Despite research advances and urgent calls by national and global health organizations, clinical outcomes for millions of people suffering with chronic pain remain poor. We suggest bringing the lens of complexity science to this problem, conceptualizing chronic pain as an emergent property of a complex biopsychosocial system. We frame pain-related physiology, neuroscience, developmental psychology, learning, and epigenetics as components and mini-systems that interact together and with changing socioenvironmental conditions, as an overarching complex system that gives rise to the emergent phenomenon of chronic pain. We postulate that the behavior of complex systems may help to explain persistence of chronic pain despite current treatments. From this perspective, chronic pain may benefit from therapies that can be both disruptive and adaptive at higher orders within the complex system. We explore psychedelic-assisted therapies and how these may overlap with and complement mindfulness-based approaches to this end. Both mindfulness and psychedelic therapies have been shown to have transdiagnostic value, due in part to disruptive effects on rigid cognitive, emotional, and behavioral patterns as well their ability to promote neuroplasticity. Psychedelic therapies may hold unique promise for the management of chronic pain.

Figure 1

Proposed schematic representing interacting components and mini-systems. Central arrows represent multidirectional interactions among internal components. As incoming data are processed, their influence and interpretation are affected by many system components, including others not depicted in this simple graphic. The brain's predictive processes are depicted as the dashed line encircling the other components, because these predictive processes not only affect interpretation of internal signals but also perception of and attention to incoming data from the environment.

Figure 2

Proposed mechanisms for acute and long-term effects of psychedelic and mindfulness therapies on chronic pain syndromes. Adapted from Heuschkel and Kuypers: Frontiers in Psychiatry 2020 Mar 31, 11:224; DOI: 10.3389/fpsyt.2020.00224.

5 Conclusions

While conventional reductionist approaches may continue to be of value in understanding specific mechanisms that operate within any complex system, chronic pain may deserve a more complex—yet not necessarily complicated—approach to understanding and treatment. Psychedelics have multiple mechanisms of action that are only partly understood, and most likely many other actions are yet to be discovered. Many such mechanisms identified to date come from their interaction with the 5-HT2A receptor, whose endogenous ligand, serotonin, is a molecule that is involved in many processes that are central not only to human life but also to most life forms, including microorganisms, plants, and fungi (261). There is a growing body of research related to the anti-nociceptive and anti-inflammatory properties of classic psychedelics and non-classic compounds such as ketamine and MDMA. These mechanisms may vary depending on the compound and the context within which the compound is administered. The subjective psychedelic experience itself, with its relationship to modulating internal and external factors (often discussed as “set and setting”) also seems to fit the definition of an emergent property of a complex system (216).
Perhaps a direction of inquiry on psychedelics’ benefits in chronic pain might emerge from studying the effects of mindfulness meditation in similar populations. Fadel Zeidan, who heads the Brain Mechanisms of Pain, Health, and Mindfulness Laboratory at the University of California in San Diego, has proposed that the relationship between mindfulness meditation and the pain experience is complex, likely engaging “multiple brain networks and neurochemical mechanisms… [including] executive shifts in attention and nonjudgmental reappraisal of noxious sensations” (322). This description mirrors those by Robin Carhart-Harris and others regarding the therapeutic effects of psychedelics (81, 216, 326, 340). We propose both modalities, with their complex (and potentially complementary) mechanisms of action, may be particularly beneficial for individuals affected by chronic pain. When partnered with pain neuroscience education, movement- or somatic-based therapies, self-compassion, sleep hygiene, and/or nutritional counseling, patients may begin to make important lifestyle changes, improve their pain experience, and expand the scope of their daily lives in ways they had long deemed impossible. Indeed, the potential for PAT to enhance the adoption of health-promoting behaviors could have the potential to improve a wide array of chronic conditions (341).
The growing list of proposed actions of classic psychedelics that may have therapeutic implications for individuals experiencing chronic pain may be grouped into acute, subacute, and longer-term effects. Acute and subacute effects include both anti-inflammatory and analgesic effects (peripheral and central), some of which may not require a psychedelic experience. However, the acute psychedelic experience appears to reduce the influence of overweighted priors, relaxing limiting beliefs, and softening or eliminating pathologic canalization that may drive the chronicity of these syndromes—at least temporarily (81, 164, 216). The acute/subacute phase of the psychedelic experience may affect memory reconsolidation [as seen with MDMA therapies (342, 343)], with implications not only for traumatic events related to injury but also to one's “pain story.” Finally, a window of increased neuroplasticity appears to open after treatment with psychedelics. This neuroplasticity has been proposed to be responsible for many of the known longer lasting effects, such as trait openness and decreased depression and anxiety, both relevant in pain, and which likely influence learning and perhaps epigenetic changes. Throughout this process and continuing after a formal intervention, mindfulness-based interventions and other therapies may complement, enhance, and extend the benefits achieved with psychedelic-assisted therapies.

6 Future directions

Psychedelic-assisted therapy research is at an early stage. A great deal remains to be learned about potential therapeutic benefits as well as risks associated with these compounds. Mechanisms such as those related to inflammation, which appear to be independent of the subjective psychedelic effects, suggest activity beyond the 5HT2A receptor and point to a need for research to further characterize how psychedelic compounds interact with different receptors and affect various components of the pain neuraxis. This and other mechanistic aspects may best be studied with animal models.
High-quality clinical data are desperately needed to help shape emerging therapies, reduce risks, and optimize clinical and functional outcomes. In particular, given the apparent importance of contextual factors (so-called “set and setting”) to outcomes, the field is in need of well-designed research to clarify the influence of various contextual elements and how those elements may be personalized to patient needs and desired outcomes. Furthermore, to truly maximize benefit, interventions likely need to capitalize on the context-dependent neuroplasticity that is stimulated by psychedelic therapies. To improve efficacy and durability of effects, psychedelic experiences almost certainly need to be followed by reinforcement via integration of experiences, emotions, and insights revealed during the psychedelic session. There is much research to be done to determine what kinds of therapies, when paired within a carefully designed protocol with psychedelic medicines may be optimal.
An important goal is the coordination of a personalized treatment plan into an organized whole—an approach that already is recommended in chronic pain but seldom achieved. The value of PAT is that not only is it inherently biopsychosocial but, when implemented well, it can be therapeutic at all three domains: biologic, psychologic, and interpersonal. As more clinical and preclinical studies are undertaken, we ought to keep in mind the complexity of chronic pain conditions and frame study design and outcome measurements to understand how they may fit into a broader biopsychosocial approach.
In closing, we argue that we must remain steadfast rather than become overwhelmed when confronted with the complexity of pain syndromes. We must appreciate and even embrace this complex biopsychosocial system. In so doing, novel approaches, such as PAT, that emphasize meeting complexity with complexity may be developed and refined. This could lead to meaningful improvements for millions of people who suffer with chronic pain. More broadly, this could also support a shift in medicine that transcends the confines of a predominantly materialist-reductionist approach—one that may extend to the many other complex chronic illnesses that comprise the burden of suffering and cost in modern-day healthcare.

Original Source

• Hypothesis and Theory: Chronic pain as an emergent property of a complex system and the potential roles of psychedelic therapies Frontiers in Pain Research: Non-Pharmacological Treatment of Pain [Apr 2024]