Opioid Exposure for Respiratory Complications

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Mayo Clinic

Disqualifiers: Pregnancy, Pulmonary pathology, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 hour

69 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how different doses of the painkiller fentanyl affect the diaphragm muscle, which aids in breathing. The researchers aim to determine if varying doses of fentanyl alter diaphragm performance during breathing tasks. Participants will receive different doses of fentanyl as part of their surgical care, and a special ultrasound will assess their diaphragm function. Individuals undergoing lower leg or hip surgeries at specific hospitals, who do not have lung issues like asthma, might be suitable for this trial. As a Phase 4 trial, this research seeks to understand how this FDA-approved and effective treatment can benefit more patients.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What is the safety track record for Fentanyl Injection?

Research shows that fentanyl, the treatment in this study, affects breathing by acting on the brain's breathing centers, especially at higher doses. However, studies have found that low doses used during procedures like spinal anesthesia do not clearly establish a risk of serious breathing problems.

As this study is in Phase 4, fentanyl has already received approval for use in other situations, indicating that its safety is fairly well understood. Nonetheless, caution remains important because fentanyl can cause serious side effects, such as breathing issues. Participants should be aware of these risks and discuss any concerns with the study team. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about this trial because it explores how different doses of opioids, specifically fentanyl, affect respiratory function during surgery using a technique called ultrasound shear wave elastography. This method allows doctors to visualize how tissues respond to opioids by measuring their stiffness, which could lead to better understanding and management of respiratory complications. Unlike traditional methods that might rely on indirect or invasive measurements, this approach provides real-time, non-invasive insights into how breathing techniques can mitigate these complications. Ultimately, the findings could improve safety and outcomes for patients undergoing surgeries requiring opioid administration.

What evidence suggests that this trial's treatments could be effective for respiratory complications?

Research has shown that fentanyl effectively reduces pain, particularly after surgery. Studies have found that it significantly lessens the need for other pain medications and improves overall pain management. However, fentanyl can also slow breathing, posing a danger at higher doses. This trial will examine the effects of different fentanyl doses on respiratory function. Participants will receive low, mid, or high doses of opioids during elective lower extremity orthopedic surgery and will undergo ultrasound shear wave elastography examinations while performing various breathing techniques. Understanding these effects is crucial when considering fentanyl for pain and breathing issues. ^{3 6 7 8 9}

Who Is on the Research Team?

Carlos Mantilla, MD, PhD

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for adult men and women who are having lower limb orthopedic surgery at St. Mary Hospital or Rochester Methodist within the Mayo Clinic in Rochester. It's not for those with lung conditions like COPD or asthma, anyone who doesn't want to participate in research, or pregnant individuals.

Inclusion Criteria

I am an adult having leg surgery at St. Mary or Rochester Methodist Hospital.

Exclusion Criteria

I do not want to participate in research studies.

I have a lung condition like COPD or asthma that needs regular treatment.

Pregnant patients

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo ultrasound shear wave elastography examination while performing different breathing techniques after being administered varying doses of opioids during surgery

1 hour

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Fentanyl Injection

Trial Overview The study is looking into how different doses of an opioid called Fentanyl affect the diaphragm muscle's ability to work harder and generate force during breathing, especially after surgery.

How Is the Trial Designed?

Group I: Ultrasound Shear Wave Elastography Examination - Mid Experimental Treatment 1 Intervention

Subjects identified as being administered mid dose opioids during an elective lower extremity orthopedic surgery per standard of care will undergo an ultrasound shear wave elastography examination while performing different breathing techniques.

Group II: Ultrasound Shear Wave Elastography Examination - Lower Experimental Treatment 1 Intervention

Subjects identified as being administered low dose opioids during an elective lower extremity orthopedic surgery per standard of care will undergo an ultrasound shear wave elastography examination while performing different breathing techniques.

Group III: Ultrasound Shear Wave Elastography Examination - Higher Experimental Treatment 1 Intervention

Subjects identified as being administered higher dose opioids during an elective lower extremity orthopedic surgery per standard of care will undergo an ultrasound shear wave elastography examination while performing different breathing techniques.

Fentanyl Injection is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Fentanyl for:

• Severe pain during and after surgery
• Breakthrough cancer pain
• Chronic pain management

Approved in European Union as Fentanyl for:

• Severe pain during and after surgery
• Breakthrough cancer pain
• Chronic pain management

Approved in Canada as Fentanyl for:

• Severe pain during and after surgery
• Breakthrough cancer pain
• Chronic pain management

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Published Research Related to This Trial

In a study of 16 asthmatic children aged 5-14 years, QVAR inhalation resulted in significantly higher lung deposition of the medication compared to other aerosol delivery systems, with lung deposition rates reaching up to 54.1% in older children.

