Combining Modern Pharmacology with Integrative Medicine: A Biopsychosocial Model for Comprehensive Pain Care

Abstract

The medical community recognized last decennia the multidimensional nature of pain and proposed multimodal biopsychosocial management. The most compelling reason to embrace integrative pain strategies is to mitigate patient risk. For patients with chronic pain and pain refractory to conservative medicine, it is essential to assess all factors involved with the chronicity. With significant themes, nutrition and microbiome, neuroplasticity, homeostasis, and the side effects of medication, acupuncture has progressively gained a place in this multimodal evaluation. Therapeutic multimodality approaches the perspective of physiological rehabilitation and chronobiological improvement of the quality of life. Illustrated by various clinical situations, the objective of management is to seek a synergy in the mechanisms of action of treatments to improve quality of life and reduce the need for xenobiotics and, consequently, the side effects. The mechanism of action of integrative medicine, and acupuncture improved with a better understanding of genetics, and epigenetics. As opposed to sham and placebo, acupuncture activates other brain regions. In controlled trials, the strict inclusion and exclusion criteria result in the treatment of a “selected” patient population, which is not always comparable to the patients seen in daily practice. The integrative approach is better illustrated by case reports.

1. Introduction

Even for modern medicine, chronic pain remains a complex, multi-faceted problem of nociception, inflammation, and abnormal physiology in the nervous system. Thanks to the knowledge of epigenetics, it becomes clear that environmental factors such as nutrition and chronobiology can modify the parameters involved in all sensitization mechanisms in chronic pain diseases. The deranged sensitization mechanisms suggest restoring the hypersensitive structures to their normal status besides the analgesic treatment.

While more research is needed to understand the progression from acute to chronic pain, the limited pain management strategies have not addressed the scope of pain.

Increased costs and lack of evidence of efficacy are not, according to the physicians (ACP) Clinical Practice Guideline, evidence-informed, comprehensive pain care while conceding that past strategies generally, and the use of opioid medications specifically, have not remedied but rather exacerbated chronic pain, abuse, addiction, illness behavior, and disability [1].

Awareness of serious adverse effects of medications is growing, including the escalating rates of accidental overdoses of prescription opioids and the development of opioid tolerance and hyperalgesia [2].

IASP 2023 global defines integrative pain care as temporally coordinated, mechanism-guided, individualized, and evidence-based integration of multiple pain treatment interventions. Considering the ever-growing burden of chronic pain, current pain management models frequently do not address the clinical problem. The complexity of chronic pain justifies a bio-psycho-social framework, integrating different management and treatment approaches is preferred.

2. Pain chronobiology and epigenetic regulation

A total of 30% genetic and 70% epigenetic factors, such as nutrition and intestinal flora, social, psychological, and affective define the status of an individual [3]. The sensibility for pain is affected by 20 genes. These are also responsible for the variation in reaction to pharmacologic treatment (see Figure 1) [5].

Figure 1.

Influences of the epigenetic modulation system. From Ref. [4].

The ignition or blocking of specific genes is epigenetically regulated. It is also sensitive to environmental factors [5].

Intra and extracellular homeostasis regulates the peripheral sensitization of the primary nociceptors. Inflammation activates the bidirectional signaling that it modulates. Even though there is no immunological response, certain bacterial infections could be accompanied by a hyperalgesic state (see Figure 2) [6].

Figure 2.

Interactions leading to vulnerability for pain.

Pharmacological treatment of chronic pain has dose-dependent side effects, including opioid tolerance, addiction, and even death. Chronic pain involves neuroplastic changes, and neuroinflammation becomes a key question in central sensitization (Figure 3).

Figure 3.

Schema of gut-brain interaction from [7].

Pain induces arousal and triggers other neurobiological stress sequels, thus disturbing sleep and enhancing pain sensitivity. Disturbed sleep or pain may induce a cycle whereby both components stabilize or augment each other. Therefore, management of sleep disturbance may alleviate pain, whereas pain relief may restore sleep and enhance long-term pain relief.

Treatment should target the different mechanisms of pain and may require a combination of treatment options. Combining therapies, such as acupuncture, with traditional pharmacology is still in its infancy.

