Although the mechanism underlying music-induced analgesia remains unclear, the relationship between music and its analgesic effect in chronic pain is well documented 23456. Such studies typically used subjective-rating scales like the Visual Analogue Scale and the McGill Pain Questionnaire to detect changes in pain perception. A hypothesis that explains the mechanisms behind music-induced analgesia invokes the involvement of endogenous opioids. This is partially because the descending pain modulatory circuit (DPMC) that produces analgesia is mediated heavily by endogenous opioids that can lead to pleasurable emotions while listening to certain genres of music 4. This link between endogenous opioids is not well-researched but has been proposed in recent literature reviews 78. Having established the relationship between music and analgesia in chronic pain, the following sections aim to illustrate endogenous opioid release as the underlying mechanism.

The pleasure associated with endogenous opioid production has been found to cause pain relief through the brain’s reward system. It is believed that music, through multiple media, eventually triggers the release of endogenous opioids associated with pleasure and creates analgesia through pain relief circuits. However, the theory linking music to opioid release is not well-established, leading to a lack of empirical data supporting the reasons outlined in this section. As endogenous opioids elicit pleasure through the neural reward system, the evidence presented here primarily focuses on how music is perceived as a neurobiological reward rather than direct opioid release. Therefore, this section describes how music activates this reward system and causes endogenous opioid release related to pleasure.

Review articles and primary research papers that were published within the last 30 years were included. They were collected from PubMed and Google Scholar using the search words “music AND opioids”, “music AND endorphins”, and “pleasure AND music”. Some clinical trials were also searched for using an additional search word like “music AND memory AND pleasure” for specificity. Exclusion criteria included a measure or description of pleasure that was not explicitly linked to the neural reward circuit, articles that discussed artificially administered opioids instead of endogenous opioids, and tests involving music mixed with other forms of treatment like meditation. All the papers that have been included were chosen because they demonstrate that listening to music elicits endogenous opioid production.

Within the opioid-based reward system, the neuropeptides enkephalins, endorphins, and dynorphins bind to mu-opioid receptors (MORs), delta opioid receptors (DORs), and kappa opioid receptors (KORs), respectively 9. These receptors and ligands are mainly found in the cortex, limbic system, and brain stem, and the limbic system consists of mesolimbic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and other regions of the forebrain. The purpose of the reward system is to enforce desirable behavior in an organism, known as instrumental conditioning 10. The introduction of music is positive reinforcement as the experience of listening is pleasant and acts as a ‘reward’ in the system, in turn, eliciting endogenous opioid production to create pleasure 11. This reinforces the idea that listening to music is a positive experience, which creates a desire to listen to it in the future. A similar mechanism is responsible for addictions to exogenous opioids (artificially created) that bind to the receptors to generate pleasure through the same system 12. Systemic MORs and DORs are specifically involved in positive reinforcement.

While the system is meant to reinforce behavior that increases survival chances, it is often related to stimuli that are simply pleasurable without a direct reward, like listening to music. This section describes how music activates this reward system to cause endogenous opioid release.

The subjective portion of musical perception is heavily influential. Personal musical preferences are a strong factor affecting such perception, as research has found that self-selected music tends to yield stronger pleasure than ‘neutral’ or research-chosen pieces, often acting as a control for emotional reactions in experimentation 3031. Emotional reactions to self-selected music include a higher frequency of chills, longer durations of chills, greater pupil sizes, and higher levels of comfort through familiarity than neutral music 32. The anticipation of an expected pleasurable response when listening to previously known music activates the reward system, both through the expectation of the positive stimulus and when directly experiencing the pleasurable response.

Systematic reviews, narrative reviews, and primary research papers that were published within the last 30 years were included. They were collected from PubMed and Google Scholar using the search words “opioids AND chronic pain”, “endorphins AND chronic pain”, and “opioids AND chronic pain AND analgesia”. Some studies were also searched for using an additional search word depending on the section, like “opioids AND chronic pain AND depression” for specificity. Exclusion criteria included a focus on acute pain instead of chronic, the use of patients with chronic pain but measuring only acute pain, determining the effect music has on only psychological conditions rather than pain intensity, and measuring opioid levels through dependency on artificial opioids. All the papers that have been included were chosen because they demonstrate that endogenous opioid production produces analgesia in patients with chronic pain.

