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16 Complementary Approaches To Reducing Pain Via The Opioid System

Written by Joe Cohen, BS | Last updated:
Medically reviewed by
SelfDecode Science Team | Written by Joe Cohen, BS | Last updated:
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The brain’s natural opioid system is believed to be highly involved in the perception and sensitivity to pain. Many pharmaceutical pain-killing (analgesic) medications target this system: but might there be more “natural” ways to stimulate the opioid system to better manage pain? Read on to learn more about some of the potential “complementary strategies” to pain management that involve this important brain system, and what the latest science has to say about them!

Disclaimer: This post is not a recommendation or endorsement for any particular type of pain-management treatment. The only way to be sure you get effective treatment is to discuss your options with your personal doctor – and none of the complementary approaches described below should ever be used to replace what your doctor has prescribed or recommended. We have written this post for informational purposes only, and its goal is simply to inform our readers about the science behind some potential complementary pain-management strategies, and what we currently know about how they might work.

The Brain’s Opioid System: A Brief Introduction

The brain’s opioid system is believed to play a critical role in regulating motivation, emotion, attachment behavior, hunger and satiety, and how one responds to stress and pain [1].

Increasing the brain’s number of these receptors – or increasing the levels of the various molecules that bind to and activate them – may produce an opioid response that could reduce pain. What are the basic components of this important brain system?

There are four major opioid receptors in our brain:

  • Mu-opioid receptors
  • Delta-opioid receptors
  • Kappa-opioid receptors
  • Nociceptin-opioid receptors

Mu-Opioid Receptors

Mu-opioid receptor (MOR) activation has been associated with [2]:

  • sedation
  • pain relief
  • slowed breathing
  • lowered blood pressure
  • euphoria

Morphine is an example of a mu-opioid activator. Additionally, endorphins (“endogenous morphines”) also activate mu-opioid receptors.

Negative side-effects of elevated mu-opioid receptor activity may include itching, nausea, and constipation [2].

Delta-Opioid Receptors

Delta-opioid receptor (DOR) activation has been associated with [3, 4]:

  • some pain relief (although less that of mu-opioid receptor activation)
  • increased levels of BDNF in the brain
  • possible “antidepressant-like” effects
  • reduction of inflammation (via inhibition of TNF-α, a pro-inflammatory cytokine)

Cannabidiol (CBD) is an example of a delta-opioid activator [5].

Negative side-effects of delta-opioid receptor activity can include seizures (especially at very high doses) [5].

Kappa-Opioid Receptors

Kappa-opioid receptor (KOR) activation has been associated with [6]:

  • moderate pain relief
  • sedation
  • increased appetite
  • increased urination (diuretic)

Oxycodone, morphine, and menthol (found in peppermint oil), are examples of kappa-opioid receptor activators [6].

Negative side-effects of kappa-opioid receptor activators can include a bad mood (dysphoria), and – in particularly high dosages – hallucinations [6].

Nociceptin Opioid Receptors

Nociceptin-opioid receptor (NOR) activation has been associated with chronic (but not acute) pain relief [7].

These receptor types are also being studied for their potential use in patients with congestive heart failure and migraines [8].

Additionally, some drugs that activate the nociceptin opioid receptor are currently being researched for their potential application in pain relief [9].

Negative side-effects of nociceptin-opioid receptor activators can include anxiety, depression, increased appetite, and increased acute pain [10].

16 Potential Complementary Strategies for Opioid-Based Pain Relief

The following lifestyle and dietary/supplement factors are currently believed to play a role in either stimulating opioid receptor activity, increasing the brain’s levels of endorphins (activating mu-opioid receptors), or increasing the overall sensitivity of opioid receptors to stimulation. In other words, these strategies and mechanisms could theoretically be applied to reduce pain, or improve overall pain sensitivity.

However, keep in mind that the science behind these is still mostly preliminary, and none of these supplements have been officially approved for treating pain issues or any other medical conditions.

In other words, there is still “insufficient evidence” for the efficacy of these supplements in treating pain or pain disorders.

Therefore, these lifestyle-based approaches should not be used to replace conventional treatment – especially for people who have been officially diagnosed with a pain-related medical condition! These are complementary approaches only, meaning that while they may help support and enhance the effectiveness of conventional treatments, they are probably not sufficient just on their own.

As always, be sure to discuss any significant lifestyle, dietary, or other changes with your doctor first before embarking on any of the “complementary” strategies discussed throughout this post! In other words, you can consider trying the strategies listed below if you and your doctor determine that they could be appropriate for you.


1) Exercise

Physical exertion can release opioids – an effect that is commonly referred to as the “runner’s high” [11].

