Accurate Education - Topical Medications For Pain: Synergy

Topical Medications for Pain:

Synergy: When 1 + 1 = 3

Multi-therapeutic Strategies

In the section, “Topical Medications for Pain,“ (please read this section before proceeding further here), it is demonstrated that topically applied medications are important primary treatment options for those with both acute and chronic pain. But to gain the most benefit from their use, one should be aware and take advantage of the synergy that exists with using multiple medications simultaneously.

Synergy is when the whole is greater than the sum of its parts. With reference to the use of medications, synergy occurs when the use of a combination of medications is more effective than the sum of the effectiveness of each of the separate medications. Synergy differs from “additive,” which is when the effectiveness of medications used together provides a simple sum of the benefits together, where 1 + 1 = 2..

This section explores what is known about the synergy of medications commonly used topically for pain. As is frequently the case, the research in this arena is limited and there is a need for more research before definitive conclusions can be drawn. That being said, we must work with what we have when it comes to treating pain. Fortunately, the medications reviewed here are generally quite safe when used topically and are relatively affordable and accessible. As such, one is encouraged to review the data presented here and explore the potential synergies that exist with the use of these medications topically.

Link to videos on this topic on Dr. Ehlenberger’s Youtube channel:

@EricEhlenbergerMD

Links to other Pertinent Educational Pages:

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Topical Medications for Pain

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OTC Watch: Always review the ingredients in topical medications. Many, if not most, of the well-known brand name topical medications have multiple products that each may have different ingredients where some may contain lidocaine, diclofenac, salicylates, menthol and camphor. Some products may also include additional ingredients such as herbal extracts.

Basic Recommendations for Synergizing Topically Applied Medications

To begin, a reminder that medications designed to be applied topically to the skin for therapeutic purposes are generally referred to as “topicals.” Technically, however, topically applied medications may be either “transdermal” or “topical.” This section focuses only on synergy of topical medications for pain.

The fact is that managing pain, either acute or chronic, seldom leads to 100% complete resolution of that pain. It follows that when it is safe and affordable, one should seek to gain the maximum benefit available which almost always is best achieved by the use of multiple medications belonging to separate classes with different mechanisms of action.

Regardless of whether the combined benefits are additive or synergistic, it makes sense therefore that when it comes to applying medications topically, it often works best to use multiple gels, creams, lotions or patches together, either simultaneously or distributed throughout the same day. The selection of which topical combinations to explore should be based on the class of a medication and its mechanism of action and, potentially, use as many different classes of medications as is feasible. What is feasible is largely based on financial limitations but may also reflect ease of use and side effects which are generally lacking or mild.

The following list of primary topical medication classes that may be explored together for their synergy or their additive benefits:

NSAIDs (diclofenac, ketoprofen, ibuprofen)
Na Channel Blocker (Lidocaine)
Ca Channel Blocker (Gabapentin)
Cannabomimetic (Palmitoylethanolamide/PEA)
Cannabinoid (Cannabidiol/CBD)
Cannabinoid (CB2 agonist) (Beta-Caryophylline/BCP)
Cannabinoid (CBR1 & CBR2 agonist) (tetrahydrocannabidiol/THC)

This is not an exhaustive list of potentially beneficial combinations of topical medications but it does cover those with the most research evidence of synergy. It should also be noted that synergistic and additive benefits may also be achieved by combining the use of oral and topical medications, including the combination of an oral and a topical formulation of the same medication such as topical and oral gabapentin.

It should also be noted that topical lidocaine is available in prescription 5% (or equivalent ZTLido 1.8%) patches as well as a 5% prescription ointment, a 3% prescription cream or a 4% over-the-counter cream. PEA (palmitoylethanolamide) is available OTC in a 2% topical formulation in addition to oral formulations.