Chronic pain can be defined as pain that remains after a period of 12 weeks following treatment after healing should have taken place, or that persists without any tissue damage 4546. Unlike acute pain, which is caused suddenly and has a directly identifiable cause, chronic pain can be created through a wide array of triggers. Furthermore, a certain portion of chronic pain patients are genetically predisposed to the condition, which applies to both the heritability of psychological comorbidities and physical dysregulation 47. 

A large portion of chronic pain patients include those who initially had acute pain caused by a tissue injury, but face persisting pain for a prolonged period after physical healing, which is nociceptive chronic pain. Neuropathic, musculoskeletal, inflammatory, and mechanical pain are also physical causes of chronic pain. However, chronic pain is often due to psychogenic factors with identifiable physical causes, acting as a large differentiating factor between chronic and acute pain.

The relationship between chronic pain and psychological comorbidities is bi-directional, as prolonged pain often leads to depression and anxiety 4849. Similarly, prolonged stress and sudden stress can give rise to chronic pain, an example being chronic back pain due to sustained high cortisol levels 50. In such cases, psychological factors may not be the sole cause, but could also exacerbate one’s perception of existing pain’s intensity.

The dysregulation of certain neurotransmitters including dopamine and endogenous cerebral opioids has been linked to the onset of chronic pain in the descending antinociceptive pathways, affecting both psychogenic and physical anomalies 51. The following sections will delve into the role increased endogenous opioid levels would, in turn, play in the creation of analgesia attenuating chronic pain.

The DPMC has been established for endogenous opioids, specifically through the periaqueductal gray (PAG)-rostral ventromedial medulla (RVM) circuit 52. An overload of noxious stimuli can trigger this circuit to create analgesia, but this section will outline how pleasurable stimuli like music can affect a similar mechanism.

The PAG is a mesencephalic structure responsible for meditating behavior against immediate threats and physical discomfort, including pain management 53. Furthermore, the structure has a high density of primarily MORs, DORs, and KORs are also expressed, suggesting that opioids are involved in this management 54. Artificial triggering of the PAG has been found to elicit an analgesic response in both humans and rats, and structures involved in the reward system have been shown to act as endogenous triggers, specifically the VTA, NAc, and hypothalamus. GABA neurons in the VTA send direct inputs to the lateral and ventrolateral portions of the PAG, and the immobility caused by such responses is blocked in the presence of endogenous opioids, likely a form of an analgesic effect trigger 55. The NAc is, while part of the reward system, also heavily implicated in chronic pain management, as positive activations of the structure accurately predicted analgesic effects in patients with chronic pain, and caused analgesia following b-endorphin injection 56. The PAG is likely to be part of such a response, as it has been suggested that the NAc, basolateral amygdala (BLA), and dorsal PAG form a circuit responsible for responding to prolonged discomfort, and potentially chronic pain 55. The NAc has been found to project to the PAG-RVM spinal cord signaling pathway through opioid systems following stressful stimulation 57. As for the hypothalamus, the lateral hypothalamus has projections that influence the ventrolateral PAG, and such afferent connections have been linked to neuro-adaptive changes following opioid release 55. The ventrolateral PAG, interestingly, is the most associated with the analgesic circuit and has the most dense enkephalin-containing terminals, and its stimulation directly elicits analgesia in humans that is affected by naloxone 58. As naloxone is an opioid antagonist, this suggests that ventrolateral-PAG-caused-analgesia is mediated by opioid release. The lateral hypothalamus is heavily implicated in the reward system through its opioid systems, hypothesized to affect orexin and GABA neurons 5960.

