1. IMMPACT-XXI July 26-27, 2018 Washington, DC
  Opioid-sparing clinical trial objectives and outcomes: chronic pain Nathaniel Katz, MD, MS Associate Professor of Anesthesia, Tufts University CEO, Analgesic Solutions
IMMPACT-XXI July 26-27, Washington, DC

2. Scenarios Hypotheses Non-opioid analgesic
Placebo
+ opioid rescue
No opioid or SAO
Patients on analgesic need lower opioid rescue vs.placebo (but have at least as good pain control)
And have lower opioid-related adverse effects
Patients on analgesic can taper off opioids (maintaining good pain control)
And have lower opioid-related adverse effects
Non-opioid analgesic
Placebo
Taper
Opioids
“Better opioids” associated with lower opioid-related adverse effects (and at least as good pain control)
And have lower opioid-related adverse effects
Morphine
Better opioid
“Opioid enhancer” group has lower opioid-related adverse effects (and at least as good pain control)
Opioid enhancer
Placebo
Opioids

3. What did we learn from this?
The concept of “opioid sparing” is meaningless without sustaining pain control
Opioid sparing can be conceived as decreasing the burden of opioid-related adverse effects on patients
This can be accomplished two ways:
PK: Modifying the opioid exposure (dose, change PK profile, get them off)
PD: Altering the pharmacology of the opioid (NME, “enhancer”)
We still need to explicate opioid-related adverse effects
And deal with other conceptual issues

4. Proposed definition of “opioid sparing”:
The implementation of an intervention to reduce the adverse effects of opioids on patients, while maintaining or enhancing pain control, by either decreasing the opioid dose, tapering it off completely, modifying its pharmacokinetic profile, or modifying its pharmacodynamic properties

5. Opioid-Related Adverse Effects
Individual side effects (e.g. nausea, vomiting, dizziness, sedation)
Opioid-related side effects as a whole (a syndrome)
Endocrinopathy
Cardiorespiratory depression (overdose) – fatal, non-fatal
Abuse
Addiction

6. Is “opioid side effects” a syndrome?
Opioid Withdrawal Syndrome:
Nausea
Stomach cramps
Muscle twitching
Feeling cold
Palpitations
Muscle tension
Aches and pains
Yawning
Runny eyes
Insomnia
A group of signs and symptoms that occur together and characterize a particular abnormality or condition
-Merriam-Webster, 2018

7. Yes, opioid side effects is a syndrome
Katz N et al, APS, 2005; Butler et al, J Anesth Clin Res 2012

8. Psychometrics of OSES: items represent one factor
Part of a larger project developing a “Post-Operative Recovery Index”
Content validity established in 97 patients with acute pain and 12 professionals using concept mapping
Conceptual evaluation and item reduction in 48 patients
Testing of alpha version in 106 patients, creation of final version
Cross-validation of final version in 132 patients
22-item OSES developed
Exploratory factor analysis yielded one primary factor (eigen value of 9.21, explaining about 42% of the variance)
Internal consistency of items was satisfactory (coefficient alpha=0.93).
Correlations between the mean of these 22 items and a priori selected comparison measures were high (rs = .75 to .80)
Item-level test-retest analyses indicated all item were stable (test-retest correlations >0.50)
Discriminant validity established between patients who had and had not taken an opioid, and in 3 subsequent RCTs in acute pain
Katz N et al, APS, 2005; Butler et al, J Anesth Clin Res 2012; Inflexxion, data on file

9. Measuring individual side effects
Let’s take SEDATION as an example
Opioid dose
Laboratory tests
EEG?
Single-item instruments:
“How sleepy are you?”
Multi-item instruments:
Eppworth Sleepiness Scale
MOS Sleep Scale
Adverse event capture

10. Measuring the syndrome opioid side effects
Opioid dose
Laboratory tests – not really
Single-item instruments:
“How much are you bothered by side effects of your treatment?”
Multi-item instruments:
OSES
Memorial Symptom Assessment Scale
Adverse event capture

11. Getting more out of AE reports
CLBP
Tapentadol
Oxycodone
Placebo
DAY 1 2 3 5 4 7 6 8
Nausea - moderate
TOLERABILITY
Katz N et al, Pain, 2015; Buynak R et al, Exp Opin Pharmacother, 2010

12.  X Measurement Approaches Opioid-Sparing Domains Opioid dose
Single-symptom questionnaire
Opioid side effects questionnaire
Lab tests
Abuse measure (e.g. MADDERS)
Adverse Events
Individual side effects 
Nausea questionnaire (single or multi-item) X
Opioid-related side effects as a whole
Opioid Side Effects Scale
Endocrinopathy
Sexual function questionnaire
F Testo
Cardiorespiratory depression (overdose)
pO2
Abuse
COMM
UDS
Addiction
SCID

13. Interpretation and Reporting Issues
What if a regimen reduces “opioid adverse effects” but increases some other adverse effects?
What if “opioid side effects” as a whole are reduced, but specific side effects within the syndrome (e.g. dizziness) are increased?
What types of study designs are best suited for opioid sparing?
Are any laboratory tests validated as surrogates for clinical opioid adverse effects, or can they be considered adverse effects alone?
EEG for sedation
pCO2 for respiratory depression
Testosterone levels for hypogonadism
Urine drug screening for abuse/addiction

14. Summary
Patients suffer from a variety of types of adverse effects of opioids
Interventions to reduce these effects, such as adding non- opioid analgesics to reduce opioid doses, modifying PK profiles, improved opioid NMEs, and opioid enhancers, could benefit patients, if pain intensity is accounted for
A variety of approaches are available to measure these benefits in clinical trials, each with strengths and limitations
Identifying and remediating gaps in available measures for these constructs would help advance this research agenda

15. Discussion???