Melatonin for Postoperative Pain

(SLOPE Trial)

Overseen By Stuti J Jaiswal, MD PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Scripps Health

Must not be taking: Prescription sleep aids, Chronic opioids

Disqualifiers: Non-English, Dementia, Liver cirrhosis, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

120 Participants Needed

Trial Summary

What is the purpose of this trial?

Prescription opioid misuse and its associated negative effects have become an epidemic in the United States, and post-operative opioid use contributes to this terrible problem. Alternative strategies to opioid prescribing are thus highly sought after in the post-operative setting. Importantly, sleep and pain have a bi-directional relationship, and inadequate or impaired sleep regularly occur following orthopedic operations. Melatonin is an endogenous sleep hormone that can be administered exogenously, and that has been shown to have some potential as an analgesic agent. Here, using the premise that melatonin may improve sleep and pain in the post-operative setting, the investigators propose a randomized clinical trial in 120 participants undergoing total knee arthroplasties. Patients will be randomized to receive either sublingual melatonin 5 mg or matched placebo starting on post-operative day (POD) 0 and through POD . The investigators will measure post-operative opioid usage as the primary outcome, and post-operative pain scores as a secondary outcome. The primary safety outcome will be sedation level, as measured by the Richmond Agitation Sedation Scale (RASS). Sleep will be measured objectively using wrist-worn actigraphy. Participants will be followed through POD 28, and will also have baseline data on sleep, pain, and cognition obtained prior to surgery.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently taking prescription sleep aids or have been using opioids long-term.

What data supports the effectiveness of the drug melatonin for postoperative pain?

Research shows that melatonin may help reduce anxiety before surgery and has some potential to lessen pain after surgery, but the results are mixed and not conclusive. More high-quality studies are needed to confirm its effectiveness for pain relief after surgery. ^{1 2 3 4 5}

Is melatonin safe for use in humans?

Melatonin is generally considered safe for short-term use in humans, with low toxicity reported in studies. However, there is a lack of long-term safety data, and its effects during pregnancy or interactions with other medications are not well-studied. It is important to use licensed preparations under controlled conditions. ^{1 6 7 8 9}

How does the drug melatonin differ from other treatments for postoperative pain?

Melatonin is unique for postoperative pain management because it not only helps reduce pain but also has calming effects, reducing anxiety and improving patient cooperation. Unlike traditional painkillers, melatonin has sedative and antioxidative properties, and it can be administered sublingually (under the tongue) for effective pain relief after surgery. ^{1 6 9 10 11}

Research Team

Stuti Jaiswal, MD PhD

Principal Investigator

Scripps Clinic Medical Group

Eligibility Criteria

This trial is for adults over 18 who are having knee replacement surgery. It's not suitable for those undergoing other types of surgeries or treatments.

Inclusion Criteria

I am scheduled for a knee replacement surgery on one knee.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either sublingual melatonin 5 mg or matched placebo nightly for 29 nights starting on post-operative day 0

4 weeks

Daily administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, including opioid usage, pain scores, and sleep metrics

4 weeks

Treatment Details

Interventions

• Melatonin

Trial Overview The study tests if melatonin can help with sleep and pain after knee surgery, comparing it to a placebo. Patients will take the treatment from the day of surgery until post-operative day 28, tracking opioid use and pain levels.

Participant Groups

Group I: Melatonin Active Control 1 Intervention

Melatonin 5 mg sublingual nightly x 29 nights, starting on post-operative day 0.

Group II: Placebo Placebo Group 1 Intervention

Placebo troche, sublingual nightly x 29 nights, starting on post-operative day 0.

Melatonin is already approved in European Union, United States for the following indications:

Approved in European Union as Circadin for:

• Insomnia in adults aged 55 and over
• Sleep disorders in children with autism spectrum disorder

Approved in European Union as Slenyto for:

• Insomnia in children and adolescents aged 2-18 with autism spectrum disorder

Approved in United States as Melatonin for:

• Sleep disorders in children with autism spectrum disorder
• Insomnia in adults

Who Is Running the Clinical Trial?

Scripps Health

Lead Sponsor

Trials

59

Recruited

43,400+

Findings from Research

Melatonin is effective in reducing preoperative anxiety in adults, as shown in 9 out of 10 studies reviewed, making it a promising alternative premedicant.

