AIAO Supplements

Abstract

Objective: This preliminary open label study investigates the efficacy of a novel botanical-based supplement with anti-inflammatory and antioxidant properties as adjuvant therapy for chronic pain management. Recent research strongly identifies the roles of neuroinflammation, sensitization of the peripheral and central nervous system and oxidative stress as driving forces in the chronification of pain.

Current evidence identifies the role of PPAR (peroxisome proliferator–activated receptors) in pain pathways. Additionally, the endocannabinoid system (ECS) has gained recent attention for its role in the management of pain through various mechanisms. As such, evidence suggests the potential synergistic benefit of combining PPAR agonists, cannabinoids and antioxidants as a novel approach for treating chronic pain.

This supplement is directed at suppressing these driving forces in chronic pain with the inclusion of pan-PPAR (peroxisome proliferator–activated receptor) agonists that modulates key metabolic and inflammatory pathways, cannabinoids that act through the ECS and other botanical antioxidants and terpenes.

Because patients suffering from chronic pain frequently have co-morbid anxiety and insomnia, this study also investigates the potential benefits for reducing these two conditions. Finally, as many chronic pain patients are treated with opioids and/or medical marijuana products, the study also seeks to determine if the use of this supplement allows for a reduction in patient reliance on these two classes of medications.

The results of this open study determined that the majority (>90%) of the subjects reported significant benefits for pain, anxiety and/or sleep with minimal adverse effects. Additionally, many subjects also identified a reduced reliance on both their use of opioids and medical marijuana. This study strongly suggests significant benefits for the management of chronic pain and associated co-morbidities. Additional studies are warranted.

Abbreviations : 2-AG, 2-arachidonoyl-glycerol; AJA, ajulemic acid; CBD, cannabidiol; FAAH, fatty acid amide hydrolase; FABP, fatty acid binding protein; PEA, Opioid Analgesic Tolerance (OAT), Palmitoylethanolamide; THC, Δ9 -tetrahydrocannabinol; VCAM, vascular cell adhesion molecule.

Introduction

The management of chronic pain continues to be a challenge not well met by current practices. The mainstay of managing chronic pain continues to rely on the use of opioids due to a lack of more effective medications for millions of patients. While offering significant benefits for managing pain, opioids are accompanied by many well-known adverse effects that well not be focused on here.

Efforts to reduce patient reliance on opioids as well as improving the safety of opioid use are the most important challenges facing chronic pain management. Clearly the use of supplements that may act synergistically with opioids for analgesia to allow for a reduction in opioid use offers one important avenue to address these challenges.

In order to treat chronic pain effectively it is important to direct treatment towards the primary driving forces that initiate the transition of acute to chronic pain as well as those that serve to maintain chronic pain. These forces include inflammation and neuroinflammation, peripheral and central sensitization and oxidative stress.

Inflammation, Neuroinflammation and Pain

Cytokines and chemokines are agents released by immune cells in response to tissue injury or inflammation. Inflammation is important in the natural healing process but when it fails to resolve and becomes chronic, it leads to and maintains chronic pain. The term “neuroinflammation” distinguishes the inflammatory reaction in the central nervous system (CNS) from inflammation in other tissues.

Neuroinflammation is promoted by pro-inflammatory cytokines and neurotrophic factors that are the driving forces for neuropathic pain. Neuroinflammation can be triggered by noxious stimuli such as trauma, infection, autoimmunity and toxins, but also by psychological stress. Neuropathic pain (NP), defined as pain initiated or caused by a lesion, dysregulation or dysfunction in the nervous system, is the foundation of chronic pain and is associated with increased production of pro-inflammatory proteins.

Analgesic therapies focused on the reduction of these pro-inflammatory agents have demonstrated a reduction in NP in both animal models and clinical studies and have led to the exploration of potential novel therapies for NP conditions.

