Lornng/cpgQA huggingface dataset:
Recommendations

Prior to initiating OT, an individualized assessment of potential opioid-related harms relative to realistic treatment goals must be completed. After initiating OT, frequent visits contribute to the appropriate use and adjustment of the planned therapy.  The Work Group recommends follow-up at least every three months or more frequently (see  Recommendation 7 and Recommendation 11) due to the balance of benefits and harms associated with this recommendation. Although the 2010 OT CPG recommended follow-up every six months, this recommended interval for follow-up and reassessment has not been sufficient to reduce the potential harm associated with LOT or adequately implement comprehensive biopsychosocial pain care. More frequent follow-up is needed in order to increase the impact of risk mitigation strategies and enhance the delivery of comprehensive, biopsychosocial pain care. Frequency of visits should thereafter be based on risk stratification. Similarly, the CDC guideline for OT recommends re-evaluating harms versus benefits within one to four weeks of starting OT or at any dose change, and at least every three months or more frequently if needed.[132]

Question: What to do before initiating OT?
Answer: an individualized assessment of potential opioid-related harms relative to realistic treatment goals must be completed

Question: What to do after initiating OT?
Answer: frequent visits contribute to the appropriate use and adjustment of the planned therapy

Question: When to follow up?
Answer: at least every three months or more frequently

Question: Why follow up at least every three months or more frequently?
Answer: due to the balance of benefits and harms

Question: Why is frequent follow-up needed?
Answer: in order to increase the impact of risk mitigation strategies and enhance the delivery of comprehensive, biopsychosocial pain care

Question: How to decide the frequency of follow-up visits?
Answer: based on risk stratification

Question: How frequently should the harms versus benefits be re-evaluated according to the CDC guideline?
Answer: within one to four weeks of starting OT or at any dose change, and at least every three months or more frequently if needed
Recommendations

At follow-up visits, a clinician should re-examine the rationale for continuing the patient on OT. Clinicians should take into account changes in co-occurring conditions, diagnoses/medications, and functional status when conducting the risk/benefit analysis for LOT. Alcohol use, pregnancy, nursing of infants, and lab abnormalities may change the risk/benefit calculus for LOT. Ongoing OT prescribing practice may include pharmacy review, informed consent, UDTs, and checking state PDMPs. A clinician should also be mindful of signs of diversion during follow-up (see Risk Factors for Adverse Outcomes of Opioid Therapy). The longer the patient is on opioids, the greater the potential for change in patient status and development of opioid-related harms.

Question: What to do at follow-up visits?
Answer: a clinician should re-examine the rationale for continuing the patient on OT

Question: What to consider at the time of re-examining at a follow-up visit?
Answer: changes in co-occurring conditions, diagnoses/medications, and functional status when conducting the risk/benefit analysis for LOT

Question: What may change the risk/benefit calculus for LOT?
Answer: Alcohol use, pregnancy, nursing of infants, and lab abnormalities

Question: What is included in the ongoing OT prescribing practice?
Answer: pharmacy review, informed consent, UDTs, and checking state PDMPs

Question: What to be aware of during follow-ups?
Answer: signs of diversion

Question: What is the relationship between the length of OT and opioid-related harms?
Answer: The longer the patient is on opioids, the greater the potential for change in patient status and development of opioid-related harms.
Recommendations

If prescribing opioids, we recommend prescribing the lowest dose of opioids as indicated by patient-specific risks and benefits. (Strong for | Reviewed, New-replaced) Note: There is no absolutely safe dose of opioids. As opioid dosage and risk increase, we recommend more frequent monitoring for adverse events including opioid use disorder and overdose. Risks for opioid use disorder start at any dose and increase in a dose-dependent manner. • Risks for overdose and death significantly increase at a range of 20-50 mg morphine equivalent daily dose. (Strong for | Reviewed, New- replaced)  We recommend against opioid doses over 90 mg morphine equivalent daily dose for treating chronic pain. (Strong against | Reviewed, New-replaced) Note: For patients who are currently prescribed doses over 90 mg morphine equivalent daily dose, evaluate for tapering to reduced dose or to discontinuation (see Recommendations 14 and 15).