Through the mechanisms illustrated, structures of the reward system activated by music actuate the PAG. The PAG-RVM circuit is well-known as one that mediates analgesic responses, specifically through the inhibition of GABA and glutamate release. The two classes of RVM neurons that respond to noxious stimuli processing are ON and OFF neurons. ON Neuron firing is associated with pain facilitation, while OFF Neuron firing is associated with pain inhibition. Therefore, it can be stated that either a decrease in ON neuron firing or an increase in OFF neuron firing is associated with the production of analgesia, and two separate circuits as illustrated in Bagley and Ingram (2020) responsible for this have been proposed 54.

The first circuit involves ON RVM neurons, as the diagram below outlines the circuit’s structure and how endogenous opioids affect it. When an individual is in pain, excitatory PAG neurons are activated and send excitatory signals to the ON RVM neurons, therefore increasing their firing: enhancing pain facilitation. However, when endogenous opioids are produced, they bind to opioid receptors on the excitatory PAG neurons. The activation of opioid receptors has an inhibitory effect, and so when the opioids bind to these neurons, it inhibits the excitatory signals they were initially sent to the excitatory RVM neurons. Due to the lower number of excitatory signals being sent to the ON RVM neurons, there is a decrease in their firing, which produces analgesia. Figure 1. is a diagrammatic representation of this circuit.

The second circuit involves OFF RVM neurons, as Figure 2. outlines the circuit’s structure and how endogenous opioids affect it. When an individual is in pain, inhibitory GABA-ergic PAG neurons are activated and send inhibitory signals to excitatory PAG neurons, therefore reducing firing in them. This, in turn, means that excitatory PAG neurons do not produce action potentials to send to OFF RVM neurons, which decreases their firing. However, when endogenous opioids are produced, they bind to opioid receptors on the inhibitory GABA-ergic PAG neurons and have an inhibitory effect similar to the one in the circuit previously described. Due to this, the inhibitory PAG neurons do not fire and do not send inhibitory signals to the excitatory PAG neurons, allowing them to fire. This is referred to as disinhibition. So, since the excitatory PAG neurons are not inhibited anymore, they send excitatory signals to the RVM OFF neurons, increasing their firing rates and producing analgesia.

The RVM neurons project to the spinal cord to influence nociceptive perception, particularly the dorsal horn (DH), which has also been linked to opioid activity 6162. Aside from the indirect effects of opioids on the RVM detailed above, the structure is also heavily associated with opioid receptors in both serotonergic and non-serotonergic neurons, and a subset are enkephalinergic, KOR-expressing, and dynorphin-expressing, although the role of these neurons in pain management is less-known 63. It is also important to note that specifically, the two outlined PAG-RVM circuits are based on research with rodents, while this paper aims to illustrate the effect of music on analgesia in humans. However, human tractography studies show that while some cortical connectivity differs between humans and rodents, midbrain and hindbrain connectivity remains similar regarding the DPMC 61. Furthermore, numerous studies involving human subjects corroborate the involvement of the PAG-RVM circuit in opioid production 646561.

Inflammation was previously listed as a cause of chronic pain, and a potential mechanism by which music creates analgesia could be through the anti-inflammatory characteristics of endogenous opioids. While chronic pain is often associated with persistence after physical inflammation is attenuated, it has been suggested that neuroinflammation is responsible for and mediates the chronification of pain 66. Such inflammation also causes central sensitization, a hyper-sensitivity to noxious stimuli that is also common to chronic pain 67. Both effects are largely mediated by cytokines, a type of regulatory protein involved in the immune system that regulates inflammation 68. Pro-inflammatory cytokines promote inflammation and exacerbate pain, while anti-inflammatory cytokines attenuate such responses.

