Hieu-Pham/cpgQA huggingface dataset:
Background information

Current or history of SUD: For patients with untreated SUD, see Recommendation 4. For  patients with diagnosed OUD, see Recommendation 17. Frequent requests for early refills or atypically large quantities required to control pain can signal an emerging SUD as well as  diversion (see Evidence for or history of diversion of controlled substances). See the VA/DoD  SUD CPG.4 Depression or history of depression: Zedler et al. (2014) reported that among patients  being treated by the VHA system that received opioids, a history of depression was  significantly associated with opioid-related toxicity/overdose compared to no history of  depression.[58] LOT has been associated with worsening depressive symptoms.[63] See the  VA/DoD MDD CPG.5 PTSD: Seal et al. (2012) (n=15,676) noted that among patients on OT, a prevalence of self inflicted injuries was significantly higher among patients with a history of PTSD (with or  without other mental health diagnoses) as compared to patients with other (or no) mental  health diagnoses.[65] For more information, see the VA/DoD PTSD CPG.6 History of drug overdose: A history of overdose is a red flag and providers should proceed with  utmost caution when considering LOT for these patients. Under 30 years of age: See Recommendation 6. 

Question: What can be signalled by frequent requests for atypically large quantities required to control pain?
Answer: an emerging SUD as well as  diversion
Background information

Current or history of SUD: For patients with untreated SUD, see Recommendation 4. For  patients with diagnosed OUD, see Recommendation 17. Frequent requests for early refills or atypically large quantities required to control pain can signal an emerging SUD as well as  diversion (see Evidence for or history of diversion of controlled substances). See the VA/DoD  SUD CPG.4 Depression or history of depression: Zedler et al. (2014) reported that among patients  being treated by the VHA system that received opioids, a history of depression was  significantly associated with opioid-related toxicity/overdose compared to no history of  depression.[58] LOT has been associated with worsening depressive symptoms.[63] See the  VA/DoD MDD CPG.5 PTSD: Seal et al. (2012) (n=15,676) noted that among patients on OT, a prevalence of self inflicted injuries was significantly higher among patients with a history of PTSD (with or  without other mental health diagnoses) as compared to patients with other (or no) mental  health diagnoses.[65] For more information, see the VA/DoD PTSD CPG.6 History of drug overdose: A history of overdose is a red flag and providers should proceed with  utmost caution when considering LOT for these patients. Under 30 years of age: See Recommendation 6. 

Question: Among patients  being treated by the VHA system that received opioids, what was significantly associated with opioid-related toxicity/overdose compared to no history of  depression?
Answer: a history of depression
Background information

Current or history of SUD: For patients with untreated SUD, see Recommendation 4. For  patients with diagnosed OUD, see Recommendation 17. Frequent requests for early refills or atypically large quantities required to control pain can signal an emerging SUD as well as  diversion (see Evidence for or history of diversion of controlled substances). See the VA/DoD  SUD CPG.4 Depression or history of depression: Zedler et al. (2014) reported that among patients  being treated by the VHA system that received opioids, a history of depression was  significantly associated with opioid-related toxicity/overdose compared to no history of  depression.[58] LOT has been associated with worsening depressive symptoms.[63] See the  VA/DoD MDD CPG.5 PTSD: Seal et al. (2012) (n=15,676) noted that among patients on OT, a prevalence of self inflicted injuries was significantly higher among patients with a history of PTSD (with or  without other mental health diagnoses) as compared to patients with other (or no) mental  health diagnoses.[65] For more information, see the VA/DoD PTSD CPG.6 History of drug overdose: A history of overdose is a red flag and providers should proceed with  utmost caution when considering LOT for these patients. Under 30 years of age: See Recommendation 6. 