BCP (beta-caryophyllene) is found in different combination creams on the internet. There are two recommended commercial products, one combining BCP (50 gms per oz) with CBD (250 gms per oz) by AliceCBD.com and one combining BCP (1500 gms per oz with 1% PEA) by TullaBotanicals.com.

Due to the wide variety of medical conditions associated with pain, the selection of an appropriated topical pain medication requires an understanding of the underlying mechanism(s) underlying both the pain and the medications potentially available to treat that pain.

Where to Start?

In general, start with inexpensive but effective topical medications first. Since insurance often pays for only the prescription topicals lidocaine and diclofenac, one should start with either lidocaine or diclofenac first to determine their individual benefits then try the two together to determined their combined benefit.

It should be noted that simultaneous use of a topical menthol product such as Biofreeze or Icy Hot can enhance the absorption of the diclofenac resulting in greater pain benefits although possible greater local. skin side effects.

Unfortunately, the other prescription topical medications effective for pain are not usually covered by insurance and are relatively expensive, so the next less-expensive topicals to add are OTC products with CBD, BCP and/or PEA. There are tw0 products providing a different two of these three:

CBD/BCP (AliceCBD.com): This combination adds both CBD and BCP
Soothe” (BCP/PEA) (TullaBotanicals.com): This combination adds both BCP and PEA

After adding one of these products and determining its benefit, try the other to determinne its benefit and onsider implementing the better of the two into your regimen. The next step if desired is to identify and add. the the missing element, either CBD or PEA depending on the product you preferred.

Following this regiment you may find the combination of lidocaine, diclofenac and BCP along with PEA and/or CBD to be your best. But if you wish to explore further, the next steps would include exploring diffferent prescription medications that can be compounded by a special compounding pharmacy. Sometmes compounded medications can be covered by insurance. The following compounded medications should be considered, especially for neuropathic pain such as peripheral neuropathies:

Gabapentin
Ketamine
Amitriptyline
Clonidine

Additional alternative topical medications offering potential pain benefits are reviewed in Topical Medications for Pain.

There is evidence for synergistic benefits with the following combinations:

(1) Topical Lidocaine (patches or creams) with Diclofenac Gel (1% or 3%)
This simple combination of two products is very accessible as over-the-counter (OTC) formulations, compounded formulations and/or prescription formulations (commercial and compounded) and may be covered by insurance.

(2) Topical Lidocaine (patches or creams), Diclofenac Gel (1% or 3%) and CBD/BCP (AliceCBD.com)

This combination adds both CBD and BCP to the above combination (1). This grouping requires 3 products.

(2) Topical Lidocaine (patches or creams), Diclofenac Gel (1% or 3%) and “Soothe” (BCP/PEA) (TullaBotanicals.com)

This combination adds both BCP and PEA to the first combination (1). This grouping requires 3 products.

(3) Topical Lidocaine (patches or creams), Diclofenac Gel (1% or 3%), CBD and “Soothe” (BCP/PEA) (TullaBotanicals.com

This combination adds both CBD, BCP and PEA to the first combination (1). This grouping requires 3 single entity products (Lidocaine, Diclofenac & CBD) and one combination product, “Soothe” BCP (1500 gms per oz) /1% PEA (TullaBotanicals.com) with high dose BCP.

(3) Topical Lidocaine (patches or creams), Diclofenac Gel (1% or 3%), PEA and CBD/BCP (AliceCBD.com)

This combination adds both PEA, CBD and BCP to the first combination (1). This grouping requires 3 single entity products (Lidocaine, Diclofenac and 2% PEA) and one combination product CBD (250 gm per oz)/BCP (50 gms per oz) (AliceCBD.com) with low dose BCP.

(4) Synergy Linalool with Naproxen

Linalool, the dominant terpene found in lavender oil, acts to enhance absorption of naproxen through the skin, providing a synergistic benefit for the use of topical naproxen and linalool together. Of note, linalool has two isometric forms: d-linalool and l-linalool. The permeation-enhancing effect of the combination of both (dl-linalool) on naproxen was found significantly greater than that of d-linalool and l-linalool alone. This benefit may not extend to diclofenac.

