treatment initiation (179). Medications should be used only after assessing that benefits outweigh risks, considering patient-specific factors. For example, consider falls risk with sedating medications like tricyclics, anticonvulsants, or opioids. Weigh NSAID risks and benefits, dose, and duration in older adults and patients with hypertension, renal insufficiency, heart failure, or peptic ulcer/cardiovascular disease risk. Topical NSAIDs are recommended over oral NSAIDs for localized osteoarthritis (e.g., knee) in patients ≥ 75 years to minimize systemic effects (176).

Experts concur that opioids should not be first-line or routine therapy for chronic pain (pain lasting >3 months or beyond normal tissue healing) outside of active cancer, palliative, and end-of-life care. This is due to limited short-term and uncertain long-term benefits, coupled with significant potential harms. While long-term nonopioid therapy benefits are also limited, their risks are considerably lower. This does not necessitate sequential “failure” of nonpharmacologic and nonopioid therapy before considering opioids. Rather, expected benefits in the clinical context must be weighed against risks before initiating any therapy. In conditions like headache or fibromyalgia, opioid benefits are unlikely to outweigh risks, regardless of prior therapies. In other cases (e.g., serious illness with poor prognosis, contraindications to other therapies, and patient-clinician agreement focusing on comfort), opioids might be appropriate regardless of prior treatments. When opioid pain medication is used, it is more effective when combined with nonpharmacologic therapy. Nonpharmacologic approaches like exercise and CBT should be used to reduce pain and improve function in chronic pain. Nonopioid pharmacologic therapy should be used when benefits outweigh risks and combined with nonpharmacologic therapy. If opioids are used, they should be integrated with nonpharmacologic and nonopioid pharmacologic therapies to maximize patient benefits in pain and function.

2. Prior to initiating opioid therapy for chronic osteoarthritis pain, clinicians in primary care clinical office practice should establish clear treatment goals with each patient, including realistic expectations for pain relief and functional improvement. Consideration should be given to the plan for opioid discontinuation should the benefits not outweigh the risks. Opioid therapy should only be continued if clinically meaningful improvements in both pain and function are achieved and outweigh patient safety risks (recommendation category: A, evidence type: 4).

Clinical evidence indicates insufficient data to determine long-term benefits of opioid therapy for chronic osteoarthritis pain, while demonstrating increased risks of serious harms, seemingly dose-dependent. Furthermore, studies on available risk assessment tools are limited and yield inconsistent results (KQ4). The clinical evidence review for these guidelines considered studies with ≥1-year outcomes comparing opioid use versus nonuse or placebo. Studies lacking a nonopioid control group found that while many patients discontinue opioids for chronic noncancer pain due to side effects or inadequate relief, weak evidence suggests that those continuing opioid therapy for ≥6 months may experience clinically significant pain relief, but insufficient evidence supports improved function or quality of life (185). These findings underscore the difficulty for clinicians in predicting whether opioid benefits will outweigh ongoing treatment risks for individual patients. Opioid therapy should not start without an “exit strategy” in case of ineffectiveness.

Experts agree that before initiating opioid therapy for chronic pain outside of active cancer, palliative, and end-of-life care, clinicians should define effectiveness evaluation and set treatment goals with patients. The distinction between acute and early chronic pain can be blurred, making it challenging to differentiate opioid initiation for chronic versus acute pain. Pain lasting >3 months or beyond normal tissue healing is generally considered chronic. However, establishing treatment goals with a patient already on opioids for 3 months would delay this crucial discussion. Clinicians often prescribe opioids in 30-day increments, and prescriptions ≥30 days likely indicate long-term opioid therapy initiation or continuation. Before prescribing opioids for ≥30 days, or when seeing new patients already on opioids, clinicians should set treatment goals. Although clinical evidence review did not assess written agreements or treatment plans (KQ4), proactive planning clarifies expectations for opioid prescribing and monitoring, and conditions for discontinuation or dose tapering (e.g., unmet goals, no longer needed, or adverse events) to enhance patient safety.

Experts believe goals should encompass both pain relief and functional improvement, thus enhancing quality of life. However, pain reduction without functional improvement might be a more realistic goal in certain clinical scenarios (e.g., progressive functional impairment diseases or catastrophic injuries like spinal cord trauma). Function includes emotional and social dimensions, along with physical aspects. Mood significantly interacts with pain and function. Validated instruments like the three-item PEG Assessment Scale (186) can track patient outcomes. Clinically meaningful improvement is defined as a 30% improvement in both pain and function scores (187). Monitoring progress towards patient-centered functional goals (e.g., walking a dog, returning to work, attending family activities) also assesses functional improvement. Clinicians should use these goals to evaluate opioid therapy benefits against risks (see Recommendation 7 for follow-up intervals). Because depression, anxiety, and other psychological comorbidities often coexist with pain and impede resolution, validated instruments should assess these conditions (see Recommendation 8), ensuring optimized treatment. If patients on opioid therapy for chronic osteoarthritis pain do not experience meaningful pain and function improvements compared to pre-opioid therapy, clinicians should consider opioid tapering and discontinuation (see Recommendation 7) and utilize nonpharmacologic and nonopioid pharmacologic pain management (see Recommendation 1).

3. Before initiating and periodically during opioid therapy for osteoarthritis pain, clinicians in primary care clinical office practice should discuss known risks and realistic benefits, as well as patient and clinician responsibilities in therapy management (recommendation category: A, evidence type: 3).

Clinical evidence review lacks studies evaluating patient education or opioid treatment plans as risk-mitigation strategies (KQ4). However, contextual evidence reveals patient information gaps about opioids and clinician communication shortcomings regarding safety. Given evidence gaps on opioids, uncertain long-term benefits, and potential serious harms, patient education and discussion are vital before starting opioid therapy. This ensures patient preferences and values inform clinical decisions. Experts agreed that key communication elements before and during opioid therapy include realistic expected benefits, common and serious harms, and clinician/patient responsibilities to mitigate risks.