Question: Among patients  being treated by the VHA system that received opioids, a history of depression was  significantly associated with what?
Answer: opioid-related toxicity/overdose
Background information

Current or history of SUD: For patients with untreated SUD, see Recommendation 4. For  patients with diagnosed OUD, see Recommendation 17. Frequent requests for early refills or atypically large quantities required to control pain can signal an emerging SUD as well as  diversion (see Evidence for or history of diversion of controlled substances). See the VA/DoD  SUD CPG.4 Depression or history of depression: Zedler et al. (2014) reported that among patients  being treated by the VHA system that received opioids, a history of depression was  significantly associated with opioid-related toxicity/overdose compared to no history of  depression.[58] LOT has been associated with worsening depressive symptoms.[63] See the  VA/DoD MDD CPG.5 PTSD: Seal et al. (2012) (n=15,676) noted that among patients on OT, a prevalence of self inflicted injuries was significantly higher among patients with a history of PTSD (with or  without other mental health diagnoses) as compared to patients with other (or no) mental  health diagnoses.[65] For more information, see the VA/DoD PTSD CPG.6 History of drug overdose: A history of overdose is a red flag and providers should proceed with  utmost caution when considering LOT for these patients. Under 30 years of age: See Recommendation 6. 

Question: What has been associated with worsening depressive symptoms?
Answer: LOT
Background information

Current or history of SUD: For patients with untreated SUD, see Recommendation 4. For  patients with diagnosed OUD, see Recommendation 17. Frequent requests for early refills or atypically large quantities required to control pain can signal an emerging SUD as well as  diversion (see Evidence for or history of diversion of controlled substances). See the VA/DoD  SUD CPG.4 Depression or history of depression: Zedler et al. (2014) reported that among patients  being treated by the VHA system that received opioids, a history of depression was  significantly associated with opioid-related toxicity/overdose compared to no history of  depression.[58] LOT has been associated with worsening depressive symptoms.[63] See the  VA/DoD MDD CPG.5 PTSD: Seal et al. (2012) (n=15,676) noted that among patients on OT, a prevalence of self inflicted injuries was significantly higher among patients with a history of PTSD (with or  without other mental health diagnoses) as compared to patients with other (or no) mental  health diagnoses.[65] For more information, see the VA/DoD PTSD CPG.6 History of drug overdose: A history of overdose is a red flag and providers should proceed with  utmost caution when considering LOT for these patients. Under 30 years of age: See Recommendation 6. 

Question: LOT has been associated with what kinds of symptoms?
Answer: worsening depressive symptoms
Background information

Current or history of SUD: For patients with untreated SUD, see Recommendation 4. For  patients with diagnosed OUD, see Recommendation 17. Frequent requests for early refills or atypically large quantities required to control pain can signal an emerging SUD as well as  diversion (see Evidence for or history of diversion of controlled substances). See the VA/DoD  SUD CPG.4 Depression or history of depression: Zedler et al. (2014) reported that among patients  being treated by the VHA system that received opioids, a history of depression was  significantly associated with opioid-related toxicity/overdose compared to no history of  depression.[58] LOT has been associated with worsening depressive symptoms.[63] See the  VA/DoD MDD CPG.5 PTSD: Seal et al. (2012) (n=15,676) noted that among patients on OT, a prevalence of self inflicted injuries was significantly higher among patients with a history of PTSD (with or  without other mental health diagnoses) as compared to patients with other (or no) mental  health diagnoses.[65] For more information, see the VA/DoD PTSD CPG.6 History of drug overdose: A history of overdose is a red flag and providers should proceed with  utmost caution when considering LOT for these patients. Under 30 years of age: See Recommendation 6. 

Question: Among patients on OT, a prevalence of self inflicted injuries was significantly higher among which patients?
Answer: patients with a history of PTSD (with or  without other mental health diagnoses) as compared to patients with other (or no) mental  health diagnoses
Background information

Current or history of SUD: For patients with untreated SUD, see Recommendation 4. For  patients with diagnosed OUD, see Recommendation 17. Frequent requests for early refills or atypically large quantities required to control pain can signal an emerging SUD as well as  diversion (see Evidence for or history of diversion of controlled substances). See the VA/DoD  SUD CPG.4 Depression or history of depression: Zedler et al. (2014) reported that among patients  being treated by the VHA system that received opioids, a history of depression was  significantly associated with opioid-related toxicity/overdose compared to no history of  depression.[58] LOT has been associated with worsening depressive symptoms.[63] See the  VA/DoD MDD CPG.5 PTSD: Seal et al. (2012) (n=15,676) noted that among patients on OT, a prevalence of self inflicted injuries was significantly higher among patients with a history of PTSD (with or  without other mental health diagnoses) as compared to patients with other (or no) mental  health diagnoses.[65] For more information, see the VA/DoD PTSD CPG.6 History of drug overdose: A history of overdose is a red flag and providers should proceed with  utmost caution when considering LOT for these patients. Under 30 years of age: See Recommendation 6. 

