Opioid utility function: methods and implications

Abstract

Opioids are complex drugs that produce profit (most importantly analgesia) as well as a myriad of adverse effects including gastrointestinal motility disturbances, abuse and addiction, sedation and potentially lethal respiratory depression (RD). Consequently, opioid treatment requires careful evaluation in terms of benefit on the one hand and harm on the other. Considering benefit and harm from an economic perspective, opioid treatment should lead to profit maximization with decision theory defining utility as (profit − loss).We here focus on the most devastating opioid adverse effect, RD and define opioid utility U = P(benefit) − P(harm), where P(benefit) is the probability of opioid-induced analgesia and P(harm) the probability of opioid-induced RD. Other utility functions are also discussed including the utility U = P(benefit AND NOT harm), the most wanted opioid effect, i.e., analgesia without RD, and utility surfaces, which depict the continuum of probabilities of presence or absence of analgesia in combination with the presence or absence of RD. Utility functions are constructed from pharmacokinetic and pharmacodynamic data sets, although pragmatic utility functions may be constructed when pharmacokinetic data are not available. We here discuss utilities of several opioids including the partial mu-opioid-receptor agonist buprenorphine, the full opioid receptor agonists fentanyl and alfentanil, and the bifunctional opioid cebranopadol, which acts at mu-opioid and nociception/orphanin FQ-receptors. We argue that utility functions give clinicians the opportunity to make an informed decision when opioid analgesics are needed for pain relief, in which opioids with a positive utility function are preferred over opioids with negative functions. Furthermore, utility functions of subpopulations will give an extra insight as a utility functions measured in one subgroup (e.g., patients with postoperative pain, good opioid responders) may not be mirrored in other patient subgroups (e.g., neuropathic pain patients, poor opioid responders).

Benefit and Risk Evaluation of Biased μ-Receptor Agonist Oliceridine versus Morphine

“…We developed a utility function that combines various endpoints into a single function allowing objective and precise comparisons among opioid analgesics. [9][10][11][12] Here we report on the comparison of a novel opioid, oliceridine, and morphine. Oliceridine is the first opioid of a new class, so-called biased ligands, that are biased toward the G-protein-coupled transduction pathway with a lesser effect on the β-arrestin pathway, and consequently may produce less respiratory depression.…”

“…9 We have recently developed utility or safety functions of several opioids to capture their contrasting effects into one function. [10][11][12] The utility function is an economic concept from decision theory and has been used in various scientific areas to describe multiple effects of treatment or behavior integrated into a single number or function. [13][14][15] The functions we developed are based on population pharmacokinetic-pharmacodynamic analyses of the opioid concentration-effect relationships.…”

Neuropathic Pain: Challenges and Opportunities

“…Our results indicate an advantage of cebranopadol over classical mu-opioid agonists considering analgesia and respiratory toxicity, most probably related to its activity at the NOP receptor. This is highly relevant given the current opioid epidemic and surge in opioid fatalities [25]. The utility function is a general concept that can be applied to determine the safety of any analgesic considering multiple endpoints [26].…”

“…This is highly relevant given the current opioid epidemic and surge in opioid fatalities [ 25 ]. The utility function is a general concept that can be applied to determine the safety of any analgesic considering multiple endpoints [ 26 ]. For example, in patients with chronic pancreatitis treated with pregabalin, the utility function showed an increase of the probability of analgesia over time relative to the probability of severe dizziness [ 27 ], suggestive that it is worthwhile to maintain pregabalin therapy in this complex patient group despite early onset toxicity.…”

Combining opioids and benzodiazepines: effects on mortality and severe adverse respiratory events

“…Lastly, this review focused on the impact of opioids and benzodiazepines on patient harm (i.e., mortality and severe respiratory adverse events) and we did not specifically review the benefits of the drug combination. This is important, as the chance of benefit versus the chance of harm [i.e., risk/benefit ratio or the utility, see review of Van Dam et al (61)] is always a consideration when prescribing a drug or drug combination for a patient. Our conclusion is that the utility of the opioid-benzodiazepine combination is negative (i.e., the chance of harm is greater than the chance of benefit) for the majority of clinical uses.…”