However, the intensity of the specific form of exercise being performed may make a big difference in the kinds of effects it has on the opioid system.

For example, some researchers have suggested that heavy weight-training, or other “intense” forms of exercise that incorporate sprinting or other anaerobic exertion, may be required for producing these opioid-system-based effects. In contrast, light-to-moderate weight training, or mild cardiovascular exercise, don’t appear to have a significant effect on raising endorphin levels [12].

2) Natural Sunlight

Most of us just feel better when we get some sun – and there might be good biological reasons behind this.

For example, according to some research, even low amounts of exposure to UV light may help stimulate the production of natural endorphins by the skin [13, 14].

However, there’s no need to overdo it! Just 30 minutes of full-body sun exposure has been reported to contribute to higher endorphin levels, and may even suppress the body’s natural responses to pain – all without significantly increasing the risk for skin cancer.

People who live in an environment that may be lacking in adequate sunlight may also be able to achieve similar effects by using a UVB light, which may mimic some of the effects of natural sunlight by stimulating the production of vitamin D throughout the body.

In contrast, UVA light has not been reported to have any significant effect on stimulating endorphin production [15].

3) Get a Massage

According to some preliminary research, massages, stroking, and other forms of intimate physical contact may have general pain-reducing effects. Some researchers believe that these effects may likely be due to the release of oxytocin, a hormone neurotransmitter that is closely associated with the positive effects of socializing and emotional bonding [16].

Although it hasn’t been fully confirmed yet, this mechanism would appear to make sense, as oxytocin has been reported to interact with the brain’s opioid system – especially through mu- and kappa-opioid receptors [16].

4) Eating Enjoyable Foods

Some preliminary studies have reported that the consumption of palatable food may help stimulate mu-opioid receptors in the basal ganglia, a set of interconnected brain regions that are heavily involved in the brain’s reward system.

According to one early human study, 16 healthy volunteers reported experiencing less pain (induced by extreme cold) after they ate a palatable, high-fat meal [17].

In another study, women (but not men) who consumed a palatable sweet food reported increased pain tolerance compared with those receiving either unpalatable food, “neutral” food, or no food at all [18].

However, there may be a downside to these potential effects. For example, some researchers have proposed that the widespread availability of highly-palatable foods – many of which tend to be high in sugar and fat – is probably one of the most important factors contributing to the increasingly-widespread problems of obesity. Moreover, the “rewarding” effects of these foods on the brain’s opioid and reward systems may be responsible for compulsive patterns of over-eating, which can lead to “addiction-like” dependence on food [19, 20].

5) Oxytocin

Oxytocin (not to be confused with oxycodone!) is a neurotransmitter hormone (neuropeptide) that has long been associated with social and emotional bonding [21].

Some people refer to oxytocin as the “love hormone” because it is believed to facilitate trust and attachment between individuals.

Although the mechanisms of oxytocin are quite complex, some researchers believe that at least part of its effects may be due to the stimulation of mu- and kappa-opioid receptors throughout the brain – and that these mechanisms may be responsible for some of its purported pain-killing (analgesic) effects [16].

Oxytocin is naturally produced and released by the brain – however, some early evidence suggests that certain probiotic strains, such as L. Reuteri, may partly increase oxytocin levels [22].

6) Cold Exposure

According to some preliminary research, intermittent swimming in cold water may stimulate pain-relief mechanisms that are mediated by our opioid system [23].

Exposure to cold – such as by taking cold showers or ice baths – has also been reported to increase levels of the “heat shock inducible factor”, a protein that stimulates mu and delta opioid receptors, according to two animal studies in rats [24, 25].

Increasing these receptors makes our innate opioids more likely to bind to and activate them. However, keep in mind that long-term or high-dose use of opioids may reduce the number of mu-opioid receptors, which could be counter-productive in the long run [2].

7) Magnesium

A few preliminary studies in chronic pain patients have reported that magnesium may amplify some of the pain-relieving effects of low doses of morphine. Some researchers have suggested that these potential effects could possibly be due to magnesium’s ability to block NMDA receptors [26, 27].

8) Sodium Butyrate

Some early research suggests that certain short-chain fatty acids, such as butyrate, may help stimulate mu-opioid receptors. This, in turn, could potentially contribute to a mild pain-relieving effect [28].

Butyrate can be consumed directly, although it can also be formed in the body from some other dietary compounds, such as resistant starch [28, 29]. Good supplementary sources of resistant starch include Jo’s Resistant Starch.

9) Capsaicin

Capsaicin, the “spicy” or “hot” compound found in cayenne and chili peppers, has been reported to stimulate the release of endorphins [30].

