Hieu-Pham/cpgQA huggingface dataset:
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: Who will have greater mortality?
Answer: patients who require  higher doses of opioids, even in those who benefit from such therapy
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: Who will have co-occurring medical conditions?
Answer: patients who require  higher doses of opioids, even in those who benefit from such therapy
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: Who will have other adverse events?
Answer: patients who require  higher doses of opioids, even in those who benefit from such therapy
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 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
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: 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
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: 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
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: 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

There is moderate quality evidence to support that opioids taken PRN (as needed) for chronic cancer pain versus regularly scheduled doses, or simultaneous PRN plus regularly scheduled, places patients at  elevated risk for opioid overdose (HR: 2.75, 95% CI: 1.31-5.78 for as needed; HR: 1.00 for regularly scheduled; HR: 1.84, 95% CI: 0.83-4.05 for simultaneous PRN plus regularly scheduled).[59]

Question: What does place patients at elevated risk for opioid overdose?
Answer: opioids taken PRN (as needed) for chronic cancer pain versus regularly scheduled doses, or simultaneous PRN plus regularly scheduled
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

Future Research: Future research is needed to better determine the impact of systematic reductions in MEDD in terms of  pain relief, specific pain and medical conditions, overdose morbidity and mortality as well as potential  adverse outcomes (e.g., the incidence of associated OUD, infectious diseases related to intravenous drug  use disorder, and drug-related crime and diversion) and to determine whether/which conditions may be  appropriately treated with LOT. Research is also needed to determine how frequency of monitoring should be impacted by dose.

Question: What needs to be better determined by researchers?
Answer: the impact of systematic reductions in MEDD in terms of  pain relief, specific pain and medical conditions, overdose morbidity and mortality as well as potential  adverse outcomes (e.g., the incidence of associated OUD, infectious diseases related to intravenous drug  use disorder, and drug-related crime and diversion) and to determine whether/which conditions may be  appropriately treated with LOT
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
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: 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
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 delivery mechanism has no evidence of benefit ove traditional opioid delivery systems in patients with chronic pain? 
Answer: either transdermal or buccal
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: 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
Recommendations

Abuse Deterrent Formulations of Opioids: The aim of most abuse deterrent formulations is to present a physical barrier to prevent chewing,  crushing, cutting, grating, or grinding of the dosage form, or present a chemical barrier, such as a gelling  agent, that will resist extraction of the opioid with use of a common solvent. Alternatively, an opioid  antagonist (naloxone or naltrexone) can be added to interfere with, reduce, or defeat the euphoria  associated with abuse of an agent intended for oral use when taken nasally or parenterally.[142] While  these properties deter abuse they do not fully prevent abuse; no opioid formulation prevents consumption  of a large number of intact capsules or tablets which continues to be the most common method of abuse.  

Question: What is the aim of most abuse deterrent formulations?
Answer: to present a physical barrier to prevent chewing,  crushing, cutting, grating, or grinding of the dosage form, or present a chemical barrier, such as a gelling  agent, that will resist extraction of the opioid with use of a common solvent
Recommendations

Abuse Deterrent Formulations of Opioids: The aim of most abuse deterrent formulations is to present a physical barrier to prevent chewing,  crushing, cutting, grating, or grinding of the dosage form, or present a chemical barrier, such as a gelling  agent, that will resist extraction of the opioid with use of a common solvent. Alternatively, an opioid  antagonist (naloxone or naltrexone) can be added to interfere with, reduce, or defeat the euphoria  associated with abuse of an agent intended for oral use when taken nasally or parenterally.[142] While  these properties deter abuse they do not fully prevent abuse; no opioid formulation prevents consumption  of a large number of intact capsules or tablets which continues to be the most common method of abuse.  

Question: What can be added to interfere with, reduce, or defeat the euphoria  associated with abuse of an agent intended for oral use when taken nasally or parenterally?
Answer: an opioid  antagonist (naloxone or naltrexone)