The study found that lung deposition of QVAR positively correlated with lung function measures (FEV1 and FVC), while gastrointestinal deposition negatively correlated with these measures, indicating that effective lung delivery is crucial for therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Distribution of technetium-99m-labelled QVAR delivered using an Autohaler device in children. Devadason, SG., Huang, T., Walker, S., et al.[2019]

The new TAA-HFA 225 formulation demonstrated similar safety and efficacy to the existing TAA-CFC aerosol in treating moderate-to-severe persistent asthma, based on a study involving 538 patients over 12 weeks.

Both TAA-HFA and TAA-CFC significantly improved pulmonary function and reduced asthma symptoms compared to placebo, with benefits observed within just one week of treatment, making TAA-HFA a viable and environmentally friendly alternative.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo-controlled, comparative study of the efficacy and safety of triamcinolone acetonide inhalation aerosol with the non-CFC propellant HFA-134a in patients with asthma. Azmacort HFA Clinical Study Group. Jacobson, K., Chervinsky, P., Noonan, M., et al.[2019]

The FDA has approved a new nasal spray formulation of fentanyl, called Lazanda-Archimedes, specifically for managing breakthrough pain in adult cancer patients who are already tolerant to opioid therapy.

This approval adds to the existing forms of fentanyl available in the US, which include intravenous, intrathecal, epidural, transdermal, and oral transmucosal options, providing more flexibility in pain management for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fentanyl nasal spray (Lazanda) for pain. [2013]

In a study involving 30 cancer patients, a high dose of fentanyl sublingual spray (FSS) significantly reduced exertional dyspnea and increased walking distance compared to baseline, indicating its efficacy in managing breathlessness.

The low dose of FSS showed a nonsignificant reduction in dyspnea but still improved walking distance, suggesting that while both doses are tolerated, the high dose may provide better symptom relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prophylactic Fentanyl Sublingual Spray for Episodic Exertional Dyspnea in Cancer Patients: A Pilot Double-Blind Randomized Controlled Trial. Hui, D., Hernandez, F., Larsson, L., et al.[2021]

The study demonstrated that the single-dose delivery system (SDS) of intranasal fentanyl spray (INFS) is pharmacokinetically bioequivalent to the multi-dose delivery system (MDS), with similar peak plasma concentrations and overall drug exposure in 48 healthy subjects.

Both delivery systems showed consistent safety profiles, with no safety concerns identified when INFS was administered alongside oral naltrexone to prevent adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-dose and multi-dose delivery systems for intranasal fentanyl spray are bioequivalent as demonstrated in a replicate pharmacokinetic study. Nave, R., Connolly, SM., Popper, L., et al.[2013]

High-dose sublingual buprenorphine/naloxone effectively stabilized two fentanyl users in the emergency department, quickly resolving their withdrawal symptoms without causing sedation or precipitated withdrawal.

Transitioning these patients to extended-release buprenorphine within 24 to 36 hours may enhance retention rates in outpatient treatment, suggesting a promising new approach for managing opioid dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

"Macrodosing" Sublingual Buprenorphine and Extended-release Buprenorphine in a Hospital Setting: 2 Case Reports. Kahan, M., Marion-Bellemare, L., Samson, J., et al.[2023]

Ciclesonide administered as an HFA nasal aerosol (CIC-HFA) and as an aqueous nasal spray (CIC-AQ) resulted in significantly lower systemic exposure of its active metabolite, desisobutyryl ciclesonide, compared to the HFA metered dose inhaler (CIC HFA-MDI), with CIC-HFA showing 10-fold lower and CIC-AQ at least 40-fold lower exposure.

All formulations of ciclesonide were well tolerated by participants, with mild adverse events occurring in only 30% of the 30 volunteers, indicating a favorable safety profile for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of ciclesonide and desisobutyryl ciclesonide after administration via aqueous nasal spray or hydrofluoroalkane nasal aerosol compared with orally inhaled ciclesonide: an open-label, single-dose, three-period crossover study in healthy volunteers. Nave, R., Herzog, R., Laurent, A., et al.[2019]

The exhalation delivery system Xhance® delivers fluticasone propionate more effectively to the nasal cavity compared to conventional nasal sprays like Flonase®, resulting in higher systemic exposure with lower risk of drug loss through drip-out or swallowing.

In a study involving 90 healthy subjects and 30 asthma patients, Xhance® showed significantly higher peak drug levels (Cmax) than Flonase® at similar doses, indicating its potential for improved efficacy, while still maintaining low systemic exposure compared to inhalational aerosols like Flovent® HFA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Comparison of the Pharmacokinetics and Bioavailability of Fluticasone Propionate Delivered via Xhance Exhalation Delivery System Versus Flonase Nasal Spray and Flovent HFA Inhalational Aerosol. Messina, JC., Offman, E., Carothers, JL., et al.[2020]

The 12 microg/h fentanyl transdermal patch was effective in treating moderate to severe pain over a 28-day trial with 227 patients, showing significant improvement in pain levels and overall therapy assessments.

