




































Chang References


Berkeley
Pharma Tech
Journal of Medicine

Correspondence: 
bchang092@gmail.com

Keywords:
Pharmaceutical
Non-pharmaceutical
Medicine
Pain
Nanotechnology

Published July 31, 2025

                                                       
Full Open Access

                                                    
Creative Commons Attribution 
License 4.0

Abstract
Pain medicine has demonstrated its significance from brief surgical procedures 
to managing chronic illnesses. Historically, a range of analgesic and opioid 
agents have been utilized as treatment options, and although effective to a 
certain extent, traditional approaches exhibit limitations. Restricted by the 
constraints of technology, current approaches fall short in specificity and 
unintended effects. This review article delves into the evolving landscape of pain 
management, focusing on emerging treatment modalities within and beyond the 
pharmaceutical setting. Non-pharmaceutical treatment modalities, including 
myofascial release, transcutaneous electrical nerve stimulation (TENS), 
photobiomodulation, and passive treatment, such as capsaicin patches, introduce 
promising, non-invasive treatment options for those experiencing chronic pain. 
The advent of nanotechnology has also introduced an exciting new avenue that 
may herald a new era in personalized medicine. With many promising 
treatment modalities currently under investigation, this review article aims to 
examine and highlight the advancements in pain medicine. It is imperative to 
understand the potential remedies these novel modalities may have in a 
multitude of neurodegenerative disorders, cancer, and other diseases.

Innovations in Pain Management: From 
Traditional Analgesics to Novel 
Therapeutic Modalities
By: Brandon Chang, Danica Hergenroeder, Glory Gage and Nathan Tan



 

1. Introduction  

Pain serves as the body's protective response to external stimuli that pose 
potential harm. While essential for signaling bodily distress, persistent or 
chronic pain can persist even after the underlying issues have been resolved, 
significantly hindering the quality of life for those affected. 

1.1 Pathways of Pain 

Pain can be classified as either chronic (long-term) or acute pain 
(short-term). The fundamental mechanisms causing this pain can be 
categorized into two main groups: nociceptive and neuropathic pain1. 
Nociceptive pain is caused by the activation of nociceptors in response to 
surface-level tissue damage, representing the most immediate level of pain 
perception. Examples of nociceptive pain include minor injuries such as 
bruising, scratches, and cuts, as well as some deeper tissue damage like 
fasciitis, tendonitis, and fractures. Nociceptive pain normally subsides with 
time, although various physical therapies and pharmacological remedies 
offer immediate pain alleviation. Neuropathic pain arises from dysfunction 
or damage to the nervous system, specifically nerves responsible for 
transmitting pain signals to the spinal cord or brain. 

Consequently, pain is perceived even in the absence of external stimuli. 
Whether caused by injury, disease, or other factors, damage to nerve fibers 
disrupt their ability to transmit accurate signals from the periphery to the 
central nervous system. Neuropathic pain syndromes can include 
post-stroke pain, spinal cord injury, multiple sclerosis (MS), and they have 
also been associated with other pain groups. Currently, the first line of 
treatment for neuropathic pain is using pharmaceuticals which include 
tricyclic antidepressants (TCA), gabapentin, anticonvulsants, and 
antidepressants2. In addition, there have been recent studies to show 
botulinum toxin has helped by inhibiting proinflammatory mediators3. 
Recognizing the interconnectedness of nociceptive and neuropathic pain is 
vital for developing comprehensive approaches to pain management. Acute 
pain typically subsides when the primary stimulus is removed, whereas 
chronic pain persists even after the primary stimulus is no longer present. 

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Classifying pain in two broad categories requires some more specificity to 
obtain effective characterization. The different conditions can be broken 
down into different categories in terms of chronic pain. These groups are 
inflammatory, musculoskeletal, and psychological pain4. Inflammatory pain 
is characterized by heightened sensitivity of nociceptive pain receptors due 
to inflammation5. Hallmark symptoms of this type of pain include increased 
pain perception, which is the result of the higher influx of pain mediators 
that localize with the increase in blood flow. This heightened sensitivity can 
manifest as allodynia, where pain occurs in response to stimuli that would 
not normally induce pain, or hyperalgesia, an exaggerated response to 
painful stimuli. Common examples of conditions associated with 
inflammatory pain include arthritis and various infections. Surgery and 
opioid use can also trigger hyperalgesia by increasing the concentration of 
calcium and upregulating calcium-dependent kinases, serving as a trigger for 
the release of neurotransmitters. 

