Vasopressin for Acute Pain

Overseen By Rachel Massalee, MS

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Maryland, Baltimore

Must not be taking: Opiates, Cocaine, Methamphetamines, others

Disqualifiers: Cardiovascular, Neurological, Psychiatric, others

Compensation: Varies

Number of Visits: 2

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you have a history of drug dependence or abuse in the past 3 months, you may not be eligible to participate.

Is vasopressin safe for use in humans?

Vasopressin has been associated with adverse effects, such as cardiovascular issues and seizures, in animal studies. However, in humans, it has been used without increasing mortality in certain conditions like vasodilatory shock after cardiac surgery. ^{1 2 3 4 5}

How is the drug arginine vasopressin unique for treating acute pain?

Arginine vasopressin (AVP) is unique for treating acute pain because it works by increasing the pain threshold through specific brain areas, rather than affecting the spinal cord or peripheral organs, which is different from many other pain treatments. ^{6 7 8 9 10}

What is the purpose of this trial?

The feeling of pain is not just a sensory experience, but is also influenced by emotions, beliefs and expectations, making pain a highly subjective experience. This is evident in clinical practice, where the behavior of the physician and the treatment context can strongly influence the pain experience of patients. Research has shown that patients' expectation that a treatment will reduce pain influences individual perception of pain, even if the treatment has no active ingredient. The expectancy-induced analgesia emerges due to a modulation of the individual pain experience of patients by an engagement of endogenous inhibitory systems in the central nervous system. The development of expectancy-induced analgesia can be generated in several ways. The investigators have previously demonstrated that social information and observational learning (e.g. the patient observes analgesia in another person receiving a treatment) can lead to expectancy-induced analgesia and pain reduction. However, the neural mechanisms (mechanisms in the brain) of how these expectancies are acquired and the neural mechanisms of analgesia induced by observational learning are unknown. The investigators recently established a procedure to investigate neural mechanisms of observational learning in placebo analgesia. Here the investigators propose to investigate the influence of vasopressin, a neurotransmitter that is important for social interaction, on observational learning. The investigators will use functional magnetic resonance imaging (fMRI), a non-invasive method, to investigate neural activity in humans. Participants will either receive vasopressin or saline with a nasal spray. During fMRI scanning, participants will then undergo an observational learning phase, where the study participants will learn the experience of analgesia in another person through a video, and a testing phase, where participants will perceive painful stimulations with the same cues as the observational phase. The comparison of the vasopressin group and the saline group will allow us to investigate how vasopressin influences behavioral effects of observational learning on pain perception as well as its effect on the neural processing of observational learning. A better understanding of how the human brain processes observationally-induced analgesia would allow us to improve the therapeutic context of pain treatments by increasing the contextual factors which help patients cope with pain.

Research Team

Luana Colloca, MD/PHD/MS

Principal Investigator

University of Maryland Baltimore School of Nursing

Eligibility Criteria

This trial is for English-speaking adults aged 18-55 who experience acute pain. It's designed to understand how a neurotransmitter involved in social interactions, vasopressin, affects learning about pain relief from watching others and how this influences personal pain perception.

Inclusion Criteria

I can speak and write in English.

Exclusion Criteria

I have a long-term pain condition or am currently experiencing pain.

Failed drug test (testing for opiates, cocaine, methamphetamines, amphetamines, and THC)

A close family member has had mania, schizophrenia, or psychosis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Observational Learning

Participants observe a video of a demonstrator experiencing analgesia to learn about pain relief through social observation

1 day

1 visit (in-person)

Testing

Participants receive heat pain to investigate how pain perception was influenced by observational learning

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the testing phase

4 weeks

Treatment Details

Interventions

• Arginine Vasopressin

Trial Overview Participants will receive either vasopressin or saline via nasal spray. They'll then watch videos showing others experiencing pain relief during an fMRI scan to see if observing these scenarios can influence their own sensation of pain through learned expectations.