Question: What is the recommended dose of opioids?
Answer: the lowest dose of opioids as indicated by patient-specific risks and benefits

Question: Is there any absolutely safe dose of opioids?
Answer: no

Question: What to do with the increment of opioid dosage and risk?
Answer: more frequent monitoring for adverse events including opioid use disorder and overdose

Question: At what dose do risks for opioid use disorder begin?
Answer: any

Question: At what dose do risks for opioid use disorder increase?
Answer: in a dose-dependent manner

Question: At what dose do the risks for overdose and death increase?
Answer: a range of 20-50 mg morphine equivalent daily dose

Question: What opioid dose is not recommended for treating chronic pain?
Answer: over 90 mg morphine equivalent daily dose

Question: What is recommended for patients who are currently prescribed doses over 90 mg morphine equivalent daily dose?
Answer: evaluate for tapering to reduced dose or to discontinuation
Recommendations

There is moderate quality evidence from retrospective cohort and retrospective case-control studies  indicating that risk of prescription opioid overdose and overdose death exists even at low opioid dosage levels and increases with increasing doses. Significant risk (approximately 1.5 times) exists at a daily dosage range of 20 to <50 mg MEDD and further increases (approximately 2.6 times) at a range of 50 to <100 mg MEDD compared to risk at <20 mg MEDD. Risk continues to increase at higher dosage ranges (≥100 mg  MEDD) (Table 2).[58,59,66,133]

Question: Is there any evidence that risk of prescription opioid overdose and overdose death exists even at low opioid dosage levels and increases with increasing doses?
Answer: There is moderate quality evidence from retrospective cohort and retrospective case-control studies

Question: At what dosage there is a significant risk?
Answer: a daily dosage range of 20 to <50 mg MEDD

Question: At what dosage does the risk increase even further?
Answer: a range of 50 to <100 mg MEDD compared to risk at <20 mg MEDD

Question: How much does the risk increase at a daily dosage range of 20 to <50 mg MEDD?
Answer: approximately 1.5 times

Question: How much does the risk increase at a range of 50 to <100 mg MEDD compared to risk at <20 mg MEDD?
Answer: approximately 2.6 times
Recommendations

In a nested case-control study of U.S. Veterans (not included in our evidence review as it was published after the end of the search date range), Bohnert et al. (2016) examined the association between prescribed opioid dose as a continuous measure (in 10 mg MEDD increments) and overdose.[134]  Prescribed opioid dosage was a moderately good predictor of overdose death, but the study did not reveal a specific dosage cut point or threshold above which risk of overdose increased dramatically. Lower prescribed opioid dosages were associated with reduced risk for overdose, but risk was not completely eliminated at lower doses; approximately 40% of overdoses were observed in patients who were prescribed <50 mg MEDD.

Question: What is a good predictor of overdose death?
Answer: Prescribed opioid dosage
Recommendations

In a prospective cohort study (not included in the evidence review as it did not include information on  acute versus chronic pain in the patient population), Dasgupta et al. (2015) compared residents of North  Carolina who had received an opioid prescription in the last year to residents who had not. The study examined the outcome of population-based rates of opioid overdose mortality by opioid dose, without use of a presupposed threshold (Table 3).[135] There was no safe dose of opioid. Among the over nine million individuals followed for one year, 629 died from opioid overdose. Of these 629 individuals, 151 had no record of having been dispensed an opioid. It is possible these opioids were obtained through illicit channels or social sharing/diversion. Of the 478 patients who died from an opioid overdose who were prescribed opioids, 235 (49%) had been prescribed <80 mg MEDD. Overdose incidence rate ratios (IRRs)  doubled each time the MEDD ranges increase from 60.0-79.9 mg to 80.0-99.9 mg (IRR 2.9 to 6.2), then to  120-139.9 mg (IRR 14.1), 160-179.9 mg (IRR 29.5), and 350-399.9 mg (IRR 63.2).