Clinicians should involve patients in decisions about starting or continuing opioid therapy. Given potential serious risks of long-term opioid therapy, ensure patients are aware of benefits, harms, and alternatives before initiating or continuing. Open, honest discussions are encouraged for mutual decisions. Important considerations include:

Be explicit and realistic about expected opioid benefits, explaining that while opioids can reduce short-term pain, there’s no solid evidence of long-term pain or function improvement, and complete pain relief is unlikely (KQ1).
Emphasize functional improvement as a primary goal, noting function can improve despite ongoing pain.
Advise patients about serious opioid adverse effects, including potentially fatal respiratory depression and opioid use disorder, which can cause distress and role impairment.
Inform patients about common opioid effects like constipation, dry mouth, nausea, vomiting, drowsiness, confusion, tolerance, physical dependence, and withdrawal symptoms upon cessation. To prevent opioid-induced constipation, recommend increased hydration, fiber intake, and physical activity. Stool softeners or laxatives may be needed.
Discuss opioid effects on safe vehicle operation, especially at initiation, dosage increases, or concurrent use of CNS depressants like benzodiazepines or alcohol.
Discuss increased risks of opioid use disorder, respiratory depression, and death at higher doses, emphasizing taking only prescribed amounts and frequency.
Review increased respiratory depression risks with combined use of opioids with benzodiazepines, other sedatives, alcohol, heroin, or other opioids.
Discuss risks to household members if opioids are shared, intentionally or unintentionally, including overdose potential even at lower doses, and young children’s susceptibility to accidental ingestion. Discuss secure, preferably locked, opioid storage and safe disposal of unused medication (188).
Emphasize periodic reassessment to ensure opioids are meeting goals and to allow for discontinuation and consideration of other nonpharmacologic or nonopioid options if opioids are ineffective or harmful.
Discuss planned risk-reduction precautions, including prescription drug monitoring program (PDMP) use (see Recommendation 9) and urine drug testing (see Recommendation 10). Consider naloxone discussion for overdose reversal (see Recommendation 8).
Assess if cognitive limitations might impair opioid therapy management (especially in older adults) and if a caregiver can co-manage medication. Discuss reassessing safer medication use with both patient and caregiver.

Given the potential for diminishing opioid benefits or increasing risks over time, clinicians should periodically review expected benefits and risks of continued opioid therapy with patients, at least every 3 months (see Recommendation 7).

Opioid Selection, Dosage, Duration, Follow-Up, and Discontinuation in Primary Care Clinical Office Practice for Osteoarthritis Pain

4. When initiating opioid therapy for chronic osteoarthritis pain, clinicians in primary care clinical office practice should prescribe immediate-release opioids instead of extended-release/long-acting (ER/LA) opioids (recommendation category: A, evidence type: 4).

ER/LA opioids include methadone, transdermal fentanyl, and extended-release formulations of oxycodone, oxymorphone, hydrocodone, and morphine. Clinical evidence indicates a higher overdose risk among patients starting ER/LA opioids compared to immediate-release opioids (77). No evidence suggests continuous ER/LA opioid use is more effective or safer than intermittent immediate-release opioids, or that ER/LA opioids reduce misuse or addiction risks (KQ3).

In 2014, the FDA revised ER/LA opioid labeling, highlighting serious risks and recommending their use be reserved for “management of pain severe enough to require daily, around-the-clock, long-term opioid treatment” when “alternative treatment options (e.g., nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate” and not for “as needed” pain relief (121). FDA also notes some ER/LA opioids are only for opioid-tolerant patients, defined as those receiving certain opioid doses (e.g., 60 mg oral morphine daily, 30 mg oral oxycodone daily, or equivalent) for at least 1 week (189). Scheduled opioid use can lead to higher total daily doses compared to intermittent use (contextual evidence). Experts indicated insufficient evidence on immediate-release opioids for breakthrough pain with ER/LA opioids outside of active cancer, palliative, or end-of-life care, and this practice might escalate dosage.

Abuse-deterrent technologies aim to prevent manipulation of ER/LA opioids and misuse via injection. FDA guidance on abuse-deterrent opioids (190) states that while these technologies may hinder manipulation, they do not prevent abuse via oral intake, the most common route, and non-oral abuse is still possible. “Abuse-deterrent” labeling does not eliminate abuse risk. No studies in the clinical evidence review assessed abuse-deterrent technology effectiveness as a risk mitigation strategy. These technologies also do not prevent unintentional oral overdose. Experts agreed no recommendations on abuse-deterrent formulations could be offered currently.

Comparing ER/LA formulations, clinical evidence shows inconsistent overdose risk results with methadone versus other ER/LA opioids for chronic pain (KQ3). Contextual evidence links methadone to disproportionate overdose deaths relative to its chronic pain prescription frequency. Methadone is also associated with cardiac arrhythmias, QT prolongation, and complex pharmacokinetics/pharmacodynamics, including a long, variable half-life and delayed, prolonged respiratory depressant effect compared to analgesic effect. Methadone pharmacodynamics have greater inter-individual variability than other opioids. For other ER/LA opioids, transdermal fentanyl has complex absorption and pharmacodynamics, with gradual serum concentration increase in the first 72 hours and variable absorption based on factors like external heat. Fentanyl dosing in mcg/hour, atypical for outpatient drugs, can be confusing. These complexities may increase fatal overdose risk, especially when methadone or fentanyl is prescribed to opioid-naïve patients or by clinicians unfamiliar with their effects.

Experts agreed that for opioid-naïve patients, clinicians should not initiate ER/LA opioids and should not prescribe them for intermittent use. ER/LA opioids should be reserved for severe, continuous pain and considered only for patients receiving daily immediate-release opioids for at least 1 week. When switching to ER/LA opioids, clinicians should consult product labeling and reduce total daily dose for incomplete opioid cross-tolerance. Exercise extra caution with ER/LA opioids and consider longer dosing intervals in patients with renal or hepatic dysfunction due to reduced drug clearance and potential for toxic accumulation. While combining immediate-release and ER/LA opioids might be necessary (e.g., transitioning from ER/LA to immediate-release by using lower doses of both temporarily), generally, avoiding this combination is preferable due to increased risk and diminishing returns for chronic pain.

When ER/LA opioids are prescribed, those with predictable pharmacokinetics/pharmacodynamics are preferred to minimize unintentional overdose risk. Methadone and transdermal fentanyl’s unique characteristics make safe prescribing particularly challenging.

Methadone should not be first-line ER/LA opioid. Only clinicians familiar with its risk profile and prepared to educate and closely monitor patients, including QT prolongation risk assessment and ECG monitoring, should consider methadone for pain. A clinical practice guideline offers further methadone prescribing guidance (191).
Transdermal fentanyl dosing and absorption are often misunderstood by clinicians and patients. Only clinicians familiar with its properties and prepared to educate patients should consider prescribing it.

5. When initiating opioids for osteoarthritis pain, clinicians in primary care clinical office practice should prescribe the lowest effective dosage. Exercise caution at any dosage, carefully reassess benefit-risk when considering increasing to ≥50 morphine milligram equivalents (MME)/day, and avoid increasing to ≥90 MME/day or carefully justify titration to ≥90 MME/day (recommendation category: A, evidence type: 3).

High-dose opioid benefits for chronic pain are unproven. Clinical evidence review found only one study (84) on dose titration effectiveness for pain control, function, and quality of life (KQ3). This trial found no difference in pain or function between liberal dose escalation and dose maintenance (average doses 52 and 40 MME/day, respectively, at trial end). Simultaneously, serious harm risks increase at higher doses. Clinical evidence links higher doses to increased risks of motor vehicle injury, opioid use disorder, and overdose (KQ2). Opioid overdose risk increases dose-dependently, with dosages of 50–127).