Acupuncture influences the opioid and cannabinoid system by releasing endogenous receptor ligands. Low-dose naltrexone also acts on both systems and upregulates the opioid and cannabinoid receptors.

Dietary choices and drug use (proton pump inhibitors, NSAIDs, steroids, antibiotics, and hormones) can influence inflammation by altering the microbiome and gut permeability. The balance of microorganisms can affect the absorption of nutrients, drugs, and the function of the immune system leading to low-grade inflammation.

One day after morphine treatment, there is a significant shift in the gut microbiome and metabolome. Morphine-induced gut microbial dysbiosis exhibited distinct characteristic signatures. Drug-microbiota dynamics could help to identify drug-drug interactions and explain inter-individual variation in drug efficacy and adverse effects. The gut microbiome can affect all classes of drugs.

The gastrointestinal microbiome plays a significant role in responses to opioids, including the development of tolerance.

The neuro-immune interactions induced by morphine have direct intestinal functional consequences. Morphine disrupts gut barrier function in a toll-like receptor (TLR)-dependent manner [8]. Low-dose naltrexone (LDN) acts on various gut mechanisms.

Analgesic tolerance to opioids induced by the gut-brain interaction suggests that peripheral mechanisms from the gut can profoundly affect the central control of opioid function. The answer to treatment can be modulated by genetic variations and the inter-individual differences in the bacterial flora of the human digestive tract. The pharmacokinetics of drug metabolism was redefined by the progress in understanding the host-microbial interaction and has improved the management of drug (ab)users.

Acupuncture influences different molecules and receptors, such as GABA, glutamate, and its other receptors (AMPA, NMDA), serotonin (5HT), and the opioid system. The treatment objective is addressing pain and preventing chronicity, focusing on drug and non-drug strategies. Therapeutics directed at maintaining microbiome homeostasis during opioid use may reduce the associated comorbidities.

2.1 Integrative pain medicine and mitigation of risk

The overlap with conventional care is growing as the scientific basis for these therapies expands. Integration across the lifespan to include personal, predictive, preventive, and participatory care.

Personalization of treatment usually means targeting a smaller subset of patients who share a particular phenotype. The economic or financial viability of stratified medicine versus empiric medicine (a medicine prescribed to all patients with a specific condition) was evaluated by Trusheim and Berndt [9] and Ozdemir et al. [10].

Personalized medicine goals require knowledge of which treatment is best for each individual, and promises increased efficiencies for health care systems. Much emphasis in developing customized therapies has been on genetic polymorphisms and blood biomarkers [10]. The predictive capacity of the data pattern must be defined. Determining clinical variables by interview remains the most helpful tool available to a treating physician for selecting the best treatment options on a case-by-case basis. Several recent studies note the need for new models and frameworks that can consistently provide professionals and consumers with helpful knowledge that physicians can meaningfully apply [11].

2.1.1 Acupuncture

Under the premise of selecting acupoints along the meridians and adopting reinforcement and reduction manipulations, acupuncture will bidirectionally regulate the clinical symptoms and signs.

The same stimulation parameters applied to the same acupoint or nerve may result in opposite regulation (restoring homeostatic balance or normalizing function), the so-called “bidirectional regulation”.

The peripheral lesions around the needle trigger physiological reactions and initiate a cascade of survival reactions. Via the reflex of the axon due to the increased blood flow in the muscle, Calcitonin Gene-Related Peptide (CGRP) and nitrous oxide (NO) are released after manual acupuncture and contribute to tissue healing [12, 13].

Acupuncture induces a brain response to the stimulation of sensory nerves, making it a physiological therapy. Acupuncture normalizes physiological homeostasis and promotes self-healing. The primary nociceptors are complex in the ligand expression of neurotransmitters and receptors, enabling autocrine and paracrine interactions.

Primary nociceptors generate bidirectional efferent messages toward the innervated tissues, and can modify (facilitate or inhibit) sensory information even before transmission to the central nervous system.

Nociceptors seem to have a mind of their own (see Figures 4 and 5) [13].

Figure 4.

Hyperalgesia at a cellular level.

Figure 5.

Interactions at the nerve endings [14].

Pain control might be influenced by the modulation of different molecules and receptors such as GABA, glutamate, and its other receptors (AMPA, NMDA, etc.), the serotonin (5HT) system, the opioid system, norepinephrine (NE), cholinergic receptors, etc. Low-frequency electroacupuncture (EA) has a better effect than a high frequency (100 Hz).