Question: Among patients on OT, what was significantly higher among patients with a history of PTSD as compared to patients with other (or no) mental  health diagnoses?
Answer: a prevalence of self inflicted injuries
Background information

Current or history of SUD: For patients with untreated SUD, see Recommendation 4. For  patients with diagnosed OUD, see Recommendation 17. Frequent requests for early refills or atypically large quantities required to control pain can signal an emerging SUD as well as  diversion (see Evidence for or history of diversion of controlled substances). See the VA/DoD  SUD CPG.4 Depression or history of depression: Zedler et al. (2014) reported that among patients  being treated by the VHA system that received opioids, a history of depression was  significantly associated with opioid-related toxicity/overdose compared to no history of  depression.[58] LOT has been associated with worsening depressive symptoms.[63] See the  VA/DoD MDD CPG.5 PTSD: Seal et al. (2012) (n=15,676) noted that among patients on OT, a prevalence of self inflicted injuries was significantly higher among patients with a history of PTSD (with or  without other mental health diagnoses) as compared to patients with other (or no) mental  health diagnoses.[65] For more information, see the VA/DoD PTSD CPG.6 History of drug overdose: A history of overdose is a red flag and providers should proceed with  utmost caution when considering LOT for these patients. Under 30 years of age: See Recommendation 6. 

Question: Where can more information be found on PTSD?
Answer: VA/DoD PTSD CPG
Background information

Current or history of SUD: For patients with untreated SUD, see Recommendation 4. For  patients with diagnosed OUD, see Recommendation 17. Frequent requests for early refills or atypically large quantities required to control pain can signal an emerging SUD as well as  diversion (see Evidence for or history of diversion of controlled substances). See the VA/DoD  SUD CPG.4 Depression or history of depression: Zedler et al. (2014) reported that among patients  being treated by the VHA system that received opioids, a history of depression was  significantly associated with opioid-related toxicity/overdose compared to no history of  depression.[58] LOT has been associated with worsening depressive symptoms.[63] See the  VA/DoD MDD CPG.5 PTSD: Seal et al. (2012) (n=15,676) noted that among patients on OT, a prevalence of self inflicted injuries was significantly higher among patients with a history of PTSD (with or  without other mental health diagnoses) as compared to patients with other (or no) mental  health diagnoses.[65] For more information, see the VA/DoD PTSD CPG.6 History of drug overdose: A history of overdose is a red flag and providers should proceed with  utmost caution when considering LOT for these patients. Under 30 years of age: See Recommendation 6. 

Question: What is a red flag in the presence of which providers should proceed with utmost caution when considering LOT for these patients?
Answer: A history of overdose
Background information

Co-administration of a drug capable of inducing fatal drug-drug interactions: Providers should carefully rule out and avoid potential drug interactions prior to initiating LOT. For example, the following combinations are dangerous:[66] i)Opioids with benzodiazepines (compared to patients with no prescription, the odds ratio [OR] and 95% confidence interval [CI] for drug-related death was OR: 14.92, 95% CI: 7.00- 31.77 for patients who filled a prescription for opioids and benzodiazepines; OR: 3.40, 95%  CI: 1.60-7.21 for patients who filled only an opioid prescription, and 7.21, 95% CI: 3.33-15.60 for patients who filled only a benzodiazepine prescription) (see Recommendation 5) [66,67], ii)Fentanyl with CYP3A4 inhibitors, iii) Methadone with drugs that can prolong the QT interval (the heart rate’s corrected time  interval from the start of the Q wave to the end of the T wave) (e.g., CYP450 2B6 inhibitors)  

Question: What should providers carefully rule out and avoid?
Answer: potential drug interactions prior to initiating LOT
Background information