Question: Is there any study on the outcome of population-based rates of opioid overdose mortality by opioid dose, without the use of a presupposed threshold?
Answer: In a prospective cohort study (not included in the evidence review as it did not include information on  acute versus chronic pain in the patient population), Dasgupta et al. (2015) compared residents of North  Carolina who had received an opioid prescription in the last year to residents who had not.
Recommendations

Achieving an improved understanding of the factors contributing to prescription opioid-related overdose is an essential step toward addressing this epidemic problem. Although it is widely accepted that progressively higher doses of prescribed opioids result in correspondingly higher risks of opioid overdose,  patients using any dose of opioids can still experience life-threatening respiratory or CNS depression,  especially when opioid-naïve. This risk begins to increase with MEDD as low as 20-50 mg. Risk is further increased when certain concomitant demographic factors, co-occurring medical or psychiatric conditions,  or interacting medications or substances exist.

Question: Which step should be taken to address the problem of opioid-related overdose epidemic?
Answer: Achieving an improved understanding of the factors contributing to prescription opioid-related overdose

Question: What is the relationship between opioid dosage and risks of opioid overdose?
Answer: progressively higher doses of prescribed opioids result in correspondingly higher risks of opioid overdose

Question: Which factors increase the risk of opioid overdose?
Answer: certain concomitant demographic factors, co-occurring medical or psychiatric conditions,  or interacting medications or substances
Recommendations

Recognizing the lack of evidence of long-term benefit associated with LOT used alone and the risks of  harms with use of opioids without risk mitigation, dosing determinations should be individualized based  upon patient characteristics and preferences, with the goal of using the lowest dose of opioids for the  shortest period of time to achieve well-defined functional treatment goals. Understandably, there will be  greater mortality, co-occurring medical conditions, and other adverse events in patients who require  higher doses of opioids, even in those who benefit from such therapy. When closer follow-up is needed,  healthcare resources and patient adherence should be considered.

Question: What should be individualized based upon patient characteristics and preferences?
Answer: Recognizing the lack of evidence of long-term benefit associated with LOT used alone and the risks of  harms with use of opioids without risk mitigation, dosing determinations

Question: Who will have greater mortality, co-occurring medical conditions, and other adverse events?
Answer: patients who require  higher doses of opioids, even in those who benefit from such therapy

Question: Who will have greater mortality?
Answer: patients who require  higher doses of opioids, even in those who benefit from such therapy

Question: Who will have co-occurring medical conditions?
Answer: patients who require  higher doses of opioids, even in those who benefit from such therapy

Question: Who will have other adverse events?
Answer: patients who require  higher doses of opioids, even in those who benefit from such therapy

Question: What should be considered when a closer follow-up is needed?
Answer: healthcare resources and patient adherence should be considered
Recommendations

Subgroups at higher risk: Risk of prescription opioid overdose is elevated across MEDD dosage levels in patients with co-occurring depression (moderate quality evidence).[66,133] Following an elevated baseline adjusted risk ratio (ARR) of 3.96, depressed patients taking 1-19 mg, 20 to <50 mg, 50 to <100 mg, and ≥100 mg MEDD had respective odds of overdose of 4.75, 5.47, 6.44, and 7.06, compared to those taking an opioid at the same dosage level without a diagnosis of depression.[66] Similarly, a history of or active SUD increases risk for serious prescription opioid-related toxicity or  overdose across opioid dosages (moderate quality evidence).[58,87,133] A retrospective cohort review of  patients with CNCP receiving LOT at least five days per week for 90 days determined that those with a  history of non-opioid SUD had 28 times the odds of developing OUD.[87] Each 50 mg increase in MEDD  nearly doubled the odds while each 100 mg MEDD increase tripled the risk for OUD. Concurrent  prescribing of sedative-hypnotics and benzodiazepines increases risk of fatal or non-fatal opioid overdose  2-10 fold across opioid dose ranges.[66,133,135]

Question: Who is at a high risk of prescription opioid overdose?
Answer: patients with co-occurring depression

Question: Following an elevated baseline adjusted risk ratio (ARR) of 3.96, what were the odds of overdose in depressed patients taking 1-19 mg, 20 to <50 mg, 50 to <100 mg, and ≥100 mg MEDD?
Answer: 4.75, 5.47, 6.44, and 7.06, compared to those taking an opioid at the same dosage level without a diagnosis of depression