Bidirectional regulation is a unique phenomenon of acupuncture therapy, seen in multiple systemic, cellular, and molecular functional systems. Not all acupoints unconditionally produce the bidirectional regulatory effect, and the corresponding factors remain to be investigated. The body’s homeostatic regulation can achieve bidirectional regulation by acupuncture or peripheral stimulation in different functional states. It is not a simple physiological response but a complex pathophysiological process [15, 16].

Acupuncture stimulates brain responses in cortical and subcortical regions, associated with modulation of the pain sensation and perception, including activation in the sensorimotor cortical and deactivation in the limbic-para limbic-neocortical network as demonstrated with functional neuroimaging studies [17]. It is postulated that the therapeutic response to acupuncture, such as down-regulation of inflammation and autonomic nervous system-mediated pain relief, is provided by a mechanistic pathway of the autonomic nervous system.

Event-related (er)-fMRI is used to evaluate the brain correlates of acupuncture stimulation, it seems to be associated with different autonomic nervous system outflow responses to needle stimuli and may result from other sensations elicited by stimuli at different bodily locations [18]. In vivo μ-opioid receptor (MOR) binding effects of traditional Chinese acupuncture versus sham acupuncture were found in chronic pain patients diagnosed with fibromyalgia [17].

2.1.2 Nutrition and microbiome

In addition to the severity of the underlying condition, interindividual variability in chronic pain depends on many factors, including its sociocultural context, patients’ genetic backgrounds, psychological factors, and pathophysiology, that can be modulated and monitored by altering nutritional habits [19]. Specific nutritional deficiencies can be associated with pain states. A study discovered that patients with pain with insufficient vitamin D levels needed twice the dose of opioids for twice as long as patients without a deficiency.

Many different types of elimination diets can be useful for patients to try.

Food and nutrition are foundational tools in treating painful and inflammatory conditions. Compelling evidence shows the benefits of a healthy diet composed mainly of unprocessed, plant-based foods.

Sugars and facts may feed into many anabolic and catabolic pathways, the handling of the body of nutrients depends on strategically positioned metabolic sensors that link the intrinsic nutritional value of a meal with intermediary metabolism.

Assessing the nutritional status is a cornerstone of integrative pain medicine. Dietary choices increase or decrease inflammation. Free-radical damage of tissues, induced by inflammation, impedes healing mechanisms, and reduces pH to levels where normal enzymatic reactions are no longer optimized. Inflammation can be reduced by an anti-inflammatory diet, such as the Mediterranean diet—which is high in vegetables, fruits, whole grains, fish, and healthy oils but low in meat (Figure 6) [21].

Figure 6.

Schema of microbiota regulation [20].

2.1.3 The effects of drug therapy on the gut microbiome

The individual diversity of the gut microbiome promotes inter-individual variations with pharmacotherapy, drug-induced toxicity, and efficacy.

The gut microbiome is affected by drug effects and the GI tract environment can be altered (e.g., pH and transit time), mucosa integrity, host and bacterial metabolic aqctivity, and the production of microbial metabolites. These changes can have secondary effects on the microbiome and cause drug-drug interactions. Drugs may also challenge both the integrity and permeability of the intestinal mucosa.

2.1.3.1 Drugs and polypharmacy

The combined use of non-steroidal anti-inflammatory drugs (NSAIDs) and PPIs differentially influenced the relative abundance of Bacteroides spp. and Erysipelotrichaceae spp. Compared to NSAIDs alone, the co-administration of drugs may precipitate shifts in the composition of the microbiota to favor the abundance of microbial taxa that have a metabolizing capacity for those drugs [22].

2.1.3.2 Effect of diet-induced changes on the gut microbiome and drug pharmacokinetics

Drug pharmacokinetics may be modulated by probiotics by changing the composition or metabolic activity of the gut microbiota. Probiotic treatment was shown to increase the microbiota-mediated degradation of the antipyretic and analgesic paracetamol, which may be mediated by probiotic-induced modulation of gut microbial enzyme activity.

Some patients are more at risk for food-drug interaction, such as chronic disease, elderly, malnourished, infant, and pregnant women.