The role of topical THC products is not yet covered here, but will be soon.

Individual Trials

It would be expected that the greater the number of medication classes combined would lead to greater benefits but this is likely to vary from individiual to individual depending on the nature of the pain being treated. In addition, the relative amounts and ratios of the different medications would also be expected to influence the final degree of benefit so some experimental trials may be needed to identify optimal uses.

Dosing Safety

There is a caveat regarding dosing that should be considered. For the most part these topical medications are very unlikely to trigger any systemic side effects due to their lack of systemic absorption. However, combining these topical medications provides additional exposure to the expedients included in the individual formulations that could result in enhanced tissue absorption that could lead to systemic absorption and the potential for systemic side effects. This caution would apply mostly to preparations with lidocaine or NSAIDs (diclofenac) .

With experimentation, one should be able to identify certain combinations that meets ones individual needs based on effectiveness, ease of use and affordability. It is likely that in the future additional commercial products will become available as well as possible commercial prescription products.

Analgesic Synergies by Medication

Lidocaine

The primary mechanism by which lidocaine reduces pain is its blockade of sodium channels in nerve cells that suppresses the propagation of pain signals and reduces nerve-based pain (neuropathic pain). However, lidocaine also has anti-inflammatory along with immuno-modulatory properties. Lidocaine suppresses the secretion of inflammatory cytokines such as TNF-α which is independent of its impact on nerve sodium channels. This secondary mechanism of action is believed to contribute to an additivr or synergistic effect with the anti-inflammatory activities of NSAIDs.

Topical Lidocaine with Non-Steroidal Anti-Inflammatory Drug (NSAID) Synergy

The combination of a sodium channel blocker (lidocaine) and a cyclooxygenase (COX) inhibitor (non-steroidal anti-inflammatory drug (NSAID) provides a dual mechanism of action of these medications on a cellular level that suppresses both inflammatory and nerve pain that is functionally synergistic.

A 2018 study evaluated topical use of lidocaine and diclofenac in post-operative pain due to anorectal surgery and demonstrated enhanced pain benefits with this combination.

Topical Lidocaine with Low Dose Opioids

Combinations of a low dose of topical lidocaine with a low dose of an opioid has been reported to provide significantly greater than additive effects for opioids including morphine, levorphanol and buprenorphine. Unfortunately, topical opioids are not commercially available and having them compounded may not be practical. The analgesic benefit achieved with oral and parenteral opioids has traditionally been attributed to their effects on the central nervous system including the spinal cord and brain. Opioids receptors are present in the peripheral nervous system and may provide safer treatment options in the future but little research on topical opioids has been performed so far.

The current knowledge of topical morphine is inadequate to recommended its general use, but recent work suggests it may be effective, particularly in the treatment of inflammatory ulcers and painful skin lesions. These conditions would not be appropriate for topical lidocaine administration.

The unanswered question is whether the synergy described here with topical opioids can be extrapolated to the presence of synergy with opioids taken orally. This has not been studied but any synergy would be expected to correlate with the tissue penetration achieved with oral opioids which is not likely to be significant.

Opioids Synergy

Opioids Synergy with CBD

Preclinical Study Evaluating Synergy Between Morphine and a CB-2 Agonist

A 2017 preclinical study showed for the first time that morphine and a CB2 agonist, JWH015 (like CBD) interact synergistically to suppress inflammatory, post-operative, and neuropathic pain. Furthermore, the synergy extends to preventing opioid-induced reward behaviors in animals, suggesting that CBD may reduce abuse risk when taken with opioids. Additionally, the combination of morphine with the CB2 agonist reduces constipation associated with morphine. The authors conclude that their data support the use of opioid-CB2 combination therapy in treating chronic pain while limiting abuse liability.

