Developing a Method to Objectively Measure Opioid Analgesia

It is generally recognized that pain assessment and management in newborns and children is an
unmet need. The Center for Disease Control found that in 2012, healthcare providers wrote 259
million prescriptions for opioid painkillers contributing to an epidemic of over
prescription. At the same time, medical professionals still see large amounts of pain left
untreated, particularly in pediatric populations. Children are often given minimal or no
analgesia for procedures that are treated much more aggressively in adults. This issue stems
from the lack of an effective method of assessing and monitoring patient analgesia. Recently
attempts have been made to objectively quantify pain but as of now, no effective standard
exists. This pilot study utilizes pupillary reflexes to characterize opioid analgesia in
pediatrics with the purpose of synthesizing the data into algorithms that detect specific
conditions and provide decision support.

Pupillometry is a useful, non-invasive clinical and research tool that can provide valuable
insights into the autonomic nervous system. Pupillary tests provide a convenient and simple
method for evaluation of autonomic function4. In normal pupillary responsiveness, pupils
should be equal in size, approximately 3-4mm in size under average light conditions, and
reactive to light at >1mm of movement. The sympathetic nervous system is activated during
periods of pain and stress and creates relaxation of the ciliary muscles resulting in
pupillary dilation, or mydriasis. In accommodation, the parasympathetic axons that innervate
the iris muscle produce constriction, or miosis. This reflex is known as the pupillary reflex
dilation (PRD) and has been shown in previous studies to occur in both awake and anesthetized
participants following a noxious stimulus5. This protocol will utilize these known reactions
to track the response to specific neurostimulation in participants receiving opioids to
determine the effect and effectiveness of the treatment.

All mu opioid agonists cause miosis (constriction of the pupil) thus reducing the
constriction amplitude and constriction velocity of the pupillary light reflex (PLR). This is
the one opioid side effect to which tolerance does not occur. However, the pharmacologic
impact is not consistent and will vary with different drugs in the class and duration of
exposure. For example, morphine and Dilaudid (hydromorphone) each produce a neuro-excitatory
metabolite that causes mydriasis or dilation of the pupil and also antagonizes the parent
drug, producing the clinical appearance of tolerance, requiring more drug to achieve the same
effect. With other drugs of this class such as fentanyl, which is commonly administered in
ICUs, mydriasis may occur due to a phenomenon called opioid induced hyperalgesia (OIH) where
there is an increased sensitivity to pain, often leading to an increased dose of drug.
Increasing the dosing in this situation can potentially exacerbate the issue, having a method
to monitor for OIH would provide decision support to physicians and allow them to recognize
and properly reconcile this issue. Evaluation of PRD in response to a 5 Hz neuro-stimulus can
differentiate between these drug-related issues and disease progression. This works because
opioid receptors populate the C fibers, which are stimulated with a 5 Hz frequency6,7,
allowing the investigators to determine dose response relationships as well as the optimized
analgesic dose and precisely determine dosing with opioid rotation. This occurs empirically
during standard of care based on a trial and error approach that risks under or overdosing
patients and having tolerance, dependence and OIH occur.

This pilot study is part of an ongoing effort to develop a method to objectively assess pain
and its response to specific interventions. It specifically aims to develop profiles of the
impact of a variety of opioids under a variety of conditions in a diverse patient population.
It will allow researchers to understand better the specific impact of drugs in this class on
the PLR and PRD. Data collected herein will help will evaluate the feasibility of using this
approach to detect and monitor opioid analgesia and open new avenues for future research in
this area.

1. Pain assessment and baseline testing

2. Standardized care where patient receives opioid dose per clinical team.

3. Testing pupillary reflexes at regular intervals and repeated pain assessments

Inclusion Criteria:

1. The subject is 7 to 21 years of age

2. The subject is receiving an opioid via bolus or a patient controlled analgesia (PCA)
apparatus as part of treatment or fentanyl infusion in the pediatric intensive care
unit (PICU) (generally postoperative patients).

3. The subject is willing and able to provide written informed assent/parental consent to
study participation

Exclusion Criteria:

1. Eye pathology precluding pupillometry

2. For patients in the PICU, patients who are hemodynamically unstable