Meanwhile, examining and explaining how gut microbiota regulates drug metabolism and toxicity will assist personalized medicine and facilitate strategies for creating new drugs with desired functionality.

2.2 Towards circuit-based tVNS: translational approaches

It is important to estimate the independent effects of the disease or drug treatment in animal and human studies, as both the CNS-related disease itself and the pharmacological treatment of the disease can alter the composition of the microbiota.

This microbiome impacts the properties and function of microglia involved in pain sensitization. To maintain homeostasis, the vagal nerve (VN) actively participates in bidirectional interactions between the gut microbiome and the brain. VN electroacupuncture promotes the expression and localization of junction proteins, decreasing intestinal permeability and protecting the intestinal epithelial barrier. Complex reflexes, such as the autonomic reflex, can be used to explain some therapeutic effects of acupuncture.

Administration of pre/probiotics to modify vagal nerve function could be a promising strategy for treating central nervous system disorders (Figure 7).

Figure 7.

The multiple bidirectional communication routes between the brain and the gut microbiota. These routes include the vagal nerve, the hypothalamic-pituitary-adrenal axis (HPA), cytokines produced by the immune system, tryptophan metabolism, and short-chain fatty acid production. Adopted from [16].

In human studies, the vital role of the VN in modulating food intake, energy metabolism, and glycemic control has been demonstrated more recently [23, 24, 25, 26, 27]. Across disciplines the pathophysiology of several disorders is attributed to the VN on a behavioral and psychological level; VN stimulation, remarkably non-invasive VN stimulation, has been studied, allowing a better understanding of the mechanisms by which VN stimulation exerts psychological and physiological effects. A more important pathway for acupuncture stimuli is via the autonomic center in the brain that works to up or down-regulate the sympathetic or para-sympathetic output. Neuroendocrine and neuroimmune pathways are also crucial for maintaining the stability of various functional systems in the body, and they can be affected by acupuncture stimulation.

2.2.1 Nutraceuticals and others

The purified products derived from plants, animals, microorganisms (e.g., essential fatty acids and enzymes), and marine sources (e.g., glucosamine, chitosan, fish oils) are called nutraceuticals. They are sold in medicinal forms e.g., tablets, capsules, and powders. The bioactive agents the nutraceuticals deliver may also be obtained through a healthy diet. They provide, however, the advantages of a formulation that promotes the absorption and the physiological effect [19].

2.2.1.1 Curcumin

Hu et al. [28] recently determined that curcumin attenuates opioid-induced hyperalgesia by inhibiting Ca²⁺/calmodulin-dependent protein kinase II α activity and found that a nano-formulation of poly(lactic-co-glycolide)-curcumin-curcumin may reverse opioid-induced hyperalgesia by inhibiting caMKIIa and downstream signaling.

Curcumin induces mitochondrial biogenesis, and has a direct activity on reactive oxygen species, and induction of NRF2. It regulates the epigenetic patterns and has a synergistic activity on drugs used to treat different painful conditions. The low bioavailability of curcumin can be improved by bio-optimization techniques, thus increasing the therapeutic and preventive potentials of the natural substance [29, 30].

2.2.1.2 PEA palmitoylethanolamide

Glia may produce their own endogenous “painkillers” and anti-inflammatory agents through their own modulators. These modulators decrease the winding-up mechanisms in neuropathic pain. Anandamide and its sister molecule PEA are such modulators, and induce a “winding down” in chronic and neuropathic pain and neuroinflammation. Both molecules are classical autacoids, fulfilling the three criteria required for autacoids of lipid transmitters.

PEA is a modulator that reduces pain by decreasing winding-up mechanisms in neuropathic pain and neuroinflammation (Figure 8).

Figure 8.

Activation of microglia by toll-like receptor (TLR) agonists and by palmitoylethanolamide (PEA). Adopted from [31].