Anti-inflammatory Medications

The management of chronic inflammation remains inadequately understood and generally ineffective. The use of steroid medications provides powerful anti-inflammatory benefits but they are accompanied by serious adverse effects most often precluding their use, especially in chronic pain. Non-steroid anti-inflammatories (NSAIDs) such as ibuprofen provide limited benefits in chronic pain but are also frequently accompanied by significant adverse effects, also precluding their use by many chronic pain patients. Additionally, recent research suggests that NSAIDs may in fact contribute to the chronification of pain by suppressing the activity of resolvins which promote the natural resolution of inflammation.

Identifying safe and effective alternative agents that provide anti-inflammatory benefits is an extremely important goal for managing pain. This is especially critical for the management of chronic pain relative to the role of neuroinflammation in the maintenance of pain.

Peroxisome Proliferator-Activated Receptors (PPARs)

Research in the last few decades has identified peroxisome proliferator-activated receptors (PPARs) that play significant roles in pain and inflammation. PPARs are ligand-activated transcription factors with three isoforms (alpha, beta/delta, and gamma). It is believed that acting on the PPARs (agonists) exert anti-neuroinflammatory activity via multiple mechanisms including preventing upregulation of inflammatory mediators. Another mechanism is to suppress activity of ion channels to provide rapid reduction of inflammatory and neuropathic pain. A third mechanism is to repress the expression of genes that produce inflammatory mediators thus providing prolonged analgesic benefit.

Cannabinoids and the Endocannabinoid System (ECS)

The ECS is actively involved in inflammation. Activation of all PPAR isoforms, primarily PPARα and γ, mediates some of the analgesic, neuroprotective, and anti-inflammatory effects of cannabinoids in the ECS along with activation of the cannabinoid CB1 and CB2 receptors and TRPV1 ion channels. Medications that impact the ECS, including PEA and the cannabinoids CBD and THC, offer significant benefit for pain driven by neuroinflammation.

Research to date, however, provides only weak evidence for the analgesic benefits of oral CBD isolate and broad spectrum products. The evidence for THC products is stronger for neuropathic pain but is still limited. Evidence suggests that combining other agents that offer additional analgesic benefits may provide a synergistic effect to enhance the analgesia provided by cannabis-based products.

Peripheral and Central Sensitization

Peripheral sensitization (PS) and central sensitization (CS) are very important processes that drive chronic pain. Sensitization is a process where nerves become more responsive to stimulation, both painful and non-painful. It may be due to a number of changes individually or in combination, including a decrease in threshold necessary for a response, an increase in magnitude of response, expansion of a receptive field and/or the emergence of spontaneous activity. The sensitization process that occurs in primary afferent nerves, those nerves carrying sensory information from the peripheral nervous system to the central nervous system, the spinal cord and brain is termed peripheral sensitization. This sensory information may be related to physical stimulation (mechanical damage or trauma, distention, contraction etc.), chemical stimulation or thermal (hot or cold) stimulation.

2. Provide a long term response benefit of analgesia for chronic pain. In other words, a benefit that would be perceived only after a period of weeks to months, manifest by a reduction in the baseline severity of the patients chronic pain. This benefit would be achieved by suppressing the driving forces of chronic pain: neuroinflammation, peripheral and central sensitization and oxidative stress.
3. Provide benefit directed at the comorbid conditions that often accompany chronic pain, including anxiety and insomnia. Recognizing the overlap of therapeutic benefits related to pain and these comorbidities offered by the constituents of the formulations, the treatment of these comorbidities would not only serve to reduce chronic pain indirectly by improving these comorbidities but also reduce the suffering imposed by these comorbidities themselves.
4. As adjuvant supplements for chronic pain relative to the concurrent therapeutic use of opioids and medical cannabis, an optimal goal is to reduce patient reliance on these agents, both of which have the potential for overuse and misuse, significant adverse events related to their use and the development of therapeutic tolerance leading to a reduction of their clinical benefits.
5. While not specifically measured in this stage of the study, it is also recognized that the constituents in these formulations that may suppress the processes of neuroinflammation and oxidative stress may also have secondary clinical benefits of reducing patient risk for the development of the chronic diseases associated with aging that are also driven by these processes. Such diseases include insulin resistance, hepatic steatosis, cardiovascular diseases and Alzhiemer’s disease and others.

