The Roles of Endogenous Endorphins and Endogenous Cannabinoids in Placebo Analgesia

Introduction

Placebo analgesia, the phenomenon where an inert treatment leads to pain relief, has been a subject of extensive research. The underlying mechanisms involve complex neurobiological processes, primarily mediated by endogenous opioid and cannabinoid systems. This essay explores the roles of endogenous endorphins and endogenous cannabinoids in placebo analgesia, emphasizing that in randomized controlled trials (RCTs) evaluating opioids or cannabinoids versus placebo, both arms experience receptor-mediated analgesia. This critical aspect is often overlooked but has significant implications for interpreting trial outcomes.

Endogenous Opioid System and Placebo Analgesia

The endogenous opioid system, comprising endorphins, enkephalins, and dynorphins, functions much like a built-in pain relief system in the body. When a person expects pain relief from a placebo, this expectation can trigger the release of these natural opioids, activating μ-opioid receptors, akin to how morphine or other opioids work. This activation reduces pain perception and is reversed by naloxone, which blocks these receptors [1, 2].

Neuroimaging studies have pinpointed specific brain regions, such as the rostral anterior cingulate cortex (rACC), dorsolateral prefrontal cortex (DLPFC), and periaqueductal gray (PAG), as key players in this process. Think of these areas as a coordinated team working together to manage pain. When activated, they release endogenous opioids that bind to μ-opioid receptors, dampening pain signals at both spinal and higher brain levels [3, 4, 5].

Endogenous Cannabinoid System and Placebo Analgesia

The endogenous cannabinoid system (ECS), involving endocannabinoids such as anandamide and 2-arachidonoylglycerol, also contributes to placebo analgesia. This system modulates pain through cannabinoid receptors (CB1 and CB2), which are widely distributed in the central and peripheral nervous systems. Placebo-induced analgesia has been shown to involve the release of endocannabinoids, which activate CB1 receptors, leading to pain relief [6, 7].

Research indicates that the ECS can be activated by non-opioid pharmacological conditioning, such as with the nonsteroidal anti-inflammatory drug (NSAID) ketorolac. In such cases, the cannabinoid receptor 1 (CB1) antagonist rimonabant can block placebo analgesia, demonstrating the critical role of endocannabinoids in this process [6]. The involvement of the ECS in placebo analgesia is further supported by studies showing that both cannabinoid and opioid antagonists can abolish placebo-induced pain relief, suggesting parallel and independent neurochemical mechanisms [7, 8].

Implications for RCTs Evaluating Opioids and Cannabinoids

In RCTs evaluating the efficacy of opioids versus placebo for analgesia, it is crucial to recognize that both arms may experience opioid receptor-mediated analgesia due to the activation of endogenous opioid systems. This phenomenon can obscure the true efficacy of the active drug, as the placebo group may also exhibit significant pain relief mediated by endogenous endorphins [1, 2]. Similarly, in RCTs evaluating cannabinoids versus placebo, both groups may experience ECS-mediated analgesia, complicating the interpretation of the results [6, 7].

The presence of receptor-mediated analgesia in both arms of these trials highlights the importance of considering the placebo effect when designing and interpreting RCTs. Failure to account for this can lead to an underestimation of the active drug's efficacy or an overestimation of the placebo response. This underscores the need for rigorous trial designs that can differentiate between the effects of the active treatment and the placebo response [1]. 

Reevaluating the Gold Standard of RCTs and the Role of Real-World Evidence (RWE)

Despite the clear implications of endogenous opioid and cannabinoid systems in placebo analgesia, these factors are often not considered in clinical trial design. Placebo has long been seen as the gold standard in research, providing a benchmark against which the efficacy of active treatments is measured. However, the complex interplay between endogenous systems and placebo responses suggests that this standard may not fully capture the true efficacy of analgesic treatments [3, 9].

For instance, the current evidence quality model, which places randomized, placebo-controlled trials at the top of the hierarchy, assumes that a simple two-group design is sufficient to capture placebo effects and their interactions with active treatments. However, this model is challenged by the findings that placebo effects consist of multiple dissociable mechanisms, including cultural variations and individual differences in placebo responsiveness [10]. This variability can significantly impact the interpretation of trial outcomes, as seen in studies where placebo responses varied widely based on the country in which the trials were conducted [10].

Real-World Evidence (RWE) might offer a more comprehensive approach when evaluating analgesia. Unlike RCTs, which are conducted under controlled conditions, RWE considers data from a variety of sources, including electronic health records, patient registries, and observational studies. This approach captures the nuances of patient experiences in real-world settings, potentially providing a more accurate picture of treatment efficacy [11]. For example, RWE can account for the variability in placebo responses and the activation of endogenous systems, offering insights that RCTs might miss due to their controlled nature [12].

Conclusion

The roles of endogenous endorphins and endogenous cannabinoids in placebo analgesia are critical for understanding the outcomes of RCTs evaluating opioids and cannabinoids for pain relief. Both systems contribute to placebo-induced analgesia, leading to receptor-mediated pain relief in both the active and placebo arms of these trials. Recognizing this phenomenon is essential for accurately interpreting trial results and improving the design of future studies.

By acknowledging the complex interplay between endogenous opioid and cannabinoid systems and placebo effects, researchers can better assess the true efficacy of analgesic treatments. Moreover, considering the potential benefits of RWE in capturing real-world patient experiences, it may be time to reassess the gold standard of RCTs in the context of analgesia research. Embracing a more holistic approach could lead to more effective and personalized pain management solutions, ultimately benefiting patients [1, 11].

Stefan Broselid, Ph.D.

References

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