Low Dose of Opioid with Topical Lidocaine (See above)

NSAIDs Synergy with Cannabinois

NSAIDs provide analgesia both by controlling peripheral inflammation through inhibition of cyclo-oxygenase enzymes and through either the disinhibition of endogenous opioid signaling or activation of endocannabinoid signaling at the level of the spinal cord, the periaqueductal gray (PAG) and rostral ventromedial region of the medulla. The inhibition of COX-2 at the spinal cord level decreases pain-promoting prostaglandin generation thus reducing pain and inflammation.

NSAIDs also appear to inhibit the enzyme fatty acid amide hydrolase (FAAH) which metabolizes anandamide, an important endocannabinoid that provides analgesia through its interaction with the CB1 (primarily) & CB2 receptors. FAAH inhibition has been shown to provide analgesic and anti-inflammatory effects in acute and chronic pain. Through these interactions, anandamide levels are elevated contributing to improved pain control. While the inhibition of COX-2 at the spinal cord level decrease both prostaglandin generation and endocannabinoid degradation, a study by Rezaei et al. (2022) indicates that the endocannabinergic mechanisms are more responsible for their analgesic benefits than the inhibition of spinal prostaglandin synthesis.

These authors concluded that the combination of ibuprofen plus a non-specific CB1 & CB2 agonist produced a significant synergistic analgesic effect in which the CB2 cannabinoid receptors were mainly involved vs. the CB1 receptors and that the combination of NSAIDs and cannabinoids administered systemically and locally may be an option in treating pain.

Of interest is recent research that suggests that diclofenac (Voltaren) and aspirin can have their analgesic effects blocked by the use of naloxone, an opioid antagonist even though these medications do not directly act on opioid receptors. It is theorized that at least some of their analgesic benefits involve interactions with the endogenous opioid system in the descending nerve pathways from the brain to the spinal cord. This benefit would not be available through the use of topical diclofenac however.

In conclusion, NSAIDs, in addition to their actions at peripheral tissues and the spinal cord, exert their analgesic effects by activating the descending pain control system at pain centers in the brain (the periaqueductal grey (PAG) and the RVM). Like the opioids and cannabinoids, NSAIDs act at the descending pain control system by activating RVM pain-inhibiting neurons and inhibiting RVM pain-facilitating neurons whose axons interact with nerves in the spinal dorsal horn. The analgesic effects of NSAIDs at the PAG are at least partly related to endogenous opioids and cannabinoid.

Of note, it has been proposed that repeated administration of NSAIDs progressively leads to tolerance to the NSAID, with subsequent cross-tolerance to opioids and the potential risk of an opioid withdrawal syndrome.

Cannabinoids Synergy (Anandamide and Beta-Caryophylline (BCP))

Animal studies have identified synergistic analgesic effects with the combination of anandamide with ibuprofen. Guindon et al. reported that the CB1 receptor participated more strongly in the synergism with IBU and anandamide, while Díaz-Reval concluded the synergism is mainly mediated by the CB2 receptor. Given the role of both CB1 & CB2 receptors in the analgesic benefits of anandamide, it suggests that the combination of NSAIDs and cannabinoids, notably BCP, a strong CB2 agonist, would provide additive and likely synergistic benefits.

In addition to the inhibition of FAAH and Cox-2, anandamide (AEA) also binds to the transient receptor potential cation channel subfamily V member 1 (TRPV1); consequently, AEA is now considered an “endovanilloid” and an “endocannabinoid.”

Therefore, a multi-therapeutic strategy combining the action on FAAH, TRPV1, and COX-2 has been suggested by Natalia Malek and Katarzyna Starowicz, upon reviewing recent studies on dual-acting compounds that interact with the endocannabionid/endovanilloid and COX systems and which may be beneficial for the treatment of chronic pain.

Palmitoylethanolamide (PEA) Synergy

Of note, this same mechanism of inhibiting FAAH to enhance analgesia has been proposed for palmitoylethanolamide (PEA).