We assessed formulations developed by Carolina Cannabinoids as monotherapy and adjuvant therapy in combination with opioids. These formulations by Carolina Cannabinoids are novel as they are the only botanical pan-PPAR agonists that are commercially available. Due to synergistic action with cannabinoids, these formulations also activate CB1, CB2, 5HT, TRPV1 and GPR receptors (7,10,11). Antioxidant activity is provided by beta carotene, CoQ10 and tocotrienols. Anti-inflammatory effects are provided primarily by PEA and cannabinoids.

In the absence of other clinically approved anti-inflammatory and antioxidant pan-PPAR agonists, these novel botanical formulations developed by Carolina Cannabinoids are promising as therapeutic interventions for chronic pain management by not only reducing current and future pain but also by reducing opioid-related adverse effects.

Patient Selection

The study subjects, patients in a chronic pain management program, were offered for purchase a supplement presented as possibly offering benefits for chronic pain, anxiety and sleep. The subjects electing to participate in the study included those who suffer from inflammatory diseases including osteoarthritis, rheumatoid arthritis and interstitial cystitis as well as those with chronic headaches, neck and low back pain, sciatica, peripheral neuropathy and fibromyalgia. Forty-one patients elected to participate in the trial.

All patients in the study group were currently taking prescription opioids at dosages ranging from 30 to 285 morphine equivalents (ME) per day. The opioids were either taken as stand-alone medications or taken with adjuvant medications including gabapentinoids, antidepressants, NSAIDs and/or medical marijuana products including CBD and THC-based formulations. During the study period one patient obtained a lumbar epidural steroid injection for low back pain associated with severe sciatica.

Primary Outcome Measures

The subjects were queried on their follow-up pain management visit one month after initiating use of their pan-PPAR supplement as to any benefits identified with use of the supplement. Patients self-reported perceived clinical benefits including reduction of pain and/or anxiety and improvement of insomnia. Additionally, when applicable, patients reported whether use of the formulation allowed for sparing of the use of therapeutic opioids or medical cannabis. Additionally, subjects were asked how use of their experimental formulation compared to previous experience of benefits associated with the use of other CBD-based OTC products.

Methods
The Trial Formulations

The trial formulations contain multiple botanical constituents which provide anti- inflammatory and antioxidant effects via different mechanisms of action. While many of the included constituents have complex, multi-mechanistic therapeutic activities, a common denominator of many of the constituents which contributes to the novelty of these formulations is PPAR activation. The synergy of their activation of different PPAR isoforms is proposed to contribute significantly to the markedly beneficial therapeutic responses to these formulations. PPAR γ isoforms are activated by a blend of proprietary botanical terpenes and hemp-derived cannabinoids including CBD and THC while PPAR α isoforms are activated by palmitoylethanolamide (PEA). Additional activation of PPAR β/δ isoforms is provided by cinnamaldehyde.

Antioxidant activity is provided by beta carotene, CoQ10 and the tocotrienols. Anti- inflammatory activity is provided by omega-3, PEA and cannabinoids. Bio-availability enhancement is achieved with water dispersible Self Micro Emulsifying Delivery System (SMEDS). Having a family of formulations with multiple constituents to achieve synergistic agonism of multiple receptors including PPARS, CB1, CB2, 5HT, TRPV1 and GPR offers improved efficacy as all these receptors impact both pain and inflammation.

Based on their pan-PPAR agonism mechanisms of action, formulations that are inclusive of CBD, THC, PEA and other botanical terpenes offer potentially significant synergistic benefits for analgesia, anxiety and insomnia. Additional benefits appear to include the potential to reduce reliance on opioids and cannabis use. When combined with botanical antioxidants such as omega-3, beta carotene, tocotrienols and CoQ10, there may be additional long term benefits for reducing chronic pain related to neuroinflammation and central sensitization as well as a reduction or limited progression of opioid analgesic tolerance.