Contextual evidence indicates no single dosage threshold eliminates overdose risk, but keeping dosages <50 MME/day is associated with lower risk than higher dosages. In 2012, approximately 70% of opioid overdose deaths involved dosages >40 MME/day (see Contextual Evidence Review).

When using opioids for chronic pain outside of active cancer, palliative, and end-of-life care, initiate at the lowest effective dose (lowest starting dose on product labeling for opioid-naïve patients, and per labeling guidance for tolerant patients). Exercise extra caution initiating opioids in patients ≥65 years and those with renal or hepatic insufficiency due to reduced drug clearance and toxic accumulation. Use caution increasing doses, increase by the smallest practical amount, as overdose risk rises with dosage increases. While specific titration intervals are not definitively recommended, prior guidelines suggest waiting at least five half-lives before increasing dose, and at least a week for methadone to ensure full effects of the current dose are evident (31). Re-evaluate patients after dose increases for pain, function, and harm risk changes (see Recommendation 7). Before increasing to ≥50 MME/day, reassess if opioid treatment is meeting goals (see Recommendation 2). If total daily opioid dose reaches ≥50 MME/day, implement extra precautions: more frequent follow-up (see Recommendation 7) and consider naloxone and overdose prevention education for patients and household members (see Recommendation 8). Avoid increasing to ≥90 MME/day, or carefully justify increasing to ≥90 MME/day based on individual benefit-risk assessment, considering diagnosis, incremental benefits for pain/function versus harms near 90 MME/day, other treatments and their effectiveness, and pain specialist consultation recommendations. If pain and function do not improve at ≥90 MME/day, or if dosage requirements escalate, discuss other pain management approaches, consider opioid tapering or discontinuation (see Recommendation 7), and consider pain specialist consultation. Some states mandate clinical protocols at specific dosage levels. For example, in Washington state, increasing long-term opioid therapy to >120 MME/day requires pain specialist consultation agreeing it’s indicated and appropriate (30). Be aware of state rules on MME thresholds and associated protocols.

Established patients on high-dose opioids, and those transferring from other clinicians, may be anxious about dose reduction. Tapering can be challenging after years at high doses due to physical and psychological dependence. However, these patients should be offered re-evaluation of high-dose opioid use given recent evidence linking dose and overdose risk. Explain nonjudgmentally to patients on ≥90 MME/day that scientific evidence shows increased overdose risk at higher doses. Empathically review continued high-dose therapy benefits and risks, and offer to collaborate on opioid tapering to safer doses. For patients agreeing to taper, collaborate on a plan (see Recommendation 7). Experts noted very slow tapers and pauses may be needed for patients tapering after years of high-dose use, allowing gradual accommodation to lower doses. Remain alert for anxiety, depression, and opioid use disorder signs (see Recommendations 8 and 12) unmasked by tapering, and arrange management. For patients agreeing to taper, and those remaining on high doses, establish goals for continued therapy (see Recommendation 2), maximize nonpharmacologic and nonopioid treatments (see Recommendation 1), and consider pain specialist consultation as needed.

6. Long-term opioid use often originates with acute pain treatment. When using opioids for acute osteoarthritis pain, clinicians in primary care clinical office practice should prescribe the lowest effective dose of immediate-release opioids and no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three days or less will often suffice; more than seven days will rarely be necessary (recommendation category: A, evidence type: 4).

Clinical evidence shows acute pain opioid use is linked to long-term use, and greater early opioid exposure increases long-term use risk (KQ5). Guidelines on acute pain opioid prescribing from emergency departments (192–194) and other settings (195,196) recommend ≤3 days of opioids in most cases, while others suggest ≤7 days (197) or 30). Physical dependence is expected in patients exposed to opioids for more than a few days (contextual evidence), so limiting prescribed days should minimize the need for opioid tapering to prevent withdrawal. Experts noted more than a few days of opioid exposure significantly increases hazards, unnecessary days increase dependence likelihood without added benefit, and shorter prescriptions minimize pills available for diversion.

Experts agreed that when opioids are needed for acute pain, prescribe the lowest effective dose and for the shortest duration needed to minimize unintentional long-term use initiation. Determine lowest effective dose using product labeling as a starting point, adjusting based on pain severity and clinical factors like renal/hepatic insufficiency (see Recommendation 8). Experts believe, based on clinical experience with acute pain duration, ≤3 days’ supply of opioids will suffice in most non-surgical/trauma cases. For example, a primary care study on acute low back pain (excluding malignancies, infections, fractures, neurological signs) showed significant pain decrease until day four after paracetamol treatment, with smaller decreases thereafter (198). Some experts suggested a range of ≤3–5 or ≤3–7 days might be appropriate for acute pain requiring >3 days opioid treatment. Some considered 7 days too long given the expected severe acute pain course in primary care.

Acute pain can often be managed without opioids. Evaluate for reversible pain causes, underlying etiologies with serious sequelae, and determine appropriate treatment. When acute pain diagnosis and severity reasonably warrant opioids, prescribe no more than needed for the expected duration of severe pain, often ≤3 days, unless circumstances clearly justify more. More than 7 days will rarely be needed. Post-surgical pain opioid treatment is outside this guideline’s scope but addressed elsewhere (30). Do not prescribe extra opioids “just in case” pain persists. Re-evaluate patients with severe acute pain lasting longer than expected to confirm or revise diagnosis and adjust management. Given longer half-lives and effects (e.g., respiratory depression) of ER/LA opioids like methadone, fentanyl patches, or extended-release oxycodone/oxymorphone/morphine, do not prescribe ER/LA opioids for acute pain.

7. Clinicians in primary care clinical office practice should evaluate benefits and harms with osteoarthritis patients within 1 to 4 weeks of starting opioid therapy for chronic pain or dose escalation. Evaluate continued therapy benefits and harms every 3 months or more frequently. If benefits do not outweigh harms, optimize other therapies and work with patients to taper to lower dosages or discontinue opioids (recommendation category: A, evidence type: 4).

Clinical evidence review lacks studies evaluating more frequent monitoring intervals (KQ4), but continuing opioid therapy for 3 months significantly increases opioid use disorder risk (KQ2). Follow-up earlier than 3 months might be needed to best prevent opioid use disorder. ER/LA opioid overdose risk may be highest in the first 2 weeks of treatment (KQ3). Contextual evidence shows patients not relieved by opioids at 1 month are unlikely to be relieved at 6 months. While the exact point within the first 3 months that opioid use disorder risk increases is unclear, reassessing pain and function within 1 month of opioid initiation allows for minimizing long-term opioid use risks by discontinuing opioids in patients without clear benefit. Experts noted overdose risks are highest in the first 3–7 days after opioid initiation or dose increase, especially with methadone or transdermal fentanyl; follow-up within 3 days is appropriate for methadone initiation/increase, and within 1 week for other ER/LA opioids.

