Pain Management with Combination Drugs: Warnings
In treating patients with co-occurring pain and anxiety disorders, prescribers are increasingly adding gabapentinoids (GABAs) and serotonergic drugs to opioids and benzodiazepines, respectively. Yet the toxicities of these drug classes and their combinations are not well understood.
Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (SNRIs).
In a study by Kuo et al., the authors conducted a matched case-control study using Medicare files from 2013-2016. The files were linked to the National Death Index. The authors compared cases in which patients died from drug overdose (Group 1) to a control group. The control group comprised Medicare enrollees who died from other causes (Group 2).
Enrollees were matched on patient characteristics and prior chronic conditions. Possession of any opioids, GABAs, benzodiazepines (benzos), and SSRIs/SNRIs in the month prior to death was defined as drug use. Combination drug use was defined as possessing at least 2 types of these prescriptions for an overlapping period of at least 7 days in the month prior to death.
The researchers found that among 4323 matches, benzo possession was associated with twice the risk for drug overdose death in Group 1. Compared with opioid-benzo co-prescribing, combinations involving SSRIs/SNRIs and opioids (or GABAs) were associated with decreased risk (adjusted odds ratio 0.55; 95% confidence interval, 0.44-0.69 for opioids and SSRIs/SNRIs; adjusted odds ratio 0.59; 95% confidence interval, 0.44-0.79 for GABAs and SSRIs/SNRIs).
Fatal drug overdose risk was similar in users of GABA-opioid, GABA-benzo, and opioid-benzo combinations.
The conclusions drawn were that benzodiazepines, prescribed alone or in combination, were associated with an increased risk of drug overdose death.
SSRIs/SNRIs were associated with a lower risk of overdose death than were benzodiazepines.
GABAs were not associated with a decreased risk compared with opioids, which raises concern about the perceived relative safety of GABAs. (See: Kuo YF, Liaw V, Yu X, et al. Opioid and benzodiazepine substitutes: Impact on drug overdose mortality in Medicare population. Am J Med. 2022 Mar 24. pii: S0002-9343(22)00191-7. doi: 10.1016/j.amjmed.2022.02.039.)
Validation of the PRODIGY Score
The general care floor encompasses mostly a low acuity inpatient area. Nevertheless, almost half of inpatient cardiorespiratory events occur in that area, often with fatal results.
Better continuous monitoring had been advocated as a means to improve patient safety.
The PRODIGY (prediction of opioid-induced respiratory depression in patients monitored by capnography) trial results were published some 2 years ago. The study aimed to define patients at greatest risk for this major adverse event after surgery.
The study covered 16 sites internationally and included a total of 1,335 patients who received parenteral opioids and were continuously monitored on a general care floor. Respiratory depression was defined as respiratory rate of less than 5 breaths per minute, oxygen (O2) saturation of less than 85%, ETCO2 of less than 15 or greater than 60 mmHg for more than 3 minutes, apnea episode lasting more than 30 seconds.
One or more episode was detected in 46% of patients. In these patients, hospital stay was increased by, on average, 3 days.
A risk prediction tool was developed, based on the findings and using a multivariable logistic regression model of 46 a priori defined risk factors.
Following up in this study, the lead author, Khanna, is urging institutions to adopt the findings to assess risk of opioid-induced respiratory depression.
Two hospitals in the Lehigh Valley Health Network started care pathways that included PRODIGY-guided bedside monitoring of all postoperative patients on the general care floor receiving parenteral opioids. Continuous oximetry was used on the first day and capnography was added in those with sleep-disordered breathing, morbid obesity, neuraxial opioids, and supplemental oxygen. Analysis of the findings indicated that there was significant improvement in key performance indicators including activation of the rapid response team, naloxone use, ICU transfer, and arrests. Monitoring provides early detection of clinical deterioration and remote notification to staff to allow quick interventions.
A PRODIGY tool was developed that includes 5 variables:
1. Age at least 60 years;
2. Male sex;
3. Opioid naivety;
4. Presence of a sleep disorder; and
5. Chronic heart failure.
Patients at high risk have a 6 times greater chance of developing opioid-induced respiratory depression. The principal author of the validation study, McLoughlin from Lehigh Valley, (results not yet published) believes that a PRODIGY score should be entered in the EMR whenever a patient enters the hospital or receives an opioid. The EMR can then be programmed to make specific recommendations either for increased, monitoring, more frequent nursing checks or care in a higher acuity unit. (See: Khanna AK et al. Prediction of opioid-induced respiratory depression on inpatient wards using continuous capnography and oximetry: An international prospective observational trial. Anes Analg. 2020; 131(4):1012-1024; and Vlessides M. PRODIGY's findings pass real-world test. Anesthesiology News; 2022: 48(5): 8-9.)