Co-administration of a drug capable of inducing fatal drug-drug interactions: Providers should carefully rule out and avoid potential drug interactions prior to initiating LOT. For example, the following combinations are dangerous:[66] i)Opioids with benzodiazepines (compared to patients with no prescription, the odds ratio [OR] and 95% confidence interval [CI] for drug-related death was OR: 14.92, 95% CI: 7.00- 31.77 for patients who filled a prescription for opioids and benzodiazepines; OR: 3.40, 95%  CI: 1.60-7.21 for patients who filled only an opioid prescription, and 7.21, 95% CI: 3.33-15.60 for patients who filled only a benzodiazepine prescription) (see Recommendation 5) [66,67], ii)Fentanyl with CYP3A4 inhibitors, iii) Methadone with drugs that can prolong the QT interval (the heart rate’s corrected time  interval from the start of the Q wave to the end of the T wave) (e.g., CYP450 2B6 inhibitors)  

Question: What combinations of drugs are dangerous?
Answer: i)Opioids with benzodiazepines (compared to patients with no prescription, the odds ratio [OR] and 95% confidence interval [CI] for drug-related death was OR: 14.92, 95% CI: 7.00- 31.77 for patients who filled a prescription for opioids and benzodiazepines; OR: 3.40, 95%  CI: 1.60-7.21 for patients who filled only an opioid prescription, and 7.21, 95% CI: 3.33-15.60 for patients who filled only a benzodiazepine prescription) (see Recommendation 5) [66,67], ii)Fentanyl with CYP3A4 inhibitors, iii) Methadone with drugs that can prolong the QT interval (the heart rate’s corrected time  interval from the start of the Q wave to the end of the T wave) (e.g., CYP450 2B6 inhibitors)
Background information

QTc interval >450 ms for using methadone: Unlike most other commonly used opioids, methadone has unique pharmacodynamic properties that can prolong the QTc interval (the heart rate’s corrected time interval from the start of the Q wave to the end of the T wave) and precipitate torsades de pointes, a dangerous or fatal cardiac arrhythmia. Patients who may be at risk include those with other risk factors for QTc prolongation, current or prior electrocardiograms (ECGs) with a prolonged QTc >450 ms, or a history of syncope. Therefore, ECGs before and after initiating methadone are highly advised (see Methadone Dosing Guidance). 

Question: Which opioid has unique pharmacodynamic properties that can prolong the QTc interval and precipitate torsades de pointes, a dangerous or fatal cardiac arrhythmia?
Answer: methadone
Background information

QTc interval >450 ms for using methadone: Unlike most other commonly used opioids, methadone has unique pharmacodynamic properties that can prolong the QTc interval (the heart rate’s corrected time interval from the start of the Q wave to the end of the T wave) and precipitate torsades de pointes, a dangerous or fatal cardiac arrhythmia. Patients who may be at risk include those with other risk factors for QTc prolongation, current or prior electrocardiograms (ECGs) with a prolonged QTc >450 ms, or a history of syncope. Therefore, ECGs before and after initiating methadone are highly advised (see Methadone Dosing Guidance). 

Question: What is QTc interval?
Answer: the heart rate’s corrected time interval from the start of the Q wave to the end of the T wave
Background information

QTc interval >450 ms for using methadone: Unlike most other commonly used opioids, methadone has unique pharmacodynamic properties that can prolong the QTc interval (the heart rate’s corrected time interval from the start of the Q wave to the end of the T wave) and precipitate torsades de pointes, a dangerous or fatal cardiac arrhythmia. Patients who may be at risk include those with other risk factors for QTc prolongation, current or prior electrocardiograms (ECGs) with a prolonged QTc >450 ms, or a history of syncope. Therefore, ECGs before and after initiating methadone are highly advised (see Methadone Dosing Guidance). 

Question: What is torsades de pointes?
Answer: a dangerous or fatal cardiac arrhythmia
Background information

QTc interval >450 ms for using methadone: Unlike most other commonly used opioids, methadone has unique pharmacodynamic properties that can prolong the QTc interval (the heart rate’s corrected time interval from the start of the Q wave to the end of the T wave) and precipitate torsades de pointes, a dangerous or fatal cardiac arrhythmia. Patients who may be at risk include those with other risk factors for QTc prolongation, current or prior electrocardiograms (ECGs) with a prolonged QTc >450 ms, or a history of syncope. Therefore, ECGs before and after initiating methadone are highly advised (see Methadone Dosing Guidance). 