Evaluate patients within 1-4 weeks of starting long-term opioid therapy or dose escalation to assess opioid benefits and harms. Consider follow-up intervals at the lower end of this range when ER/LA opioids are started or increased, or when daily dose is ≥50 MME/day. Strongly consider shorter follow-up (within 3 days) when starting or increasing methadone. At follow-up, assess function, pain control, and quality of life using tools like the PEG scale (186) and/or patient progress toward meaningful functional goals (see Recommendation 2). Also inquire about common adverse effects like constipation and drowsiness (see Recommendation 3), and assess for early warning signs of serious problems like overdose (e.g., sedation, slurred speech) or opioid use disorder (e.g., craving, increased use, difficulty controlling use). Ask patients about their preferences for continuing opioids, considering pain/function effects versus adverse effects.

Due to potential shifts in benefit-risk balance over time, regularly reassess all patients on long-term opioid therapy, including new patients already on long-term opioids, at least every 3 months. At reassessment, determine if opioids still meet treatment goals, including sustained pain and function improvement, whether patients have experienced common/serious adverse events or early warning signs, opioid use disorder signs (e.g., difficulty controlling use, work/family problems), whether benefits still outweigh risks, and if dosage can be reduced or opioids discontinued. Ideally, reassessments should be in-person by the prescribing clinician. In practices using virtual visits (e.g., remote areas), video/audio follow-up is acceptable, with in-person visits at least annually. Re-evaluate patients at higher risk of opioid use disorder or overdose (e.g., depression or other mental health conditions, substance use disorder history, overdose history, ≥50 MME/day, or concurrent CNS depressants) more frequently than every 3 months. If meaningful pain/function improvements are not sustained, if patients are on high-risk regimens (e.g., ≥50 MME/day or opioids with benzodiazepines) without benefit, if patients believe risks outweigh benefits or request dose reduction/discontinuation, or if patients experience overdose or serious adverse events (e.g., hospitalization, disability) or warning signs, collaborate with patients to reduce or discontinue opioids. Maximize nonpharmacologic and nonopioid pain treatments (see Recommendation 1) and consider pain specialist consultation as needed.

Considerations for Tapering Opioids in Primary Care Clinical Office Practice

While clinical evidence review lacks high-quality studies comparing tapering protocols for opioid reduction/discontinuation (KQ3), tapers reducing weekly dose by 10%–50% of the original dose have been recommended by other guidelines (199), and a rapid taper over 2–3 weeks for severe adverse events like overdose (30). Experts noted tapers slower than 10% per week (e.g., 10% per month) may be appropriate and better tolerated, especially for patients on opioids long-term (e.g., years). Opioid withdrawal during pregnancy is linked to spontaneous abortion and premature labor.

When reducing/discontinuing opioids, use a taper slow enough to minimize withdrawal symptoms (e.g., craving, anxiety, insomnia, abdominal pain, vomiting, diarrhea, diaphoresis, mydriasis, tremor, tachycardia, piloerection). A 10% weekly dose reduction is a reasonable starting point; tapering plans can be individualized based on patient goals/concerns. Tapers may need pauses and restarts when patients are ready, and slowing down at low doses. Tapers are considered successful with any progress. Once the smallest available dose is reached, extend intervals between doses. Opioids can be stopped when taken less than once daily. More rapid tapers may be needed for patient safety (e.g., overdose at current dose). Ultrarapid detoxification under anesthesia is risky, including death, and should not be used (200). Seek expertise when tapering opioids during pregnancy due to potential risks to mother and fetus from withdrawal. Patients not taking opioids (including diverting) do not need tapers. Discuss with patients undergoing tapering the increased overdose risk upon abrupt return to a previously higher dose. Primary care clinicians should collaborate with mental health providers and specialists to optimize nonopioid pain management (see Recommendation 1) and psychosocial support for taper-related anxiety. More detailed tapering guidance, including withdrawal symptom management, is available (30,201). If a patient shows opioid use disorder signs, offer or arrange treatment (see Recommendation 12) and consider naloxone for overdose prevention (see Recommendation 8).

Assessing Risk and Addressing Harms of Opioid Use in Primary Care Clinical Office Practice for Osteoarthritis Patients

8. Before initiating and periodically during continued opioid therapy for osteoarthritis pain, clinicians in primary care clinical office practice should evaluate risk factors for opioid-related harms. Incorporate risk mitigation strategies into the management plan, including considering offering naloxone when factors increasing overdose risk are present, such as overdose history, substance use disorder history, higher opioid dosages (≥50 MME/day), or concurrent benzodiazepine use (recommendation category: A, evidence type: 4).

Clinical evidence review lacks data on how opioid harms vary by patient demographics or comorbidities (KQ2). However, contextual evidence and expert opinion suggest certain risk factors increase susceptibility to opioid harms, warranting added risk mitigation strategies. Assess these risk factors periodically, with frequency varying by risk factor and patient characteristics. More frequently changing factors, like alcohol use, require more frequent follow-up. Consider naloxone, more frequent re-evaluation (see Recommendation 7), and referral to pain and/or behavioral health specialists when risk factors are present, such as overdose history, substance use disorder history, higher opioid doses (≥50 MME/day), and concurrent benzodiazepine use.

Patients with Sleep-Disordered Breathing, Including Sleep Apnea in Primary Care Clinical Office Practice

Sleep-disordered breathing risk factors include congestive heart failure and obesity. Experts noted careful monitoring and cautious dose titration if opioids are prescribed for mild sleep-disordered breathing. Avoid prescribing opioids to patients with moderate/severe sleep-disordered breathing whenever possible to minimize overdose risks (contextual evidence).

Pregnant Women in Primary Care Clinical Office Practice

Opioid use during pregnancy may pose additional risks to mother and fetus. Some studies link opioid use in pregnancy to stillbirth, poor fetal growth, preterm delivery, and birth defects (contextual evidence). Importantly, opioid use in pregnancy can lead to neonatal opioid withdrawal syndrome. Clinicians and patients should carefully weigh risks and benefits when deciding to initiate opioid therapy for chronic pain during pregnancy. Before starting opioid therapy for reproductive-age women, discuss family planning and how long-term opioid use might affect future pregnancies. For pregnant women already on opioids, seek expertise if considering tapering due to potential risks to mother and fetus from withdrawal (see Recommendation 7). For pregnant women with opioid use disorder, medication-assisted therapy with buprenorphine or methadone is associated with improved maternal outcomes and should be offered (202) (see Recommendation 12). Clinicians caring for pregnant women on opioids for pain or buprenorphine/methadone for opioid use disorder should arrange delivery at a facility prepared to monitor and treat neonatal opioid withdrawal syndrome. If travel to such a facility is unduly burdensome, local delivery is acceptable, with newborn monitoring and transfer if needed. Neonatal toxicity and death have been reported in breastfed infants of mothers taking codeine (contextual evidence); prior guidelines recommend avoiding codeine in breastfeeding mothers, or limiting to the lowest dose and a 4-day supply if used (203).

