Digital pill biosensors for monitoring opioid medication use

In a research paper published in the Anesthesia & Analgesia, Brigham and women’s hospital investigators report on the results from a pilot study of 15 individuals who received a prescription to take oxycodone digital pills as needed following treatment for acute fractures.

Recently first digital pill was approved by the FDA for use with the antipsychotic drug Abilify, used to treat schizophrenia, bipolar disorder and depression. Opioids such as oxycodone are frequently prescribed on an as-needed basis for managing acute conditions, but uncertainty exists around how patients take the prescribed drug. Digital pills may offer a unique window into patterns of medication usage.

To conduct their pilot study, the investigators approached 26 individuals in the Emergency Department who had been diagnosed with an acute fracture. (Fifteen completed the study.) The team instructed participants to use oxycodone (one to two 5-mg oxycodone digital pills every six to eight hours) as needed for pain. Unused pills were returned after seven days.

The team used the eTectRx ID-Cap system. Each pill in the system consists of a unique radiofrequency emitter and a standard gelatin capsule containing an oxycodone tablet. When the capsule dissolves, the medication is released, and chloride ions energize the emitter. The patient wears a sticky patch on their abdomen, attached to a cable reader (the size of an iPod) that stores data about pill ingestion. (Since the study was conducted, advances in the technology have miniaturized the reader and added steps to validate the user of the system and provide directed feedback through a smartphone app.)

The digital pill system recorded a total of 112 ingestion events, compared to 134 ingestions based on pill count (84 percent accuracy). However, all missed ingestion events were traced back to two study participants who ingested digital pills without wearing the reader or did not interact with the reader due to severe pain. Most oxycodone doses were ingested within the first three days after discharge. On average, patients ingested only six pills, despite being given 21.

Citation: Chai, Peter R., Stephanie Carreiro, Brendan J. Innes, Brittany Chapman, Kristin L. Schreiber, Robert R. Edwards, Adam W. Carrico, and Edward W. Boyer. “Oxycodone Ingestion Patterns in Acute Fracture Pain With Digital Pills.” Anesthesia & Analgesia 125, no. 6 (2017): 2105-112.
doi:10.1213/ane.0000000000002574
Funding: National Institutes of Health
Adapted from press release by Brigham And Women’s Hospital.

Research in mice shows molecular mechanism underlying Oxycodone addiction

RGS9-2, a key signaling protein in the brain known to play a critical role in the development of addiction-related behaviors, acts as a positive modulator of oxycodone reward in both pain-free and chronic pain states, according to a study conducted at the Icahn School of Medicine at Mount Sinai and published in the journal Neuropsychopharmacology. The mechanisms of oxycodone action uncovered through this study will help scientists and physicians develop strategies and tools to dissociate the analgesic (pain relief) actions of opioids from the addiction-related effects.

Pixabay images

Using mouse models of acute and chronic pain, Mount Sinai researchers found that RGS9-2, the intracellular protein that controls the function of opioid receptors in the brain reward center, promotes addiction to oxycodone in pain-free, acute, and chronic pain states. Mice that lacked the gene responsible for encoding RGS9-2 (RGS9KO mice) showed less propensity to develop addiction-related behaviors. Furthermore, the loss of RGS9-2 function does not affect the acute analgesic effects of oxycodone. The research team also found that RSG9-2 plays a protective role towards the development of oxycodone tolerance, as RGS9KO mice became tolerant to the analgesic effects of the drug earlier than those that had the gene. Researchers found that the same mechanisms control sensitivity to oxycodone addiction in pain-free as well as chronic pain states.

Oxycodone is a painkiller that is widely prescribed for acute and chronic pain conditions and is also among the most abused opioids. Oxycodone acts on the same brain receptors as morphine and heroin, the mu opioid receptors, which are present in many areas of the brain that mediate pain relief but are also expressed in the brain network associated with addiction. While there has been an extensive investigation into the mechanisms underlying the analgesia, dependence, and addiction potential of morphine, the mechanism by which oxycodone exerts its actions remained unknown.