Question: Which one is a dangerous or fatal cardiac arrhythmia?
Answer: torsades de pointes
Background information

QTc interval >450 ms for using methadone: Unlike most other commonly used opioids, methadone has unique pharmacodynamic properties that can prolong the QTc interval (the heart rate’s corrected time interval from the start of the Q wave to the end of the T wave) and precipitate torsades de pointes, a dangerous or fatal cardiac arrhythmia. Patients who may be at risk include those with other risk factors for QTc prolongation, current or prior electrocardiograms (ECGs) with a prolonged QTc >450 ms, or a history of syncope. Therefore, ECGs before and after initiating methadone are highly advised (see Methadone Dosing Guidance). 

Question: What unique properties does methadone have?
Answer: unique pharmacodynamic properties that can prolong the QTc interval (the heart rate’s corrected time interval from the start of the Q wave to the end of the T wave) and precipitate torsades de pointes, a dangerous or fatal cardiac arrhythmia
Background information

QTc interval >450 ms for using methadone: Unlike most other commonly used opioids, methadone has unique pharmacodynamic properties that can prolong the QTc interval (the heart rate’s corrected time interval from the start of the Q wave to the end of the T wave) and precipitate torsades de pointes, a dangerous or fatal cardiac arrhythmia. Patients who may be at risk include those with other risk factors for QTc prolongation, current or prior electrocardiograms (ECGs) with a prolonged QTc >450 ms, or a history of syncope. Therefore, ECGs before and after initiating methadone are highly advised (see Methadone Dosing Guidance). 

Question: Why are ECGs highly advised before and after initiating methadone?
Answer: Patients who may be at risk include those with other risk factors for QTc prolongation, current or prior electrocardiograms (ECGs) with a prolonged QTc >450 ms, or a history of syncope.
Background information

QTc interval >450 ms for using methadone: Unlike most other commonly used opioids, methadone has unique pharmacodynamic properties that can prolong the QTc interval (the heart rate’s corrected time interval from the start of the Q wave to the end of the T wave) and precipitate torsades de pointes, a dangerous or fatal cardiac arrhythmia. Patients who may be at risk include those with other risk factors for QTc prolongation, current or prior electrocardiograms (ECGs) with a prolonged QTc >450 ms, or a history of syncope. Therefore, ECGs before and after initiating methadone are highly advised (see Methadone Dosing Guidance). 

Question: Which patients may be at risk?
Answer: those with other risk factors for QTc prolongation, current or prior electrocardiograms (ECGs) with a prolonged QTc >450 ms, or a history of syncope
Background information

Evidence for or history of diversion of controlled substances: The clinician should communicate to patients that drug diversion is a crime and constitutes an absolute contraindication to prescribing additional medications. Because suspicion is subjective and may be based on impression, bias, or prejudice, it is important that providers who suspect diversion base treatment plans on objective evidence. Suspicions may be confirmed by a negative mass spectrometry/liquid chromatography UDT for the substance being prescribed in the absence of withdrawal symptoms in someone who is receiving opioids. A negative UDT for the prescribed opioid could also by itself be a sign of diversion. Signs of diversion may also include frequent requests for early refills or atypically large quantities required to control pain. Routine UDT, however, may not reliably detect synthetic opioids (e.g., methadone, fentanyl, tramadol) or semi-synthetic opioids (e.g., oxycodone, hydrocodone, hydromorphone). When there is evidence that the patient is diverting opioids, discontinue opioids according to Recommendations 14 and 15 and assess for underlying OUD and/or psychiatric comorbidities. Consultation with a pain specialist, psychiatrist, or SUD specialist may be warranted. Also consider consultation with local risk management and/or counsel. For patients with OUD, keep in mind that sudden discontinuation of opioids due to suspected diversion may place them at high risk for illicit opioid use and resulting opioid overdose (see Recommendation 17).

Question: What should the clinician communicate to patients?
Answer: that drug diversion is a crime and constitutes an absolute contraindication to prescribing additional medications