Patients with Renal or Hepatic Insufficiency in Primary Care Clinical Office Practice

Use extra caution and increased monitoring (see Recommendation 7) to minimize opioid risks in patients with renal/hepatic insufficiency, given their reduced drug processing/excretion, opioid accumulation susceptibility, and smaller therapeutic window between safe doses and overdose-associated doses (contextual evidence; see Recommendations 4, 5, and 7).

Patients Aged ≥65 Years in Primary Care Clinical Office Practice

Inadequate pain treatment in older adults (≥65 years) is documented (204). Pain management in older patients is challenging due to increased risks of both nonopioid (see Recommendation 1) and opioid therapies. Reduced renal function and medication clearance in older adults, even without renal disease, may increase opioid accumulation risk and reduce the therapeutic window. Some older adults have cognitive impairment, increasing medication error risk and making opioid-related confusion more dangerous. Older adults are also more likely to have comorbidities and take multiple medications, some interacting with opioids (e.g., benzodiazepines). Use extra caution and increased monitoring (see Recommendations 4, 5, and 7) to minimize opioid risks in patients ≥65 years. Experts suggested educating older adults on opioids to avoid risky behaviors like multiple prescribers and saving unused medications. Implement interventions to mitigate common opioid risks in older adults, such as exercise or bowel regimens for constipation, falls risk assessment, and cognitive impairment monitoring.

Patients with Mental Health Conditions in Primary Care Clinical Office Practice

Psychological distress often hinders pain and function improvement in chronic pain patients. Using validated instruments like GAD-7 and PHQ-9 or PHQ-4 to assess anxiety, PTSD, and/or depression (205) may improve overall pain treatment outcomes. Use extra caution and increased monitoring (see Recommendation 7) to lessen increased opioid use disorder risk in patients with mental health conditions (including depression, anxiety, PTSD), and increased overdose risk in depressed patients. Prior guidelines note opioid therapy should not start during acute psychiatric instability or uncontrolled suicide risk, and behavioral health specialist consultation should be considered for any patient with suicide attempt history or psychiatric disorder (31). Patients with anxiety and other mental health conditions are more likely to receive benzodiazepines, exacerbating opioid-induced respiratory depression and overdose risk (see Recommendation 11). Optimize treatment for depression and other mental health conditions, consulting behavioral health specialists as needed. Depression treatment can improve pain and depression symptoms, and may decrease overdose risk (contextual evidence). For chronic pain in depressed patients, strongly consider tricyclic or SNRI antidepressants for analgesic and antidepressant effects if not contraindicated (see Recommendation 1).

Patients with Substance Use Disorder in Primary Care Clinical Office Practice

Illicit drugs and alcohol are listed as contributory factors in many opioid-related overdose deaths (contextual evidence). Prior guidelines recommend screening tools to identify patients at higher misuse/abuse risk. However, clinical evidence review shows current risk-stratification tools (e.g., Opioid Risk Tool, SOAPP-R, Brief Risk Interview) are insufficiently accurate for classifying patients as low or high risk for abuse/misuse (KQ4). Always exercise caution when considering or prescribing opioids for chronic pain outside of active cancer, palliative, and end-of-life care, and do not overestimate these tools’ ability to rule out long-term opioid therapy risks.

Ask patients about drug and alcohol use. Single screening questions can be used (206). For example, “How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?” (one or more positive) was 100% sensitive and 73.5% specific for drug use disorder detection in primary care versus standardized diagnostic interview (207). Validated screening tools like DAST (208) and AUDIT (209) can also be used. Use PDMP data (see Recommendation 9) and drug testing (see Recommendation 10) to assess for concurrent substance use that might increase opioid use disorder and overdose risk. Provide specific counseling on increased overdose risks with combined opioids, drugs, or alcohol (see Recommendation 3), and ensure effective substance use disorder treatment when needed (see Recommendation 12).

Clinical evidence review lacks data on how opioid harms differ by past/current substance use disorder (KQ2), although substance use disorder history was linked to misuse. Patients with drug/alcohol use disorders likely face greater opioid use disorder and overdose risks than those without. If considering opioid therapy for chronic pain outside of active cancer, palliative, and end-of-life care for patients with drug/alcohol use disorders, discuss increased risks, carefully weigh opioid benefits versus risks, and incorporate risk mitigation strategies, such as considering naloxone (see Offering Naloxone to Patients When Factors That Increase Risk for Opioid-Related Harms Are Present) and more frequent monitoring (see Recommendation 7). Pain management in patients with substance use disorder can be complex; consider consulting substance use disorder and pain specialists. Communicate with patients’ substance use disorder treatment providers if opioids are prescribed.

Patients with Prior Nonfatal Overdose in Primary Care Clinical Office Practice

While studies directly addressing overdose risk in patients with prior nonfatal overdose prescribed opioids are lacking, experts believe prior nonfatal overdose significantly increases future fatal/nonfatal overdose risk. If patients experience nonfatal opioid overdose, work to reduce and discontinue opioids if possible (see Recommendation 7). If continuing opioid therapy for chronic pain outside of active cancer, palliative, and end-of-life care in patients with prior overdose, discuss increased risks, carefully consider opioid benefits versus substantial risks, and incorporate risk mitigation strategies, such as considering naloxone (see Offering Naloxone to Patients When Factors That Increase Risk for Opioid-Related Harms Are Present) and more frequent monitoring (see Recommendation 7).

Offering Naloxone to Patients When Factors That Increase Risk for Opioid-Related Harms Are Present in Primary Care Clinical Office Practice

Naloxone, an opioid antagonist, reverses severe respiratory depression; layperson administration can save lives. Naloxone precipitates acute withdrawal in opioid-dependent patients. Serious adverse effects like pulmonary edema, cardiovascular instability, and seizures are rare at labeled overdose doses (210). Contextual evidence review lacks studies on naloxone prescribing effectiveness for overdose prevention in chronic pain opioid patients. However, naloxone provision is effective in preventing opioid-related overdose deaths at the community level through community-based distribution to at-risk individuals (mostly illicit opiate users), and effectiveness is plausible in clinical settings. Experts agreed initiating opioid treatment when risk factors are present is undesirable. Opinions varied on naloxone utility and when to offer it. Most experts agreed clinicians should consider offering naloxone when prescribing opioids to patients at increased overdose risk, including overdose history, substance use disorder history, concurrent benzodiazepine use (see Recommendation 11), risk of returning to a high dose after tolerance loss (e.g., recent prison release), and higher opioid doses (≥50 MME/day). Practices should educate patients receiving naloxone prescriptions and household members on overdose prevention and naloxone use. Naloxone co-prescribing can be facilitated by clinics with training resources and collaborative pharmacist models. Resources for naloxone prescribing in primary care are at http://prescribetoprevent.org.