Beta-Caryophylline (BCP)

CBD Synergy

Topical cannabinoids have anti-inflammatory, anti-itching, analgesics, wound healing and anti-proliferative effects on the skin. Research has identified many skin conditions that benefit from topical application of CBD including aging skin, dry skin, eczema, psoriasis and wound healing.

Evidence supports that CBD and BCP work in combination via inflammatory mechanisms to produce safe therapeutic benefits superior to the individual effect of CBD and BCP. This is particualarly true for pain benfits.

Various potential mechanisms may contribute to the synergistic interaction between CBD and BCP. CBD acts on the TRPV1 receptor (transient receptor potential vanilloid 1) and the 5-HT1A receptor (serotonin 1A receptor) while BCP is a selective CB2 receptor agonist. A potential cross-talk between these receptors and, consequently, enhancement of their down-stream signaling may play a role in the synergistic analgesic effects of this combination. Pharmacokinetics interaction between CBD and BCP may also play a role.

In a study published in 2013 evaluating CBD combined with BCP in an animal model of spinal cord injury, (SCI) additive and synergistic pain benefits were identified. It is currently believed that SCI pain involves both neuropathic and inflammatory components, as anti-inflammatory mediators in spinal cord tissue and surrounding CSF are markedly increased following this injury. A reduction in a phantom limb pain model was noted by CBD/BCP along with reduced spinal inflammatory markers. However, these benefits were blocked by CB1 but not CB2 antagonists, implying that additional mechanisms are involved with this synergistic action of BCP combined with CBD.

The authors suggest the possibility that there are spinal cord injury-induced changes in cannabinoidergic pain processing leading to increased sensitivity to dorsal horn CB1 mediated effects that may, directly or indirectly via downstream effects, activate novel upregulated antinociceptive CB1 sites or induce changes in endocannabinoid levels. Upon further evaluation the authors determined that CBD alone produces little effect and BCP alone produces marginal effect on CB1 receptors but the combination of CBD and BCP appears to enhance CB1 activity. It was proposed that CBD/BCP may allosterically facilitate one another’s effect on CB1 receptors, supporting theoretical contribution of CB1 receptor activation, at least in part, to SCI antinociceptive effects. It was concluded that the combination of CBD and BCP may be particularly effective in reducing neuropathic pain resulting from spinal cord injury.

Multi-therapeutic Strategy

A multi-therapeutic strategy combining the action on FAAH, TRPV1, and COX-2 has been suggested by Natalia Malek and Katarzyna Starowicz, upon reviewing recent studies on dual-acting compounds that interact with the endocannabionid/endovanilloid and COX systems and which may be beneficial for the treatment of chronic pain.

FAAH Inhibition

Endogenous cannabinoids are synthesized “on demand” in areas of cellular stress but unfortunately these locally released endocannabinoids have a very short half-life due to rapid breakdown by enzymes including FAAH, which breaks down AEA and other related compounds including N-palmitoylethanolamine (PEA), oleoylethanolamine (OEA), N-arachidonoyl glycine (NAGly. Pharmacological inactivation of FAAH results in elevation of endocannabinoids in the spinal cord and brain stem and may offer a means to treat chronic pain,

FAAH Inhibitors:

1. Palmitoylethanolamide (PEA)
2. NSAIDs (ibuprofen)

TRPV1 Antagonism

TRPV1 is a non-selective ion channel that is highly associated with pain processing and is linked to the endocannabinoid system (ECS) through the agonist AEA and is a promising target for the development of new analgesic and anti-inflammatory drugs. TRPV1 is present in peripheral sensory nerves, the spinal cord and some brain stem nuclei involved in pain perception (nociception), including periaqueductal gray matter (PAG) and the cingulate cortex. Evidence indicates that TRPV1 is essential in signalling pain and therefore blocking TRPV1 is a potential strategy to reduce pain.