Participant Groups

Group I: Arginine vasopressin Experimental Treatment 3 Interventions

Under direction of a research team member, participants will self-administer intranasal vasopressin shortly before beginning the fMRI experiment. The of AVP will be 40IU. The quantity per unit (1 mL) of Arg8-vasopressin synthetic, manufactured by Polypeptide Group Inc. (http://www.polypeptide.com) was 0.323 mg. This amount was diluted in 0.9% sodium chloride (B. Broun Medical Inc.).

Group II: Saline Placebo Group 3 Interventions

Under direction of a research team member, participants will self-administer intranasal normal saline shortly before beginning the fMRI experiment. Investigators, staff, and participants were blinded to the treatment options. Each of the agents will be administrated by means of a nasal spray. Participants will be instructed by a nurse/PI to self-administer the nasal spray as follows: one spray in each nostril alternating sides, 30 seconds apart for a total of two sprays per nostril.

Who Is Running the Clinical Trial?

University of Maryland, Baltimore

Lead Sponsor

Trials

729

Recruited

540,000+

Findings from Research

In a study involving 16 healthy dogs, arginine vasopressin (AVP) at doses of 0.1 and 1.0 U/kg/min significantly increased mean arterial pressure and systemic vascular resistance, but also led to decreased heart rate and cardiac output, indicating potential cardiovascular risks at higher doses.

The findings suggest that while AVP can effectively raise blood pressure, its use should be carefully monitored in clinical settings, especially at doses above 0.01 U/kg/min, due to the associated negative effects on heart function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Vasopressin intravenous infusion causes dose dependent adverse cardiovascular effects in anesthetized dogs]. Martins, LC., Sabha, M., Paganelli, MO., et al.[2019]

In an in vitro study using cerebellar brain slices from adult rats, vasopressin did not affect the survival rate of Purkinje cells after simulated ischemia-reperfusion, indicating no direct protective or harmful effect on brain injury.

The study tested various concentrations of vasopressin (ranging from 5 to 500 pg/ml) and found no significant differences in cell survival compared to the control group, suggesting that vasopressin may not play a role in mitigating brain injury in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of vasopressin on survival of Purkinje neurons in rat cerebellar slices after an in vitro simulated ischemia. Jeon, YS., Lee, SY., Lee, J., et al.[2019]

The AVP analogue [dPTyr (Me)]AVP effectively blocks the blood pressure-raising effects of exogenous arginine vasopressin (AVP) in conscious rats, demonstrating its potential as a vasopressor antagonist.

In fluid-deprived rats with elevated endogenous AVP levels, administration of the AVP analogue resulted in a significant drop in blood pressure, primarily due to reduced peripheral vascular resistance, indicating its efficacy in modulating vascular responses under certain physiological conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vascular effects of arginine vasopressin during fluid deprivation in the rat. Aisenbrey, GA., Handelman, WA., Arnold, P., et al.[2019]

Administering arginine vasopressin (AVP) directly into the brains of rats led to a rapid decrease in body temperature, indicating a significant physiological effect.

Repeated administration of AVP resulted in increased sensitivity, with the same dose causing convulsions on the second injection and even lower doses (10 ng) triggering seizures, highlighting potential safety concerns with its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Convulsive and hypothermic effects of vasopressin in the brain of the rat. Kasting, NW., Veale, WL., Cooper, KE.[2019]

In a study of 66 cardiac surgical patients, the use of arginine vasopressin (AVP) in addition to norepinephrine did not increase the predicted mortality rates, suggesting it is a safe option for treating vasodilatory shock.

However, patients receiving AVP experienced significantly higher rates of renal complications (36.4% vs. 9.1%) and infections (30.3% vs. 3.0%), indicating potential safety concerns despite its efficacy in managing shock.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vasopressin, when added to norepinephrine, was not associated with increased predicted mortality after cardiac surgery. Suojaranta-Ylinen, RT., Vento, AE., Pätilä, T., et al.[2017]

Intraventricular injections of arginine vasopressin (AVP) significantly increased pain thresholds in rats, indicating its potential role in enhancing antinociception, particularly at doses of 50 or 100 ng.