Question: What does increase the risk for serious prescription opioid-related toxicity or overdose across opioid dosages in patients?
Answer: a history of or active SUD

Question: What does increase the risk of fatal or non-fatal opioid overdose 2-10 fold across opioid dose ranges?
Answer: Concurrent  prescribing of sedative-hypnotics and benzodiazepines
Recommendations

In patients receiving LOT, moderate quality evidence indicated that men are 50% more likely (HR: 1.44,  95% CI: 1.21-1.70) to escalate to high-dose opioids (defined as >200 mg MEDD) and twice as likely to  experience an opioid-related death (adjusted HR: 2.04, 95% CI: 1.18-3.53) compared to women.[136] Risk  of opioid overdose morbidity or mortality is also increased in non-Hispanic white versus non-Hispanic black  patients (moderate quality evidence).[59,136]

Question: In patients receiving LOT, who are 50% more likely to escalate to high-dose opioids and twice as likely to  experience an opioid-related death?
Answer: men
Recommendations

Long-acting opioids, as further discussed below, should not be used for treatment of acute pain, on an as needed basis, or during initiation of LOT (see Short-acting versus Long-acting Opioids). In general,  however, no single opioid or opioid formulation is preferred over the others. However, individuals may  have a better response, degree of safety, or tolerability depending on their individual characteristics and  preferences. Additional information for use when deciding on appropriate pharmacological treatment of  pain for a specific patient can be found in Appendix D.

Question: What should not be used for treatment of acute pain?
Answer: Long-acting opioids

Question: Which opioid/opioid formulation is preferred over the others?
Answer: no single
Recommendations

There was insufficient evidence to recommend for or against any specific opioid or opioid formulation,  specifically the following:  Short-acting versus long-acting opioids (for LOT for chronic pain), Route of administration/delivery among alternatives such as transdermal, buccal, sublingual, or pumps, Abuse deterrent formulations of opioids compared to non-abuse deterrent formulations, Tramadol and other dual-mechanism opioids. Buprenorphine for pain (compared to other opioids), Methadone (with QT monitoring).

Question: Which opioid/opioid formulation did not have enough evidence to be recommended for or against?
Answer: any specific opioid or opioid formulation,  specifically the following:  Short-acting versus long-acting opioids (for LOT for chronic pain), Route of administration/delivery among alternatives such as transdermal, buccal, sublingual, or pumps, Abuse deterrent formulations of opioids compared to non-abuse deterrent formulations, Tramadol and other dual-mechanism opioids. Buprenorphine for pain (compared to other opioids), Methadone (with QT monitoring).
Recommendations

Short-acting versus Long-acting Opioids: Avoid use of long-acting agents for acute pain (with exception of oxycodone/acetaminophen extended release [ER] tablets), on an as-needed basis, or for initiation of OT.[10,137-139] There is very low quality evidence to recommend for or against short-acting versus long-acting opioids for maintenance of OT.  There were two RCTs included in the evidence review that looked at safety and efficacy. One RCT  comparing long-acting to short-acting dihydrocodeine found no statistically or clinically significant  differences in stability of pain intensity between the two groups, as well as no difference in adverse events. Although study results may be inconclusive due to poor study design, the authors state that they do not  support the use of long-acting agents for chronic non-malignant pain.[140]

Question: Which long-acting agents can be used for acute pain?
Answer: oxycodone/acetaminophen extended release [ER] tablets
Recommendations

A second non-inferiority RCT compared once-daily hydromorphone ER to twice-daily oxycodone  controlled-release in patients with moderate-to-severe cancer pain. The primary efficacy endpoint was  patient assessment of “Brief Pain Inventory (BPI) worst pain in the past 24 hr.” Results demonstrated  similar improvements in BPI and that the once-daily hydromorphone formulation was non-inferior to the  twice-daily oxycodone formulation. Treatment-emergent adverse events were comparable between the  groups as well.[141] The efficacy of long-acting opioids used once-daily is non-inferior to twice-daily use. There was a lack of statistical analysis of the outcomes and a lack of statistical power in both studies, and a  small sample size in one study.

