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

200 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate opioid dose effects on the ability of the diaphragm muscle to generate higher force behaviors.

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 data supports the effectiveness of the drug Fentanyl for respiratory complications?

Fentanyl is effective in managing breakthrough pain in cancer patients who are already on opioid therapy, as seen with the nasal spray formulation Lazanda. It is also used for conscious sedation during medical procedures, indicating its effectiveness in pain management and sedation. ^{1 2 3 4 5}

Is fentanyl generally safe for human use?

Fentanyl, used in various forms like nasal sprays and patches, has been tested for safety in humans, especially for managing pain in cancer patients. It is important to note that fentanyl is a potent opioid, and its use requires careful management to ensure safety, including appropriate dosing and risk management protocols. ^{1 6 7 8 9}

How does the drug Fentanyl Injection differ from other treatments for respiratory complications?

Fentanyl Injection is unique because it is a powerful opioid pain reliever that works by binding to specific receptors in the brain to reduce pain and can be administered intravenously, allowing for rapid onset of action. This is different from other treatments that may not provide such quick relief or may not be suitable for severe pain management. ^{10 11 12 13 14}

Research Team

Carlos Mantilla, MD, PhD

Principal Investigator

Mayo Clinic

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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 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]

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]

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 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 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]

References

1. United States pubmed.ncbi.nlm.nih.gov

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

2. Netherlands pubmed.ncbi.nlm.nih.gov

"Macrodosing" Sublingual Buprenorphine and Extended-release Buprenorphine in a Hospital Setting: 2 Case Reports. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Drug utilization study on immediate release Fentanyl in Spain. Prevalence, incidence, and indication. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Fentanyl citrate (fentanyl sublimaze). [2013]

5. United States pubmed.ncbi.nlm.nih.gov

Quality of life and cancer pain: satisfaction and side effects with transdermal fentanyl versus oral morphine. [2022]

6. England 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. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Nasal delivery of fentanyl. [2018]

8. Germany 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. [2013]

9. United States pubmed.ncbi.nlm.nih.gov

Prophylactic Fentanyl Sublingual Spray for Episodic Exertional Dyspnea in Cancer Patients: A Pilot Double-Blind Randomized Controlled Trial. [2021]

10. England pubmed.ncbi.nlm.nih.gov

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

11. United States 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. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Distribution of technetium-99m-labelled QVAR delivered using an Autohaler device in children. [2019]

13. United States 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. [2020]

14. United States 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. [2019]