The study found that AVP's effects on pain modulation are localized to specific brain regions, as pain stimulation altered AVP levels in the hypothalamus but did not affect levels in the pituitary, spinal cord, or serum.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Only through the brain nuclei, arginine vasopressin regulates antinociception in the rat. Yang, J., Song, CY., Liu, WY., et al.[2006]

Arginine vasopressin (AVP) is effective in treating refractory shock conditions, such as severe sepsis and cardiogenic shock, by restoring vasomotor tone and preserving renal blood flow, especially in patients with low plasma levels of AVP.

Low doses of AVP and its analog terlipressin can be beneficial as adjunct vasopressors in advanced shock states that do not respond to traditional treatments, making them a valuable option in critical care settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of vasopressin in current anesthetic practice. Park, KS., Yoo, KY.[2019]

Microinjection of arginine vasopressin (AVP) into the caudate nucleus of rats increased their pain threshold in a dose-dependent manner, indicating its role in reducing pain sensitivity.

The use of an AVP-receptor antagonist reversed the pain-relieving effects of AVP, suggesting that AVP in the caudate nucleus is crucial for its antinociceptive effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Arginine vasopressin in the caudate nucleus plays an antinociceptive role in the rat. Yang, J., Chen, JM., Liu, WY., et al.[2022]

Intranasal administration of arginine vasopressin (AVP) significantly reduced orthopedic pain in patients 2-4 weeks post-surgery, demonstrating a dose-dependent effect based on visual analogue scale (VAS) measurements.

The study, which included 653 orthopedic patients, found that AVP levels in cerebrospinal fluid (CSF) increased after treatment, correlating negatively with pain levels, while not affecting plasma AVP concentrations or vital signs, indicating a safe profile for pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intranasal Vasopressin Relieves Orthopedic Pain After Surgery. Yang, FJ., Ma, L., Yang, J., et al.[2020]

In a study involving 157 ICU patients and 70 healthy volunteers, both copeptin and arginine vasopressin (AVP) levels were significantly higher in critically ill patients, indicating their potential role in assessing the severity of illness.

The copeptin/AVP ratio was notably elevated in patients with sepsis and systemic inflammatory response syndrome (SIRS), suggesting that copeptin may not accurately reflect AVP levels in these conditions, which could impact treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Copeptin and arginine vasopressin concentrations in critically ill patients. Jochberger, S., Morgenthaler, NG., Mayr, VD., et al.[2006]

References

1. Brazil pubmed.ncbi.nlm.nih.gov

[Vasopressin intravenous infusion causes dose dependent adverse cardiovascular effects in anesthetized dogs]. [2019]

2. Korea (South) pubmed.ncbi.nlm.nih.gov

Effect of vasopressin on survival of Purkinje neurons in rat cerebellar slices after an in vitro simulated ischemia. [2019]

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

Vascular effects of arginine vasopressin during fluid deprivation in the rat. [2019]

4. Canada pubmed.ncbi.nlm.nih.gov

Convulsive and hypothermic effects of vasopressin in the brain of the rat. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Vasopressin, when added to norepinephrine, was not associated with increased predicted mortality after cardiac surgery. [2017]

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

Only through the brain nuclei, arginine vasopressin regulates antinociception in the rat. [2006]

7. Korea (South) pubmed.ncbi.nlm.nih.gov

Role of vasopressin in current anesthetic practice. [2019]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Arginine vasopressin in the caudate nucleus plays an antinociceptive role in the rat. [2022]

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

Intranasal Vasopressin Relieves Orthopedic Pain After Surgery. [2020]

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

Copeptin and arginine vasopressin concentrations in critically ill patients. [2006]