1. Patients were offered the option to purchase a 32-day therapeutic supply (one 240ml bottle) of one of four formulations from Carolina Cannabinoids as an adjuvant therapy to their current pain management regimens.
2. Patients who were cannabinoid-naive were encouraged to first trial Product 1, containing Anti-Inflammatory & Antioxidant Complex with broad spectrum CBD.
3. Patients currently incorporating medical THC-based cannabis products as part of their pain management regimen were encouraged to first trial either the Anti-Inflammatory & Antioxidant Complex with full spectrum, low dose THC (Product 2) or high dose THC (Product 3), depending on their current level of THC tolerance and dosing.
4. Patients with a history of adverse events associated with previous use of CBD were encouraged to first trial the Anti-Inflammatory & Antioxidant Complex with no CBD or THC (Product 4).

The four formulations from Carolina Cannabinoids:

1. Anti-Inflammatory&AntioxidantComplexwithBroadSpectrum2000mgCBD (THC free) per 240ml bottle
2. Anti-Inflammatory&AntioxidantComplexwithFullSpectrum(3000mgCBD: 300 mg THC) per 240ml bottle
3. Anti-Inflammatory&AntioxidantComplexwithFullSpectrum(3000mgCBD: 450 mg THC) per 240ml bottle
4. Anti-Inflammatory&AntioxidantComplex(noCBDorTHC)per240mlbottle

Patients were advised to slowly titrate up the dosing of their formulations, initially starting with a 1/2 tsp (2.5ml) oral dose at night then to slowly increase this dose to twice a day then three times a day as tolerated to achieve a target dose of 7.5 mL per day.

It was recommended patients take their formulations orally before meals, and swallow with warm water.

Warnings were provided regarding the potential for mild adverse effects including drowsiness, belching and nausea. Patients were informed of the risks of Cyp P450 enzyme inhibition with cannabinoids that could impact serum levels of other medications leading to possible adverse effects.

Person to person interviews by a physician and/or physician assistant were engaged to obtain feedback evaluations to asses patients responses to the formulations.

Results

Patients reported potent analgesic benefits in those suffering from inflammatory diseases including osteoarthritis, rheumatoid arthritis and interstitial cystitis. Patients with fibromyalgia also reported benefits for their pain, fatigue and non-restful sleep. Many patients throughout the pain spectrum reported improvement with anxiety and insomnia.

Opioid sparing benefits were frequently reported, surprisingly including those patients trialing the formulation that included CBD without THC. These opioid sparing benefits were observed with the use of the pan-PPAR agonists in patients taking as little as 30 ME/day or as much as 270ME/day. There appeared to be a trend toward greater opioid- sparing benefits with the use of the pan-PPAR agonist formulations that included THC.

Of note, one patient with severe rheumatoid arthritis noted exceptional “10/10” pain relief with the PPAR formulation with CBD but no THC, describing herself as being “ecstatic” with her response to the supplement. Anxiolytic benefits were reported with use of both PPAR formulations with or without THC but there appeared to be a trend to a more frequent benefit with use of the non- THC formulation.

One surprise result was reported by a patient taking both opioids and medical marijuana who received a lumbar epidural steroid injection for severe sciatica while taking the pan- PPAR formulation with THC. This patient volunteered an “unexpectedly high degree of pain relief” that surprised both the patient and the interventional pain physician who performed the injection. Given that this patient was already using THC at substantial doses, the benefit he received was postulated as coming from the synergy from the pan-PPAR agonists and CBD.

Later in the study patients were queried as to the presence of cannabis product sparing with the use of the pan-PPAR formulations and a positive correlation was found predominantly in THC containing formulations. Because this question was not presented until later in the study, only 9 patients were queried but of these 9, eight patients noted a reduction in their use of THC-based medical cannabis products, including one patient using the CBD non-THC formulation.

The formulations were well tolerated with minimal adverse effects limited to mild drowsiness, nausea and belching that did not require discontinuation of use. Also noted were complaints of the formulation’s disagreeable taste which did lead to discontinuation of use in two subjects.