2.2.1.3 Low-dose naltrexone

Within a specific dosage window, opioid antagonists such as naltrexone can exert a “paradoxical” analgesic effect. Low-dose naltrexone (LDN) produces the modulation of neuro-inflammation, and stimulates the glial cells to release inflammatory chemicals in the central nervous system. The dosage producing these effects is low compared to the dosage approved for all alcohol and opioid dependency. The pharmacological actions enhance the analgesic effects of endogenous opioids and cannabinoids. Naltrexone modulates the toll-like receptor 4, NO, and filamin A. LDN is safe, with very few side effects, and recent clinical pilot trials in fibromyalgia and multiple sclerosis showed pain reduction and quality of life enhancing impact [32]. It also improved pain tolerance in cold pressor tests and the ability of post-detoxification patients to relate interpersonally with other participants in human relationships (Tables 1 and 2).

Synchrome/model	Type of study (number of subjects)	Notable outcomes	References
Cholestasis pruritis	Case report (1)	Reduction of pruritis and improved mental status despite concurrent opioid therapy	Zylics et al. [34]
Osteoarthritis	Phase II randomized controlled trial (362)	Adding two mcg naltrexone to concurrent opioid therapy provides more significant analgesia.; High dropout rate due to opioid side effects.	Chandalore et al. [35]
Low back pain	Phase III randomized controlled trial (712)	Adding two mcg of naltrexone to opioid therapy provides a more favorable response and reduces side effects.; A high dropout rate precluded further application.	Webster et al. [36]
Axillary brachial plexus blockade	Randomized controlled trial (112)	Onset of time for motor and sensory blockade was longer with additional 100 ng of naloxone.; Added naloxone prolongs motor blockade and analgesia.	Movafegh et al. [37]
Buprenorphine antinociception in healthy subjects	Double-blind crossover trial (10)	Applying buprenorphine with naloxone in 166:1 ratio boost tolerance to cold pressor test	Hay et al. [38]
Postoperative pain control following colorectal surgery	Randomized controlled trial (72)	Adding 0.25 mcg/kg/h of naloxone during surgery and postoperative period lowered opioid consumption shortened length of stay, and hastened bowel function recovery.	Xiao et al. [39]
Postoperative pain control following lumbar discectomy	Randomized controlled trial.; (80)	Adding 0.25 mcg/kg/h of naloxone during first 24 h postoperative period reduced opioid consumption and side effects	Firouzian et al. [40]

Table 1.

Summary of clinical experience with low-dose naloxone/naltrexone. Adopted from [33].

Disease classification	Type of study (number of subjects)	Notable outcomes	Reference
Primary progressive multiple sclerosis	Open-label uncontrolled phase II (40)	Safe and tolerable (primary outcome); Significantly reduced spasticity	Gironi et al. [41]
Multiple sclerosis	Randomized placebo-controlled trial (60)	Significant benefits for mental health per quality-of-life indices	Cree et al. [42]
Relapsing-remitting and secondary progressive multiple sclerosis	Retrospective cohort (215)	Majority reported improvement in quality of life and reduced fatigue.; Well-tolerated treatment with insomnia and nightmares as adverse effects in a minority of cases	Turel et al. [43]
Relapsing-remitting multiple sclerosis	Retrospective cohort (54)	LDN, as a single therapy, did not result in disease exacerbation.	Ludwig et al. [44]
Multiple sclerosis	Quasi-experimental pharmacoepidemiological cohort (341)	Exposure to LDN did not reduce the amount of disease-modifying therapies used	Raknes and Smäkbrekke [45]

Table 2.

Clinical experience on LDN in multiple sclerosis. Adopted from [33].

3. Observational studies to evaluate the effectiveness of healthcare

The fundamentals of neurophysiology learn that the revalidation of the main chronobiological rhythm results in regulating sleep, food, and the vicious circle involved in pain sensitization.

Although randomized controlled trials are considered the most valuable method for proving the efficacy of a treatment. This method cannot be applied to every treatment. Black [46] discusses the advantages and disadvantages of strictly regulated randomized controlled trials (RCTs). Measuring treatment outcomes of one intervention in patients with complex diseases for whom it would be unethical to drop most ongoing treatments. The numbers to be included in RCTs for demonstrating superiority in effect are too small to identify sometimes rare side effects. The blinding in RCTs cannot be maintained sufficiently long to assess the long-term impact. Building evidence is often a step-wise process, where an effect is noted and reported in a case report. These findings can be confirmed in retrospective and prospective studies, and if possible, the effect can be compared to a placebo or another treatment in an RCT.

