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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether melatonin (also known as Circadin, Slenyto, or PedPRM) can reduce pain and the need for opioids after knee surgery. By improving sleep, melatonin might also lessen post-surgery pain, offering a safer alternative to opioid medications. Participants will be divided into two groups, receiving either melatonin or a placebo for 29 nights following their surgery. The trial seeks individuals who are about to undergo knee replacement surgery and do not regularly use opioids or prescription sleep aids. As an unphased trial, this study provides a unique opportunity to contribute to research that could enhance post-surgery recovery and reduce reliance on opioids.

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.

Is there any evidence suggesting that melatonin is likely to be safe for humans?

Research shows that melatonin is generally safe for short-term use in people. Studies have found that a 5 mg dose of melatonin before surgery can effectively and safely reduce postoperative pain. This is the same dose tested in the trial. Melatonin has low toxicity, making it unlikely to harm the body. However, information on its long-term safety remains limited. Overall, melatonin appears to be a well-tolerated option for managing pain after surgery. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Unlike standard pain management treatments that often rely on opioids or non-steroidal anti-inflammatory drugs (NSAIDs), melatonin is being explored for its potential to alleviate postoperative pain through a different mechanism. Melatonin is unique because it is a natural hormone that regulates sleep, and researchers believe it might also possess analgesic (pain-relieving) properties. This treatment is administered sublingually (under the tongue), potentially allowing for quicker absorption and onset of action. Researchers are excited about melatonin due to its potential to provide pain relief with fewer side effects and lower risk of dependency compared to traditional pain medications.

What evidence suggests that melatonin might be an effective treatment for postoperative pain?

This trial will compare melatonin with a placebo to evaluate its effectiveness in managing postoperative pain. Research has shown that melatonin might help with pain and reduce the need for opioids after surgery. Some studies indicate that melatonin can ease pain and improve sleep after surgeries like jaw surgery. One study found that it might be as effective as other pain-relief options like dexmedetomidine and gabapentin for managing pain and anxiety after certain surgeries. Melatonin also seems to help people sleep better after surgery, which is important for recovery. While some results vary, these studies suggest that melatonin could be a promising non-opioid option to manage post-surgical pain and improve sleep. ^{6 7 8 9 10}

Who Is on the Research Team?

Stuti Jaiswal, MD PhD

Principal Investigator

Scripps Clinic Medical Group

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12066642/

The impact of postoperative pain interventions on circadian ... Recent studies have shown that postoperative pain not only affects the physiological state of patients but may also disrupt their circadian rhythms.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0020138322007811

Effectiveness of melatonin treatment for sleep disturbance ... Recent studies have demonstrated that postoperative melatonin administration has beneficial effects on pain and opioid use in orthognathic surgery[15] ...

3. bmcanesthesiol.biomedcentral.com bmcanesthesiol.biomedcentral.com/articles/10.1186/s12871-022-01851-x

Comparison of the effect of melatonin, dexmedetomidine, and ... This study aimed to compare the effects of melatonin, dexmedetomidine, and gabapentin on postoperative pain and anxiety following laminectomy.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT01505465

Study of Melatonin on Sleep, Pain, and Confusion After ... Previous studies have found conflicting results regarding the potential for melatonin to improve sleep and pain in the perioperative period [14] .

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9519126/

Effects of Melatonin Treatment on Perioperative Sleep Quality Melatonin treatment can improve postoperative sleep quality. A 6mg daily dose of melatonin may have a better beneficial effect, which needs further exploration.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9692143/

The Effect of Preoperative Oral Melatonin on Postoperative ... It seems that the use of melatonin at a dose of 5 mg before the surgery is an effective and safe option for reduction of postoperative pain intensity, amount of ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06724432

Analgesic and Antioxidant Effects of Melatonin in Pediatric ... We tested the hypothesis that melatonin reduces postoperative pain and oxidative stress involving sirtuin pathway in children undergoing surgery.

8. sciencedirect.com sciencedirect.com/science/article/pii/S2049080121002958

Effects of preoperative melatonin on postoperative pain ... The mean pain intensity after surgery in patients receiving 5 mg melatonin was significantly lower than in the placebo group and in patients receiving 10 mg ...

9. withpower.com withpower.com/trial/melatonin-for-postoperative-pain-0ecdf

Melatonin for Postoperative Pain · Info for Participants 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, ...

10. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1111/aas.14342

Intravenous MELAtonin for prevention of Postoperative ... The primary outcome is the incidence of emergence agitation, assessed dichotomously as any Watcha score >2 during the participant's stay in the ...