“Although oxycodone produces similar analgesic and behavioral effects to those observed with morphine, our study demonstrates that the intracellular actions of morphine and oxycodone are distinct,” says Venetia Zachariou, Ph.D., Associate Professor in the Fishberg Department of Neuroscience and The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai. “Our work reveals that intracellular factors that prevent the actions of morphine may actually promote the actions of oxycodone. This information is particularly important for pain management strategies, as a common course is to have patients oscillate between oxycodone and morphine to achieve pain relief.”

This study provides new information on pathways involved in behavioral responses to oxycodone in pain-free and neuropathic pain states, which will help researchers and clinicians to determine the risks and benefits of oxycodone prescription for the treatment of pain. This knowledge may lead to the development of more efficacious and less addictive compounds for pain management.

Citation: Sevasti Gaspari, Valeria Cogliani, Lefteris Manouras, Ethan M Anderson, Vasiliki Mitsi, Kleopatra Avrampou, Fiona B Carr and Venetia Zachariou. “RGS9-2 Modulates Responses to Oxycodone in Pain-Free and Chronic Pain States.” Neuropsychopharmacology 2017.
DOI: 10.1038/npp.2017.4
Research funding: National Institute of Neurological Disorders and Stroke
Adapted from press release by The Mount Sinai Hospital.

Research uncovers link between long-term opioid use and preexisting psychiatric and behavioral disease

A wide range of pre-existing psychiatric and behavioral conditions and the use of psychoactive drugs could be important risk factors leading to long-term use of opioid pain medications, reports a study in Journal Pain, the official publication of the International Association for the Study of Pain (IASP).

long term opioid addiction

Using a nationwide insurance database, the researchers identified 10.3 million patients who filed insurance claims for opioid prescriptions between 2004 and 2013. The study looked at whether pre-existing psychiatric and behavioral conditions and use of psychoactive medications were predictors of later opioid use.

“We found that pre-existing psychiatric and behavioral conditions and psychoactive medications were associated with subsequent claims for prescription opioids,” write Patrick D. Quinn, Ph.D., of Indiana University, Bloomington, and colleagues. The association appears stronger for long-term opioid use, and especially for patients with a previous history of substance use disorders.

The results also suggest that some outcomes viewed as harmful outcomes of opioid use substance use disorders, depression, suicidal or self-injuring behavior, and motor vehicle crashes are also predictors of which patients are at risk of long-term use of prescription opioids.

Overall, the results suggested a “modest” increase in any opioid prescriptions for patients with previous psychiatric or behavioral conditions (depression or anxiety disorders, opioid or other substance use disorders, suicide attempts or other self-injury, motor vehicle crashes, and sleep disorders) or use of psychoactive medications.

About 1.7 percent of patients with opioid prescriptions become long-term opioid users (six months or longer). But the risk became substantially higher for patients with mental health conditions or psychoactive medication use. Relative increases in rates of long-term opioid use ranged from 1.5 times for patients taking medications for attention-deficit/hyperactivity disorder, to about 3 times for those with previous substance use disorders other than opioids, to nearly 9 times for those with previous opioid use disorders.

Amid the continuing opioid epidemic, it’s important to understand which patients select (or are selected for) treatment with these pain medications. Previous studies have suggested a pattern of “adverse selection”: patients at greatest risk of harmful outcomes, including those with substance abuse and other psychiatric conditions, may be more likely to be prescribed opioids in higher doses and for longer durations.

Dr. Quinn and coauthors conclude: “Our findings support the ideas that clinical practice has deviated from the ‘careful selection’ under which most clinical trials are conducted and that thorough mental health assessment and intervention should be considered in conjunction with the use of long-term opioid therapy.

Citation: Quinn, Patrick D., Kwan Hur, Zheng Chang, Erin E. Krebs, Matthew J. Bair, Eric L. Scott, Martin E. Rickert, Robert D. Gibbons, Kurt Kroenke, and Brian M. D’onofrio. “Incident and long-term opioid therapy among patients with psychiatric conditions and medications: a national study of commercial health care claims.” Pain 158, no. 1 (2017): 140-148.
DOI: 10.1097/j.pain.0000000000000730
Adapted from press release by Wolters Kluwer publications.