9. Clinicians in primary care clinical office practice should review a patient’s controlled substance prescription history using state prescription drug monitoring program (PDMP) data to identify patients receiving opioid dosages or dangerous combinations placing them at high overdose risk. Review PDMP data when starting opioid therapy for chronic osteoarthritis pain and periodically during therapy, ranging from every prescription to every 3 months (recommendation category: A, evidence type: 4).

PDMPs are state databases collecting controlled prescription drug dispensing data from pharmacies, and in some states, dispensing physicians. Some federal clinicians, including some in the Indian Health Care Delivery System, lack state licenses and PDMP access. Some states mandate PDMP review before each opioid prescription (see state-level PDMP policies at http://www.namsdl.org/prescription-monitoring-programs.cfm). Clinical evidence review lacks studies evaluating PDMP effectiveness on overdose, addiction, abuse, or misuse outcomes (KQ4). However, despite limited evidence on state-level PDMP effectiveness on prescribing and mortality (28), contextual evidence shows most fatal overdoses involve patients receiving opioids from multiple prescribers and/or high daily doses; PDMP data provides information on both risk factors. PDMP data is also useful when patient medication history is unavailable (e.g., new patients from other areas) and during care transitions. Contextual evidence also shows PDMP information can be misused, e.g., patient dismissal from practices (211), potentially harming patient safety.

Contextual review found state policy variations affecting PDMP data timeliness (and review benefits) and clinician workload in accessing PDMP data. States allowing delegated access to other healthcare team members can reduce prescriber workload. These differences may alter the benefit-workload balance across states. Experts agreed PDMPs are useful tools to consult when starting opioid therapy and periodically during long-term therapy. However, experts disagreed on PDMP check frequency during long-term therapy, given PDMP access issues and reporting delays in some states. Most agreed PDMP data should be reviewed every 3 months or more frequently during long-term opioid therapy. A minority noted annual PDMP review during long-term therapy would be reasonable without risk factors, given current PDMP access burden in some states and lack of evidence on optimal review interval for patient outcomes.

Review PDMP data for opioids and other controlled medications from other prescribers to identify patients at high overdose risk due to high doses or dangerous combinations (e.g., opioids with benzodiazepines). Ideally, review PDMP data before every opioid prescription. This is recommended in states with functional PDMPs and practicable access (e.g., clinician and delegate access), but not currently possible in states without functional PDMPs or those limiting prescriber access. As vendors and practices improve PDMP integration into clinical workflow (e.g., data in EHRs), clinician access is expected to improve. Improved PDMP data timeliness will enhance its value in identifying patient risks.

If patients have high opioid doses, dangerous medication combinations, or multiple controlled substance prescriptions from different clinicians, several actions can improve patient safety:

Discuss PDMP information with patients and confirm awareness of additional prescriptions. PDMP data can be occasionally incorrect (e.g., incorrect name/birthdate, nickname/maiden name, identity theft).
Discuss safety concerns, including increased respiratory depression and overdose risks, with patients receiving opioids from multiple prescribers or medications increasing risk when combined with opioids (e.g., benzodiazepines), and consider naloxone (see Recommendation 8).
Avoid concurrent opioid and benzodiazepine prescribing whenever possible. Communicate with others managing the patient to discuss needs, prioritize goals, weigh concurrent benzodiazepine and opioid exposure risks, and coordinate care (see Recommendation 11).
Calculate total daily MME for concurrent opioid prescriptions to assess overdose risk (see Recommendation 5). If patients receive high daily opioid doses, discuss safety concerns, consider tapering to a safer dose (see Recommendations 5 and 7), and consider naloxone (see Recommendation 8).
Discuss safety concerns with other clinicians prescribing controlled substances for the patient. Ideally, first discuss concerns with the patient and inform them of care coordination plans with other prescribers for safety improvement.
Consider substance use disorder possibility and discuss concerns with patients (see Recommendation 12).
If suspecting patients are sharing/selling opioids, consider urine drug testing to help determine if opioids can be discontinued without withdrawal (see Recommendations 7 and 10). A negative drug test for prescribed opioids might indicate the patient is not taking them, although consider other reasons (see Recommendation 10).

Experts agreed clinicians should not dismiss patients based on PDMP information. This can harm patient safety, represent abandonment, and miss opportunities to provide lifesaving information (e.g., opioid risks and overdose prevention) and interventions (e.g., safer prescriptions, nonopioid pain treatment [see Recommendation 1], naloxone [see Recommendation 8], and substance use disorder treatment [see Recommendation 12]).

10. When prescribing opioids for chronic osteoarthritis pain, clinicians in primary care clinical office practice should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications, other controlled prescription drugs, and illicit drugs (recommendation category: B, evidence type: 4).

Concurrent opioid pain medication use with other opioids, benzodiazepines, or heroin can increase overdose risk. Urine drug tests can reveal unreported drug use. They can also help identify when patients are not taking prescribed opioids, potentially indicating diversion or other clinical issues like adverse effects. Urine drug tests do not accurately indicate opioid or other drug quantity or dose. Clinical evidence review lacks studies evaluating urine drug screening effectiveness for risk mitigation during opioid prescribing for pain (KQ4). Contextual evidence shows urine drug testing can provide useful information about patients assumed not to be using unreported drugs. Urine drug testing results can be misinterpreted and may be associated with harmful practices (e.g., stigmatization, inappropriate care termination). Routine urine drug testing with standardized clinic/practice policies may destigmatize its use. While random drug testing might also destigmatize, experts deemed truly random testing impractical in clinical practice. Some clinics collect urine at every visit but only send for testing randomly. Experts noted that besides direct urine drug test costs, often not fully covered by insurance and burdensome for patients, clinician time is needed for interpretation, confirmation, and communication.

Experts agreed that before starting opioids for chronic osteoarthritis pain and periodically during therapy, clinicians should use urine drug testing to assess for prescribed opioids, other controlled substances, and illicit drugs that increase overdose risk when combined with opioids, including nonprescribed opioids, benzodiazepines, and heroin. Expert opinions differed on whether this recommendation should apply to all patients, or whether individual decision-making based on patient values, preferences, and clinical situations was appropriate. While experts agreed on urine drug testing before initiating opioid therapy for chronic pain, they disagreed on frequency during long-term therapy. Most agreed annual urine drug testing for all patients was reasonable. Some noted this interval may be too long or short in some cases, and follow-up interval should be clinician discretion. Prior guidelines recommend more frequent testing in patients at higher substance use disorder risk (30). However, experts deemed risk prediction before urine drug testing challenging, and current tools do not reliably identify low-risk patients.