Although it might seem ironic or counter-intuitive, capsaicin has been reported to reduce (“down-regulate”) the number of pain receptors (nociceptors), which could potentially translate to reduced pain sensitivity [31].

10) Probiotics

Certain strains of “probiotic” bacteria may have some effect on the opioid system.

For example, the probiotic strain L. acidophilus has been reported to increase the expression of certain opioid receptors throughout the gastrointestinal tract, such as mu-opioid and cannabinoid receptors. Some researchers have theorized that this mechanism may contribute to an anti-pain (analgesic) effect, although much more research would be needed to properly confirm this effect [32].

11) Acupuncture

Although acupuncture is highly controversial, some researchers who study it believe that the body’s innate opioid system may play some role in its potential effects. (Note that this could be the case even if acupuncture’s effects are based solely on the “placebo effect,” as this effect could still involve the opioid system somehow.) [33].

12) Pregnenolone

Pregnenolone is a hormone that the body produces from cholesterol, and is the starting point for making other important hormones, including testosterone, estrogen, progesterone, and cortisol.

Some early evidence suggests that higher levels of pregnenolone may be associated with increased levels of beta-endorphins. However, it is not yet clear whether pregnenolone itself is responsible for this, or if this is instead due to the estrogen that pregnenolone gets converted into [34].

Relatedly, low blood levels of pregnenolone have been associated with elevated sensitivity to pain, further suggesting a potential connection between this hormone and pain control [34].


The following potential “alternative strategies” for stimulating the opioid system to combat pain are based solely on studies in animals or cells, and are therefore considered to be “lacking evidence” for any direct effects in healthy humans.

As such, the sections below should be considered as “jumping off points” for future research, and no solid conclusions can be formed regarding their potential efficacy in humans until much more additional research is done.

13) Mild “Heat Stress”

We all know that a nice hot shower or bath can do wonders for our mood – but what are the biological reasons for this?

According to one animal study, mice were reported to have increased levels of endorphins (beta-endorphins) after swimming in warm water. They were also reported to show behaviors suggesting a reduction in their overall sensitivity to pain [23].

14) Be More Social

According to some preliminary research in animals, the positive rewarding feelings associated with social activity may be due to the stimulation of mu-opioid receptors in the nucleus accumbens (a brain region highly involved in reward and motivation) [35].

Relatedly, another animal study has reported that mice who experienced close social contact before a surgery were better able to recover from the surgery, compared to mice who were made to live alone (i.e. without adequate social stimulation). The well-socialized mice also reportedly showed fewer behavioral signs of pain, and possibly also reduced post-surgical inflammation.

Finally, another study has reported that socially-Isolated mice with nerve damage had much higher levels of the pro-inflammatory cytokines IL-1B and IL-6 in their brains.

15) Melatonin

Melatonin – one of the natural compounds that your body and brain uses to regulate the sleep cycle – may have some potential pain-relieving (analgesic) effects. Preliminary findings from one cell study suggest that this may be due to melatonin’s stimulating effects on the release of endorphins (beta-endorphins) throughout the brain [36].

One factor that can suppress melatonin production is light exposure – especially light from artificial sources, such as television, computer, or phone screens. Therefore, some people believe that avoiding “blue light” at night may help keep melatonin levels regulated (and thereby prevent sleep issues).

16) Low-Level Laser Therapy (LLLT)

Low-level laser therapy – or just “LLLT” for short – has been reported to have many potential therapeutic benefits, one of which is pain relief.

According to one preliminary animal study, LLLT exposure may stimulate the production or release of natural (“endogenous”) opioids by various types of cells throughout the body and brain [37].

Nonetheless, much more research will be needed to confirm these potential effects in humans.

About the Author

Joe Cohen, BS

Joe Cohen, BS

Joe Cohen flipped the script on conventional and alternative medicine… and it worked. Growing up, he suffered from inflammation, brain fog, fatigue, digestive problems, insomnia, anxiety, and other issues that were poorly understood in traditional healthcare. Frustrated by the lack of good information and tools, Joe decided to embark on a learning journey to decode his DNA and track his biomarkers in search of better health. Through this personalized approach, he discovered his genetic weaknesses and was able to optimize his health 10X better than he ever thought was possible. Based on his own health success, he went on to found SelfDecode, the world’s first direct-to-consumer DNA analyzer & precision health tool that utilizes AI-driven polygenic risk scoring to produce accurate insights and health recommendations. Today, SelfDecode has helped over 100,000 people understand how to get healthier using their DNA and labs.
Joe is a thriving entrepreneur, with a mission is to empower people to take advantage of the precision health revolution and uncover insights from their DNA and biomarkers so that we can all feel great all of the time. 


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