Question: What was the efficacy of long-acting opioids used once-daily compared to twice-daily use?
Answer: non-inferior
Recommendations

There is concern for additional overdose risk associated with long-acting versus short-acting opioids. A  study (not included in the evidence review due to its design) suggests increased risk for non-fatal overdose  in VA patients with initiation of a long-acting opioid compared with immediate-release opioids.[137] Also,  recent research demonstrates that patients with CNCP on long-acting OT have a significantly increased risk  of all-cause mortality compared to patients with CNCP who are taking an analgesic anticonvulsants or a  low-dose antidepressant.[10]

Question: Who has a significantly increased risk  of all-cause mortality compared to patients with CNCP who are taking an analgesic anticonvulsants or a  low-dose antidepressant?
Answer: patients with CNCP on long-acting OT
Recommendations

Route of Administration/Delivery: The systematic evidence review for this CPG did not find any studies that compared alternative delivery  systems (e.g., fentanyl transdermal, fentanyl buccal) to other delivery systems (e.g., oral, intravenous)  (information on transdermal and sublingual buprenorphine is included in the following section on  Buprenorphine for Pain). The concomitant use of oral and transdermal opioids or oral and intrathecal pumps should be approached with extreme caution and warrants specialty consultation. Discussions of  intrathecal pumps are beyond the scope of this guideline.

Question: What should be approached with extreme caution and warrants specialty consultation?
Answer: The concomitant use of oral and transdermal opioids or oral and intrathecal pumps
Recommendations

Although some patients may prefer either transdermal or buccal opioid delivery for opioids, there is  significant potential for harm from OT with these delivery mechanisms, with no evidence of benefit over  traditional opioid delivery systems in patients with chronic pain. Clinicians need to be especially aware of  the risks associated with a fentanyl transdermal delivery system (or patch) (Appendix D) including its: Unique pharmacokinetic profile, Continuous delivery, even after the patch is removed due to depot effect, Increased rate of delivery, Unpredictable variation in rate of delivery  - Due to alterations in temperature due to external heat, skin integrity, and amount of  adipose tissue, Among patients with fever, skin damage, or cachexia.

Question: Which opioid delivery for opioids has significant potential for harm from OT?
Answer: either transdermal or buccal

Question: Which delivery mechanism has no evidence of benefit ove traditional opioid delivery systems in patients with chronic pain? 
Answer: either transdermal or buccal

Question: What are the risks associated with a fentanyl transdermal delivery system (or patch)?
Answer: Unique pharmacokinetic profile, Continuous delivery, even after the patch is removed due to depot effect, Increased rate of delivery, Unpredictable variation in rate of delivery  - Due to alterations in temperature due to external heat, skin integrity, and amount of  adipose tissue, Among patients with fever, skin damage, or cachexia
Recommendations

Given the potential serious risks with starting fentanyl and challenges with tapering, clinicians intent on  prescribing transdermal fentanyl for chronic pain are encouraged to consult with other clinicians (e.g., pain  specialists, pharmacists) and to be familiar with the unique properties of fentanyl. Specific safety  precautions that all clinicians should be aware of regarding transdermal fentanyl include: Transdermal fentanyl should not be used in opioid-naïve patients; Patients need to be informed that: Heat (e.g., sun exposure, heating pad, febrile condition) can increase the rate and quantity  of absorption, Proper application includes: being sure to take old patch off; never applying damaged patch  or a patch to non-intact skin; proper disposal to avoid exposure to children and pets, and precautions taken against possible diversion of remaining drug in used patch; Adjusted dose (i.e., decreased patch size) should be used in patients with renal or hepatic  insufficiency and considered in elderly patients and those with febrile illness

Question: Which specific safety precautions should all clinicians be aware of regarding transdermal fentanyl?
Answer: Transdermal fentanyl should not be used in opioid-naïve patients; Patients need to be informed that: Heat (e.g., sun exposure, heating pad, febrile condition) can increase the rate and quantity  of absorption, Proper application includes: being sure to take old patch off; never applying damaged patch  or a patch to non-intact skin; proper disposal to avoid exposure to children and pets, and precautions taken against possible diversion of remaining drug in used patch; Adjusted dose (i.e., decreased patch size) should be used in patients with renal or hepatic  insufficiency and considered in elderly patients and those with febrile illness