In most cases, initial urine drug testing can use a relatively inexpensive immunoassay panel for common opioids and illicit drugs. Less commonly prescribed opioids may require specific testing. Confirmatory testing adds substantial costs and should be based on the need to detect specific opioids not identified by standard immunoassays or unexpected results. Clinicians should be familiar with drugs included in their practice’s urine drug testing panels and interpret results. For example, a positive “opiates” immunoassay detects morphine, possibly reflecting morphine, codeine, or heroin use, but does not detect synthetic opioids (e.g., fentanyl, methadone) and may miss semisynthetic opioids (e.g., oxycodone). However, many labs use an oxycodone immunoassay detecting oxycodone and oxymorphone. In some cases, positive results for specific opioids may reflect metabolites from opioids the patient is taking, not necessarily use of the specific opioid tested. For example, hydromorphone is a hydrocodone metabolite, and oxymorphone is an oxycodone metabolite. Detailed guidance on urine drug test interpretation, including test ordering, expected results, drug detection time, drug metabolism, and other considerations, is available (30). Do not test for substances where results would not affect patient management or implications are unclear. For example, tetrahyrdocannabinol (THC) positive test clinical implications may be uncertain. Restricting confirmatory testing to situations and substances where results are reasonably expected to affect patient management can reduce urine drug testing costs, given substantial confirmatory testing costs. Before ordering urine drug testing, plan responses to unexpected results. Explain to patients that urine drug testing aims to improve safety and explain expected results (e.g., prescribed medication presence, absence of unreported drugs including illicit drugs). Ask patients about prescribed and other drug use and potential unexpected results. This allows patients to disclose changes in opioid or other drug use. Discuss unexpected results with the local laboratory or toxicologist and with the patient. Patient discussion before confirmatory testing can sometimes yield candid explanations for substance presence/absence, obviating expensive confirmatory testing. For example, a patient may explain negative prescribed opioid test results because they discontinued opioids due to ineffectiveness. If unexpected results are unexplained, confirmatory testing using selective methods (e.g., gas or liquid chromatography/mass spectrometry) may be warranted to clarify.

Use unexpected results to improve patient safety (e.g., pain management strategy change [see Recommendation 1], opioid tapering/discontinuation [see Recommendation 7], more frequent re-evaluation [see Recommendation 7], naloxone offering [see Recommendation 8], or substance use disorder treatment referral [see Recommendation 12], as appropriate). If prescribed opioid tests are repeatedly negative, confirming the patient is not taking them, discontinue prescription without tapering. Do not dismiss patients from care based on urine drug test results, as this can constitute patient abandonment and harm patient safety, potentially leading to patients obtaining opioids from alternative sources and clinicians missing opportunities to facilitate substance use disorder treatment.

11. Clinicians in primary care clinical office practice should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible (recommendation category: A, evidence type: 3).

Benzodiazepines and opioids both cause central nervous system depression and can reduce respiratory drive. Concurrent use likely increases potentially fatal overdose risk. Clinical evidence review did not address benzodiazepine co-prescription risks in opioid patients. However, contextual evidence from epidemiologic series shows concurrent benzodiazepine use in large proportions of opioid-related overdose deaths, and a case-cohort study found concurrent benzodiazepine and opioid prescription nearly quadrupled overdose death risk compared to opioid prescription alone (212). Experts agreed that while opioid prescription to benzodiazepine patients may be appropriate in some circumstances (e.g., severe acute pain in patients on stable low-dose benzodiazepines), clinicians should avoid concurrent opioid and benzodiazepine prescribing whenever possible. Given that other CNS depressants (e.g., muscle relaxants, hypnotics) can potentiate opioid-related CNS depression, consider if concurrent use benefits outweigh risks. Check PDMP for concurrent controlled medications from other clinicians (see Recommendation 9) and consider involving pharmacists and pain specialists in the management team when co-prescribing opioids with other CNS depressants. Due to greater benzodiazepine withdrawal risks compared to opioid withdrawal, and because opioid tapering can induce anxiety, when patients on both benzodiazepines and opioids need tapering to reduce fatal respiratory depression risk, opioid tapering first may be safer and more practical (see Recommendation 7). Taper benzodiazepines gradually if discontinued, as abrupt withdrawal can cause rebound anxiety, hallucinations, seizures, delirium tremens, and rarely death (contextual evidence review). A common tapering schedule with moderate success is a 25% benzodiazepine dose reduction every 1–2 weeks (213,214). CBT increases tapering success rates and may be helpful for patients struggling with benzodiazepine tapering (213). If benzodiazepines prescribed for anxiety are tapered/discontinued, or if opioid patients need anxiety treatment, offer evidence-based psychotherapies (e.g., CBT) and/or specific antidepressants or nonbenzodiazepine anxiety medications. Experts emphasized communicating with mental health professionals managing the patient to discuss needs, prioritize goals, weigh concurrent benzodiazepine and opioid exposure risks, and coordinate care.

12. Clinicians in primary care clinical office practice should offer or arrange evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone combined with behavioral therapies) for patients with opioid use disorder (recommendation category: A, evidence type: 2).

Opioid use disorder (previously opioid abuse or dependence) is defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) as a problematic opioid use pattern leading to clinically significant impairment or distress, manifested by at least two defined criteria within a year (http://pcssmat.org/wp-content/uploads/2014/02/5B-DSM-5-Opioid-Use-Disorder-Diagnostic-Criteria.pdf) (20).

Clinical evidence review found opioid dependence prevalence (DSM-IV criteria) in primary care chronic pain opioid patients to be 3%–26% (KQ2). Contextual evidence and moderate quality evidence show opioid agonist or partial agonist treatment with methadone maintenance therapy or buprenorphine is more effective in preventing relapse in opioid use disorder patients (151–153). Some studies suggest combining behavioral therapies with these treatments can reduce opioid misuse, increase retention during maintenance therapy, and improve compliance post-detoxification (154,155); clinical practice guidelines also recommend behavioral therapies (215). Cited studies primarily evaluated illicit opioid use history, not prescription opioid use for chronic pain. Recent studies in prescription opioid dependence patients (DSM-IV criteria) found buprenorphine and buprenorphine-naloxone maintenance therapy effective in relapse prevention (216,217). Community treatment need often exceeds buprenorphine/methadone maintenance therapy capacity (218), and patient cost can be a buprenorphine treatment barrier due to limited insurance coverage for opioid use disorder (219). Oral or long-acting injectable naltrexone can also be medication-assisted treatment for opioid use disorder in nonpregnant adults, especially highly motivated individuals (220,221). Experts agreed opioid-prescribing clinicians should identify opioid use disorder treatment resources in the community and collaborate to ensure sufficient treatment capacity at the practice level.