Overall, patients reported a superior response to the test formulations when compared to their previous experience with PEA supplements and medical cannabis products with similar CBD and terpenes content when used as an adjuvants to opioids. This superior response also applied to previous full spectrum, terpene-rich CBD products previously manufactured by Carolina Cannabinoids.

Discussion

In fourteen years of a non-invasive clinical pain management practice, a host of complementary and alternative medications (CAM) have been recommended and trialed by hundreds of chronic pain patients. These CAM treatments have included palmitoylethanolamide (PEA), anti-inflammatories, antioxidants, CBD, terpenes and phyochemicals, often taken alone or in various combinations.

This also includes previous trials with custom formulations developed by Carolina Cannabinoids (CC) containing only broad spectrum CBD and botanical terpenes which also demonstrated significantly inferior responses compared with the formulations used in this study. Given the similarity of the previous CC formulations to the trial formulations, the enhanced benefits provided by the trial formulations is highly likely to be based on the presence of the pan-PPAR agonists in the trial formulations and the synergistic benefits they contributed.

The therapeutic benefits provided by these earlier agents have not been consistent and have rarely reduced patient reliance on opioids. The use of these treatments are frequently discontinued, having failed to be convincing for their usefulness by the patients. While arguably the clinical benefits of these treatments may nevertheless have been present but under the radar, the lack of recognition of benefit ultimately led to treatment failure through discontinuation.

The clinical response noted in this preliminary, open label investigation of these novel formulations has been surprisingly impactful, with greater than 90% of patients achieving a relatively rapid and favorable clinical response, beneficial enough to warrant their continued purchase for use. While these results alone are remarkable relative to pain relief, the additional benefits for anxiety and insomnia are significant as well.

It is important to remember that in addition to the recognizable beneficial acute therapeutic responses, it is quite possible that there will be long term beneficial therapeutic responses that would otherwise be forsaken if the acute responses did not drive the continued use of the formulations. This one month study did not allow for recognition or measurement of the long term impact of these formulations on neuroinflammation, peripheral and central sensitization and oxidative stress, but this can be the focus of additional investigations.

Based on this study it appears evident that there is a synergistic benefit achieved by the combination of pan-PPAR agonists along with other botanical anti-inflammatories and antioxidants that has produced the unexpected high percentage of beneficial responses in this study group.

Based on these preliminary findings, further studies are warranted to evaluate both acute and long term benefits for pain and other comorbid conditions as well as to also explore reduction of patient reliance on opioids and cannabis.

These formulations represent an important novel, paradigm shift in chronic pain management by focusing not just on the acute response to chronic pain but also on the driving forces that maintain chronic pain. To my knowledge there has never been a formulation developed that has been directed in this way.

Conclusion

Supplementation with this unique formulation of botanical pan-PPAR agonists, cannabinoids, anti-inflammatories and antioxidants in chronic pain patients treated with opioids alone or with adjuvant medications including cannabis-based products appears to provide significant analgesic, anxiolytic and sleep benefits in numerous pain conditions including inflammatory conditions and fibromyalgia. Additional benefits also suggested by this study include a reduction in dosing of opioids and medical cannabis products. The unexpectedly profound analgesic enhancement of an epidural steroid injection for severe sciatica also suggests a possible synergistic effect when combined with steroids.

Future Investigation

Based on this preliminary clinical evaluation, appropriate clinical trials with larger sample sizes are warranted for further evaluations of botanical pan-PPAR agonist formulations regarding their benefits for their acute response for pain, anxiety and insomnia. Additionally, based on current theories of the role of neuroinflammation in the chronification of pain and central sensitization, studies are also warranted to evaluate the long term impact of botanical pan-PPAR agonist formulations on these debilitating conditions.

Dual PPAR agonists, which bind to both the α and γ PPAR isoforms, are currently under active investigation for treatment of a larger subset of symptoms of metabolic syndrome including diabetes mellitus and insulin resistance hyperlipidemia
and atherosclerosis. However many of these experimental compounds have been associated with significant adverse effects. As such, future evaluation of botanical pan- PPAR agonist formulations as shown in this study to be well tolerated is warranted for patients suffering from metabolic disorders as well as chronic pain.

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