The analgesic effects of melatonin are less clear, with mixed results in studies regarding its ability to reduce pain or opioid use during the perioperative period, indicating a need for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of melatonin as an anxiolytic and analgesic in the perioperative period: a qualitative systematic review of randomized trials. Yousaf, F., Seet, E., Venkatraghavan, L., et al.[2022]

Melatonin has shown significant analgesic and anxiolytic effects in surgical patients, with reductions of 20 mm and 19 mm on a pain scale compared to placebo, based on a systematic review of randomized studies.

However, a specific study using a human burn model found no significant analgesic effects of exogenous melatonin compared to placebo, indicating that while melatonin may be effective in some contexts, its efficacy in humans remains inconsistent and requires further high-quality research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The analgesic effects of exogenous melatonin in humans. Andersen, LP.[2022]

This study will investigate the effects of 2 mg of oral melatonin (Circadin) on sleep disturbance and pain intensity in 60 adults with severe chronic pain lasting at least 3 months, using a randomized double-blind placebo-controlled cross-over design over 20 weeks.

The primary outcome is sleep disturbance, while secondary outcomes include pain intensity and various sleep measures, allowing for a comprehensive assessment of melatonin's potential analgesic and sleep-improving effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II double-blind randomised controlled trial of exogenous administration of melatonin in chronic pain (DREAM-CP): a study protocol. Adam, R., Kanakarajan, S., Onyeakazi, U., et al.[2021]

Melatonin can effectively improve sleep and adjust circadian rhythms when taken at the right times, helping with issues like jet lag and shift work, but its effectiveness is closely related to the timing and dosage.

While melatonin is generally safe for short-term use in healthy adults, there is a lack of long-term safety data, and its use should be carefully managed to avoid potential negative effects, especially with unregulated preparations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of circadian rhythm disorders--melatonin. Arendt, J., Deacon, S.[2019]

Melatonin has natural analgesic properties that are most effective at night, aligning with its circadian rhythm, which could explain why patients report less pain and need fewer painkillers during nighttime.

Future research may focus on developing melatonin analogues that enhance pain relief without the addiction risks associated with traditional opioids, potentially offering a safer alternative for pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pineal opioid receptors and analgesic action of melatonin. Ebadi, M., Govitrapong, P., Phansuwan-Pujito, P., et al.[2019]

In a study of 60 patients undergoing colorectal surgery, preoperative administration of 6 mg sublingual melatonin significantly reduced postoperative pain severity compared to a placebo, particularly at 2, 6, 12, and 24 hours after surgery.

Patients receiving melatonin also exhibited higher levels of cooperation and calmness post-surgery, suggesting that melatonin not only alleviates pain but may also help reduce anxiety and improve overall patient experience.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of Preoperative Sublingual Melatonin on Postoperative Pain Severity in Patients Undergoing Colorectal Surgery: A Triple-Blinded Randomized Trial. SaberMoghaddam, M., Sheybani, S., Bakhtiari, E., et al.[2022]

References

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

Efficacy and safety of melatonin as an anxiolytic and analgesic in the perioperative period: a qualitative systematic review of randomized trials. [2022]

2. Denmark pubmed.ncbi.nlm.nih.gov

The analgesic effects of exogenous melatonin in humans. [2022]

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

Absence of analgesic effect of intravenous melatonin administration during daytime after laparoscopic cholecystectomy: a randomized trial. [2022]

4. Japan pubmed.ncbi.nlm.nih.gov

Effects of preoperative oral melatonin medication on postoperative analgesia, sleep quality, and sedation in patients undergoing elective prostatectomy: a randomized clinical trial. [2021]

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

Impact of Melatonin on Sleep and Pain After Total Knee Arthroplasty Under Regional Anesthesia With Sedation: A Double-Blind, Randomized, Placebo-Controlled Pilot Study. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Phase II double-blind randomised controlled trial of exogenous administration of melatonin in chronic pain (DREAM-CP): a study protocol. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Treatment of circadian rhythm disorders--melatonin. [2019]

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

Study on the preventive effect of ramelteon on the onset of sleep disorder after general anesthesia in patients with autism spectrum disorder: A study protocol. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Pineal opioid receptors and analgesic action of melatonin. [2019]

10. Iran pubmed.ncbi.nlm.nih.gov

The Effect of Preoperative Sublingual Melatonin on Postoperative Pain Severity in Patients Undergoing Colorectal Surgery: A Triple-Blinded Randomized Trial. [2022]

11. China pubmed.ncbi.nlm.nih.gov

[Effects of the pineal body and melatonin on sensitivity to pain in mice]. [2013]