A satisfactory understanding of the actions of. TRPV1 is an important and not yet fully there. TRPV1 has a complex polymodal activation profile because it is able to sense multiple stimuli, such as noxious pain, heat, protons, ligand binding, and a number of products of cellular mechanisms. Several TRPV1 antagonist candidate drugs have failed in clinical trials because, by interfering with the detection of the various stimuli, they triggered serious side effects . TRPV1 desensitization by agonists such as capsaicin have been shown to be effective in treating some nerve pain such as diabetic neuropathy and post-herpetic neuroalgia.

TRPV1 Antagonists:

1. Capsaicin (TRPV1 desensitizer)

COX Inhibitors

The basis for using NSAIDs) for treating pain and inflammation is mostly because they inhibit cyclo-oxygenase (COX) enzymes, COX-1 and COX- 2. Cyclooxygenases are enzymes that catalyze the production of prostanoids, including prostaglandins and prostacyclins (PGI) that are essential for gastrointestinal and kidney functioning, and thromboxanes (TXA), responsible for platelet functioning. COX- 2 activity increase production of pro-inflammatory compounds including cytokines, mitogen and growth factor which all play key roles in enhancing the transmission of pain to the brain and spinal cord. Blocking COXs can also stop the conversion of endocannabinoids into prostanoid-like and so benefit the treatment of chronic pain. So the inflammatory process can dramatically reduce the level of endocannabinoids and increase pain, while inhibiting inflammation can reduce pain. NSAIDs also have the ability to inhibit FAAH and increase levels of AEA offering another mechanism of reducing pain. Although widely used, NSAIDs do not always provide adequate relief and they. have the risk for serious complications, including internal bleeding (5–10% of chronic NSAIDs therapy) and severe kidney damage.

COX Inhibitors:

1. NSAIDs

Resources:

New Articles – Synergy

CBD – BCP Synergy

Combined non-psychoactive Cannabis components cannabidiol and β-caryophyllene reduce chronic pain via CB1 interaction in a rat spinal cord injury model – 2022

NSAIDs – Cannabinoids Synergy

NSAIDs – Menthol Synergy

Diclofenac systemic bioavailability of a topical 1% diclofenac + 3% menthol combination gel vs. an oral diclofenac tablet in healthy volunteers a randomized, open-label, crossover study – PubMed

NSAID – Ldocaine Synergy

References:

Topicals – Analgesic Overviews

Topicals – Arnica

Clinical Trials, Potential Mechanisms, and Adverse Effects of Arnica as an Adjunct Medication for Pain Management – 2021

Topicals – Formulations

Topical Analgesics – Critical Issues Related to Formulation and Concentration – 2016

Topical Cannabinoids

CBD – Quality Control

Topical CBD

Tolerability profile of topical cannabidiol and palmitoylethanolamide a compilation of single-centre randomized evaluator-blinded clinical and in vitro studies in normal skin – PubMed – 2021

Topical – Chinese (TCM)

Topical Clonidine

Topical Compounded Medications

Topical Essential Oils & Aromatherapy

Topical Frankincence (Boswellia Serrata)

Topical Gabapentin

Topical Ketamine

Topical Lidocaine

Topical Menthol

Topical NSAIDs

Topical Opioids

Topical PEA

Topicals – Neuropathic Pain

Topicals – Arthritis

Topicals – Rheumatoid Arthritis

Topical Terpenes

Terpenes – Routes of Use:

Terpenes – CB2 Receptor

Topical Terpenes – Wound Healing:

Beta-caryophyllene enhances wound healing through multiple routes – 2019

Topical Terpenes – Individual Terpenes

Topical β-Caryophyllene

Synergies

National Academy of Sciences

The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research

www.Healer.com

This website appears to be good resource for exploring medical marijuana.

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Accurate Education – Topical Medications For Pain: Synergy