The next classification of pain to consider is musculoskeletal pain. It is 
highly prevalent in the general population, affecting approximately 37% of 
the United States population, with an economic burden of $635 billion per 
year6. Musculoskeletal pain is discomfort that arises in muscles, bones, 
ligaments, tendons, and various supportive tissues in the body, as a result of 
defects of certain receptors. The most common agitators for this type of 
pain include overuse, poor posture, and various underlying medical 
conditions, leading to other ailments including both osteoarthritis and 
rheumatoid arthritis7. It remains closely connected with inflammatory pain, 
as damaging the tissue as a result of bad posture or overuse, may cause 
inflammation. 

During inflammation or tissue injury, damaged cells and immune cells 
release a variety of substances known as inflammatory mediators, such as 
bradykinin, nerve growth factor (NGF), prostaglandin E2 (PGE2), 
pro-inflammatory cytokines [e.g. interleukin (IL)-1β, IL-6, tumor necrosis 
factor-α (TNF-α)] and chemokines (e.g. chemokine ligand 2). These 
inflammatory mediators act both directly on peripheral nociceptors, 
eliciting sensitization, and indirectly by promoting inflammation and the 
release of prostaglandins8. 

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Psychological pain is relatively a new term and is still being discussed as to 
what the full criteria are. It is generally being discussed as relating to either 
psychological disorders such as severe depression or relating to physical pain 
like migraines and headaches9. In addition, due to the developing research 
on this type of pain, there is no definite way to treat this type of pain and no 
concrete definition of this pain yet. 

Across various pain classifications, a shared pathway of pain reception 
emerges, initiated by A-delta and C-fibers – A-delta fibers emit rapid and 
localized signals, while C-fibers transmit non-localized pain signals10. These 
primary afferent axons serve as modalities for sensory perception, 
transducing pain signals from chemical to electrical within neurons. The 
electrical signals are transmitted along neuronal pathways to the central 
nervous system. Upon reaching synapses, axons convert electrical signals 
into chemical signals, which are then reconverted into electrical signals upon 
reception by dendritic cells. The presence of myelinated sheaths serves to 
expedite conduction speed along these pathways. Notably, ions such as 
calcium, potassium, and sodium play crucial roles in the transmission of 
these neurotransmitters. At a broader level, stimulatory molecules, 
including various growth factors, prostaglandins, and proteases are released 
upon contact with noxious stimuli. These molecules then access various 
channels, which facilitates the release of more pain mediators from nerve 
terminals, such as glutamate and interleukins. The signals are then sent to 
the central nervous system, specifically the spinal cord or dorsal horn, where 
they are interpreted in the primary sensory cortex. Understanding the 
intricacies of this pain perception pathway is essential for elucidating 
mechanisms behind pain perception and advancing targeted therapeutic 
modalities. 

1.2 Physiology of Pain 

Having understood the pain reception mechanisms and pathways, the next 
step in designing an effective pain medicine is identifying proper targets. 
Some of the mediators previously discussed, like glutamate, have significant 
interactions with NMDA pain receptors, primarily situated in the central 
nervous system. This interaction heightens sensitivity to pain while 

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simultaneously reducing the effectiveness of opioid receptor agents. 
Therefore, N-methyl-D-aspartate (NMDA) receptor-targeted modalities 
involve much of the research in pain medicine11. Another receptor of 
interest, dopamine, is classified into different types, each with distinct roles 
in pain modulation. D1 dopamine receptors, for instance, trigger the 
production of higher levels of cAMP (cyclic-adenosine-monophosphate), 
which in turn enhances PKA (protein kinase A) activity. In contrast, D2 
dopamine receptors inhibit cAMP and PKA activity, exerting an opposing 
effect on D1 receptors. D1 receptors play a role in pain development and 
maintenance, while D2 receptors act to block pain signals. Shifting our 
focus to opioids; there are three main types of opioid receptors: delta-opioid 
peptide/receptor (DOP), kappa-opioid peptide/receptor (KOP), and 
mu-opioid peptide/receptor (MOP), each with their subtypes. In addition, 
there is a fourth receptor named nociception receptor (NOP) that is 
considered a non-opioid receptor of the opioid receptor family. NOP works 
similarly to the opioid receptors but does not bind or become affected by 
naloxone, the common opioid antagonist. Due to its lack of response to 
naloxone, it is frequently questioned if the classification of the opioid 
receptor is correct. Activation of DOP receptors may lead to spinal analgesia 
and reduced gastric motility12. KOP receptor activation also induces spinal 
analgesia but may increase urination and raise the risk of depression. MOP 
receptor activation provides analgesic effects but can lead to respiratory 
depression, sedation, cardiovascular complications, and nausea. Though 
these interactions serve as promising pain remedies, it is important to 
understand the unintended effects they may cause. Drugs that are capable of 
capitalizing on these reception functionalities will be reviewed later in the 
document. 