If suspecting opioid use disorder based on patient concerns/behaviors, PDMP data findings (see Recommendation 9), or urine drug testing (see Recommendation 10), discuss concerns with patients and allow them to disclose related concerns/problems. Assess for opioid use disorder using DSM-5 criteria (20), or arrange specialist assessment. For patients meeting opioid use disorder criteria, offer or arrange evidence-based treatment, usually medication-assisted treatment with buprenorphine or methadone maintenance therapy combined with behavioral therapies. Oral or long-acting injectable naltrexone, a long-acting opioid antagonist, can also be used in nonpregnant adults. Naltrexone blocks opioid effects if used but requires daily oral therapy or monthly injections adherence. For pregnant women with opioid use disorder, medication-assisted therapy with buprenorphine (without naloxone) or methadone is associated with improved maternal outcomes and should be offered (see Recommendation 8). Consider naloxone for overdose prevention in patients with opioid use disorder (see Recommendation 8). For patients with problematic opioid use not meeting opioid use disorder criteria, offer opioid tapering/discontinuation (see Recommendation 7). For patients choosing but unable to taper, reassess for opioid use disorder and offer opioid agonist therapy if criteria are met.

Physicians not certified to provide office-based buprenorphine can undergo training to get a SAMHSA waiver to prescribe buprenorphine for opioid use disorder. Physicians prescribing opioids in communities lacking sufficient opioid use disorder treatment capacity should strongly consider obtaining this waiver. SAMHSA provides waiver information (222). Clinicians do not need a waiver to offer naltrexone for opioid use disorder.

Additional guidance is available (215) on buprenorphine treatment induction, use, and monitoring (Part 5) and naltrexone treatment (Part 6) for opioid use disorder, and on goals, components, and types of effective psychosocial treatment recommended with pharmacological treatment (Part 7). Clinicians unable to provide treatment should arrange care from a substance use disorder treatment specialist, such as an office-based buprenorphine or naltrexone provider, or a SAMHSA-certified opioid treatment program. Assist patients in finding qualified providers and arrange follow-up and ongoing care coordination. Do not dismiss patients from practice due to substance use disorder, as this can harm patient safety and represent patient abandonment. Opioid use disorder identification is an opportunity to initiate lifesaving interventions, and clinician collaboration with patients regarding safety is crucial for treatment success. While opioid use disorder alters expected opioid therapy benefits and risks for pain, patients with co-occurring pain and substance use disorder need ongoing pain management maximizing benefit-risk. Continue nonpharmacologic and nonopioid pain treatments as appropriate (see Recommendation 1) and consider pain specialist consultation for optimal pain management.

Resources to help arrange treatment include SAMHSA’s buprenorphine physician locator (http://buprenorphine.samhsa.gov/bwns_locator); SAMHSA’s Opioid Treatment Program Directory (http://dpt2.samhsa.gov/treatment/directory.aspx); SAMHSA’s Provider Clinical Support System for Opioid Therapies (http://pcss-o.org), offering expertise in substance use disorder treatment, opioid use disorder, and pain/opioid misuse interface; and SAMHSA’s Provider’s Clinical Support System for Medication-Assisted Treatment (http://pcssmat.org), offering expert physician mentors to answer assessment and treatment questions for substance use disorders.

Box 1. Summary of Recommendations

Determining When to Initiate or Continue Opioids for Chronic Pain

Nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain. Clinicians should consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, they should be combined with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate (recommendation category: A, evidence type: 3).
Before starting opioid therapy for chronic pain, clinicians should establish treatment goals with all patients, including realistic goals for pain and function, and should consider how opioid therapy will be discontinued if benefits do not outweigh risks. Clinicians should continue opioid therapy only if there is clinically meaningful improvement in pain and function that outweighs risks to patient safety (recommendation category: A, evidence type: 4).
Before starting and periodically during opioid therapy, clinicians should discuss with patients known risks and realistic benefits of opioid therapy and patient and clinician responsibilities for managing therapy (recommendation category: A, evidence type: 3).

Opioid Selection, Dosage, Duration, Follow-Up, and Discontinuation

When starting opioid therapy for chronic pain, clinicians should prescribe immediate-release opioids instead of extended-release/long-acting (ER/LA) opioids (recommendation category: A, evidence type: 4).
When opioids are started, clinicians should prescribe the lowest effective dosage. Clinicians should use caution when prescribing opioids at any dosage, should carefully reassess evidence of individual benefits and risks when considering increasing dosage to ≥50 morphine milligram equivalents (MME)/day, and should avoid increasing dosage to ≥90 MME/day or carefully justify a decision to titrate dosage to ≥90 MME/day (recommendation category: A, evidence type: 3).
Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids and should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than seven days will rarely be needed (recommendation category: A, evidence type: 4).
Clinicians should evaluate benefits and harms with patients within 1 to 4 weeks of starting opioid therapy for chronic pain or of dose escalation. Clinicians should evaluate benefits and harms of continued therapy with patients every 3 months or more frequently. If benefits do not outweigh harms of continued opioid therapy, clinicians should optimize other therapies and work with patients to taper opioids to lower dosages or to taper and discontinue opioids (recommendation category: A, evidence type: 4).

Assessing Risk and Addressing Harms of Opioid Use

Before starting and periodically during continuation of opioid therapy, clinicians should evaluate risk factors for opioid-related harms. Clinicians should incorporate into the management plan strategies to mitigate risk, including considering offering naloxone when factors that increase risk for opioid overdose, such as history of overdose, history of substance use disorder, higher opioid dosages (≥50 MME/day), or concurrent benzodiazepine use, are present (recommendation category: A, evidence type: 4).
Clinicians should review the patient’s history of controlled substance prescriptions using state prescription drug monitoring program (PDMP) data to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. Clinicians should review PDMP data when starting opioid therapy for chronic pain and periodically during opioid therapy for chronic pain, ranging from every prescription to every 3 months (recommendation category: A, evidence type: 4).
When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs (recommendation category: B, evidence type: 4).
Clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible (recommendation category: A, evidence type: 3).
Clinicians should offer or arrange evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies) for patients with opioid use disorder (recommendation category: A, evidence type: 2).

Box 2. Definition of Recommendation Categories and Evidence Types

Recommendation Categories

Category A: Strong recommendation. Indicates that for most patients, the intervention is appropriate and clinicians should follow the recommendation unless a clear and compelling rationale for an alternative approach is present.
Category B: Recommendation. Indicates that for different patients, there will be different choices that are appropriate, and clinicians need to help patients arrive at a management decision consistent with patient values and preferences and specific clinical situations.

Evidence Types

Type 1: Evidence from ≥1 properly designed and implemented randomized, controlled trial or meta-analysis of randomized, controlled trials addressing the question directly.
Type 2: Evidence from ≥1 properly designed and implemented controlled trial, either randomized or nonrandomized, addressing the question directly; evidence from observational studies (cohort or case-control) or multiple time-series studies with or without intervention.
Type 3: Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.
Type 4: Evidence from studies not directly addressing the question but providing information that can be extrapolated to the question.