The safety profile of the lower dose patch was comparable to higher doses, with no unexpected adverse events and a lower drop-out rate, making it particularly suitable for elderly or opioid-naïve patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase III study to assess the clinical utility of low-dose fentanyl transdermal system in patients with chronic nonmalignant pain. Otis, J., Rothman, M.[2013]

Intranasal fentanyl is rapidly absorbed and offers a promising method for pain management, particularly for breakthrough pain in cancer patients, with advantages over oral forms such as faster onset and easier administration.

New formulations of fentanyl nasal sprays, like PecFent and Instanyl, are designed to minimize runoff and improve absorption, making them more effective while also requiring lower volumes for effective dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nasal delivery of fentanyl. Watts, P., Smith, A., Perelman, M.[2018]

Fentanyl is a synthetic opioid commonly used for conscious sedation during endoscopic procedures, providing effective pain relief and patient cooperation.

It is often preferred over meperidine when combined with droperidol and midazolam to create a state of neuroleptanesthesia, enhancing the safety and efficacy of the sedation process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fentanyl citrate (fentanyl sublimaze). Claussen, DS.[2013]

The transition from chlorofluorocarbons (CFCs) to hydrofluoroalkanes (HFAs) in aerosol propellants has allowed for better design of inhalers, enhancing the delivery of asthma medications to both small and large airways.

The aerosol system using beclomethasone dipropionate in HFA propellant (Qvar) aims to improve the therapeutic ratio, meaning it seeks to maximize the effectiveness of the medication while minimizing systemic side effects for asthma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing drug delivery to the lung: design of a CFC-free corticosteroid metered-dose aerosol system. Donnell, D.[2019]

The use of immediate release fentanyl (IRF) in Spain significantly increased from 2.1 to 3.8 Defined Daily Doses per 10,000 inhabitants between 2012 and 2017, indicating a growing trend in opioid consumption.

Notably, 27% of new IRF users did not have a diagnosis of breakthrough cancer pain or cancer, with many having musculoskeletal disorders, raising concerns about potential misuse and dependence in non-cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug utilization study on immediate release Fentanyl in Spain. Prevalence, incidence, and indication. González-Bermejo, D., Rayón-Iglesias, P., Rodríguez-Pascual, A., et al.[2021]

In a study of 504 advanced cancer patients, those using transdermal fentanyl reported higher overall satisfaction with their pain management compared to those using sustained-release oral morphine.

Patients on transdermal fentanyl experienced significantly fewer and less impactful side effects from their pain medication, which may contribute to their greater satisfaction, despite being older and having lower functioning and well-being scores.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of life and cancer pain: satisfaction and side effects with transdermal fentanyl versus oral morphine. Payne, R., Mathias, SD., Pasta, DJ., et al.[2022]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S000709121930008X

Opioid-induced respiratory depression in humans: a review ... The authors provide a detailed overview of opioid-induced respiratory depression with reference to pharmacokinetic/pharmacodynamic (PKPD) modelling.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7864237/

Multi-Level Regulation of Opioid-Induced Respiratory ... Opioids depress minute ventilation primarily by reducing respiratory rate. This results from direct effects on the preBötzinger Complex as well as from ...

3. purduepharma.com purduepharma.com/news/2024/10/28/new-study-explores-nalmefene-and-naloxone-for-reversal-of-respiratory-depression-induced-by-fentanyl-in-a-clinical-opioid-induced-respiratory-depression-model/

New Study Explores Nalmefene and Naloxone for Reversal of ... Nalmefene (1 mg) reversed fentanyl-induced respiratory depression similar to or better than IM naloxone and intranasal (IN) naloxone.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/16764215/

Opioid-induced respiratory effects: new data on ... Fentanyl produced dose-dependent depression of respiration with apnoea at doses > or = 3 microg/kg, while buprenorphine caused depression that levelled at ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0104001421004097

Safety and effectiveness of adding fentanyl or sufentanil to ... Spinal fentanyl and sufentanil significantly reduced postoperative pain and opioid consumption, increased analgesia and pruritus.

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK470415/

Opioid Toxicity - StatPearls - NCBI Bookshelf Naloxone should be administered immediately when an opioid overdose is suspected as the cause of respiratory and CNS depression, without delay ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2011/022510s000lbl.pdf

ABSTRAL® (fentanyl) sublingual tablets CII - accessdata.fda.gov Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves both a reduction in the ...

8. publications.ersnet.org publications.ersnet.org/content/erj/48/3/683

Incident opioid drug use and adverse respiratory outcomes ... The purpose of this study was to evaluate the association of new opioid use with the risk of adverse respiratory outcomes among older adults with COPD.

9. mayoclinic.org mayoclinic.org/drugs-supplements/fentanyl-transdermal-route/description/drg-20068152

Fentanyl (transdermal route) - Side effects & dosage May increase risk for more serious side effects. Asthma, acute or severe or; Respiratory depression (serious breathing problem) or; Short-term ...