Endogenous opioids have been found to reduce inflammation by affecting cytokine production. Specifically, β - endorphins reduce the production of IL-2 and interferon IFN-γ, both of which are pro-inflammatory while increasing the quantity of IL-4, a notably anti-inflammatory cytokine through MOR interactions 69. Through the same MOR affinity, other studies have found that β - endorphins created by immune cells produce IL-18, IL-10, and IFN-γ, all of which are anti-inflammatory 70. Aside from cytokines, β - endorphins also prevent splenocyte proliferation and the vesicular release of noradrenaline and substance P, all of which are involved in inflammatory responses 6971. An important factor to consider is that some of these endogenous opioids affect and are created in the immune system, while those produced following exposure to pleasurable stimuli are neuronal. Opioid receptors are expressed by immune cells and are the same or similar to the neuronal type, and MOR mRNA and protein have been identified in immune cells in the central nervous system, as microglia and astrocytes regulate neurological cytokine upregulation 7273. Furthermore, the NOP receptor levels in immune cells are near those seen in the central nervous system in humans 74. This suggests that neuronal opioids could still influence immune cell responses.

Psychosomatic chronic pain is, instead of a physical tissue injury, caused or magnified by psychological factors like affective disorders and stress. Given that endogenous opioids act as both mood and pain regulators, low opioid levels due to psychological conditions that are largely dependent on experiencing pleasure could affect the body’s ability to produce analgesia.

Pertaining through stress, increased cortisol production through the Hypothalamus–pituitary–adrenal ^HPA axis has been linked to the presentation of chronic pain due to increased pain sensitivity 75. Cortisol production can also augment symptoms of chronic pain, including cognitive challenges and fatigue, which could potentially lead to declines in positive mood, creating a cycle that further exacerbates the perception of chronic pain. Furthermore, changes in cortisol levels following sleep disturbance are related to changes in pro-inflammatory cytokine production, increasing pain intensity through heightened inflammation. However, all of these processes are not so linear and involve numerous mediating factors including endogenous opioids that ultimately affect chronic pain. Opioids and cortisol have been previously found to have an inversely proportional relationship, as opioids cause an inhibition of ACTH, which regulates cortisol production, and cortisol levels in humans 76. It may be significant that females have cortisol responses that are more heavily influenced by endogenous opioids than males since women are also at higher risk of experiencing chronic pain 77. Increased opioid levels after listening to music could produce analgesia by either attenuating the stress itself or by restoring depleted opioid levels caused by stress 78. 

A wide array of psychological conditions are equally linked to psychogenic chronic pain, as anxiety and depression have been found to lower pain thresholds, and traumatic experiences in childhood influence chronic pain development in adulthood 7980. They are also heavily associated with the endogenous opioid system, with its dysregulation linked to depression and stress-induced psychiatric disorders, specifically involving beta-endorphins 8182. Therefore, interest has shifted towards affecting the opioid system to treat such conditions, which is an example of how music can influence chronic pain by first attenuating the intensity of the disorders 83. The interconnected role of opioids in nociception signaling and such disorders has been researched and proven, more so than that with cortisol.

Research on endogenous opioids and their role in analgesia typically highlights their short-term effects, which tend to fade soon after the stimulus that triggers opioid production is no longer present. However, it is important to note that opioids also have long-term effects, which are particularly relevant to chronic pain, a condition characterized by its prolonged nature.

The anti-inflammatory effects of opioids extend beyond the immediate period during which opioids are active. By reducing inflammation, opioids can potentially lessen pain associated with an injury on a more permanent basis. This is because decreased inflammation can lead to long-term reductions in pain, even after these opioids are no longer present or functional in the body.

Furthermore, endogenous opioids have been shown to cause hyperalgesia, which paradoxically increases one’s pain sensitivity 84. This effect characteristically develops over time and reflects the complex, sometimes counterproductive, role of opioids in pain management. Exogenous opioids, which are designed to produce a more potent response than their endogenous counterparts, have been more extensively studied concerning hyperalgesia 85. While the development of hyperalgesia following exogenous opioid use is not definitive, the existing evidence suggests that endogenous opioids could have similar prolonged influences.

A less-explored effect of opioids is their role in promoting neuroplasticity 86. Beta-endorphins, a type of endogenous opioid, have been found to enhance neurogenesis, the process by which new neurons are formed. This suggests that opioids might influence the neural networks involved in pain perception and management. If these networks are altered due to opioid release, it could lead to long-term changes in how pain is processed and experienced, which could be a potential area of further research.