The debate regarding these research design issues within conventional medicine has risen in parallel with the growing emphasis on team-based medicine and integrative medical teams for “evidence” of effectiveness and efficacy to meet the standards of “evidence-based medicine.”

These standards are predominantly set out for pharmacological treatment, but the EBM model does not evaluate all parts of acupuncture efficacy and strategies in researching complex interventions.

The «whole system» methodology opens the research on Integrative Medicine efficacy with enhanced EBM validation.

Internal and external validity address the usefulness and effectiveness of a treatment. They are complementary and must be addressed separately in different studies. The results must be seen together. The hierarchy of evidence is one of the internal efficacies, not of evidence in general. Other research methodologies must be used and validated.

The results of observational studies help to target treatments and provide information for future research. The mechanisms of action could be elucidated by basic research, and meta-regression could better explain variability in response. Combining the evidence from different sources in a decision-analytical modeling can be used for economic evaluations [47].

4. Conclusions

Pain management is shifting from a model of highly specialized pain care to multimodal evidence-informed options fitted to a patient’s whole experience of pain and therapeutic goals. Ideas changed due to the emerging science about the impact on pain states by the microbiome, mitochondria, fascia, glia and neuroplasticity, and movement disorders. Evidence-informed practice is based on evaluating and disseminating current research, including biological, medical, and behavioral science, secondary to pain for future pain treatments.

Emerging epigenetic data show that NPIs are valid approaches in chronic disease treatments on par with allopathic therapies regarding goals and risks. These approaches have proven superior to some conventional treatments because they tend not to cause such severe side effects.

It might be interesting to look at the quantitative and qualitative changes resulting from single interventions or combining non-pharmacological interventions to further test their efficacy and safety, as well as to improvise on existing therapeutic strategies to prevent or cure disease and disability.

Illustrated by various clinical situations, the objective of management is to seek synergy in the mechanisms of action of treatments to improve quality of life, reduce the need for xenobiotics, and consequently the side effects participating in vicious circles chronicity.

The current imperative is to determine what works best under what conditions.

Multiple medical problems often face limited treatment options, the increased risk of adverse effects, complex drug interactions, and the concurrent use of multiple medications.

From our current perspective, the potential benefit of including nutrition in personalizing pain medicine is formidable and highly promising. The role of personalized nutrition and nutraceuticals, by considering how they might be helpful in managing chronic pain, as well as their physiological features (such as body mass and microbiome) and pathological ones.

The need for a multidisciplinary evaluation and treatment focusing on drug metabolism and chronobiology is highlighted. This multimodal approach influences pain via synergistic non-drug associations like pharmaco-nutritional, acupuncture, neuro-acupuncture, and PEA. Acupuncture in this multidisciplinary model is a multimodal pain regulator. The therapeutic and post-effect are augmented by cellular physiological rehabilitation.

Conflict of interest

No conflict of interest to declare.

Appendix

The philosophy behind the score sheets states that individuals or groups define a standard for the quality of their performance. Then, they describe the standard in terms of a set of requirements. This set is the score sheet. It allows for peer evaluation and self-evaluation of an activity. Grading proceeds by determining the fraction of requirements fulfilled and is objective and reproducible. The score sheet exists prior to the execution of any activity and thus induces iteration until the performance becomes satisfactory. Any individual or group can adapt the method to any professional activity by selecting the pertinent requirements to fulfill their standard of excellence.

Abbreviations

5HT	5 hydroxy tryptamine
ACP	association of clinical practice guidelines
AMPA	ampa receptors glutamate receptor
ATP	adenosine triphosphate
Cx43	connexin 43
DRG	dorsal root ganglion
EA	electro acupuncture
er-fMRI	event-related functional magnetic resonance imaging
fMRI	functional magnetic resonance imaging
GABA	gammma aminobutyric acid
IASP	international association for the study of pain
LDN	low dose naltrexone
LPS	lipopolysaccharide binding protein
MOR	mu opioid receptor
NE	norepinephrine
NMDA	n methyl D asparatate receptors
NO	nitrous oxyde
NSAID	non-steroidal anti-inflammatory drug
P2X	recepteurs purinergiques
pH	degree of acidity
TLR4	toll like receptor 4
tVNS	transcutaneous vagus nerve stimulation
VN	vagal nerve