1.3 Comorbidities 

Pain is most commonly encountered in conjunction with its comorbidities, 
which is where most of the dedicated research efforts have been focused. 
Neurodegenerative disorders are normally associated with loss of 
coordination, memory, and motor movements. Understandably, treatment 
for these neurodegenerative disorders is focused on either restoring or 
retarding the progression of the disorders. However, patients report great 
levels of pain; thirty-eight to seventy-five percent in Alzheimer's disease and 

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other dementias, forty to eighty-six percent in Parkinson's disease and 
related disorders, and nineteen to eighty-five percent in motor neuron 
diseases report a high prevalence of pain13. Scientists are currently struggling 
to classify the type of pain experienced by patients, due to poor diagnostics, 
difficulties in patient self-reporting, and complex neuronal pathways. This 
article will be analyzing the ongoing research on the modalities of pain in 
Parkinson’s Disease (PD), the most rapidly growing neurodegenerative 
disorder, which can be applied to other neurodegenerative disorders. In a 
study conducted by Cattaneo et al., a classification of pain at four levels was 
reported. The first level of this grouping isolates pain into PD-related and 
non-PD-related (level 1: relationship to PD). This idea stems from 
correlation, as many patients with PD are elderly. In the subsequent level, 
the two aforementioned types of pain are classified as nociceptive or 
neuropathic; if it is not clear which of the two classifications ought to be 
picked, pain is included in the "miscellaneous" classification (level 2: the 
broader categorical system). In the third level, the different types of pain are 
categorized according to the categories: musculoskeletal, visceral, cutaneous, 
peripheral, or central (tier 3: broad type). In the last (fourth) level, different 
aspects from a clinical, pathogenetic, and therapeutic point of view are 
specified (tier 4: specific structures and pathology). Another important 
classification method that is frequently used is that of Ford, which considers 
five categories: musculoskeletal, dystonic, neuropathic/radicular, 
central/primary, and akathisia14. 

A significant proportion of diabetes patients experience chronic pain. 
Musculoskeletal pain and neuropathy are the common symptoms of pain, 
stemming from alterations in the structural matrix and mechanical 
properties of periarticular connective tissues, owing to an unusual 
deposition of collagen15. These defects further lead to rheumatic problems 
such as the reduced mobility of joints, stiff hand and carpal tunnel 
syndromes, shoulder capsulitis, and tenosynovitis16. These trends may 
reflect correlation rather than causation. But according to a study sampling 
populations with nondiabetics, diabetics, and prediabetics, the results 
showed that, compared to prediabetic and nondiabetic individuals, diabetic 
subjects have a higher prevalence of lower limb pain (11.1%), back pain 
(8.9%), abdominal pain (6.7%), and neck pain (4.4%). A chi-squared test 
confirmed that diabetic and prediabetic patients had a significantly higher 

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prevalence of chronic pain17. If this problem is not properly dealt with, 
chronic pain may spiral into larger health problems, causing a greater 
disruption in the lives of many. 

Cancer-related chronic pain affects about 40-70% of patients with cancer 
diagnostics and 33-40% of long-term cancer survivors suffer from chronic 
pain18. There exist numerous sources of pain, including the tumor itself, 
chemotherapeutic agents, and surgical interventions. All of these factors can 
not only cause physical pain, but also significant psychological pain. 
Delivery of therapeutics is currently a hot area of research in cancer research 
and will be covered in this article. 

2. Previous Treatment Modalities 

2.1 Nonopioid Drugs 

Popular pharmaceutical drugs fall into three primary categories: 
nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and 
adjuvant analgesics. NSAIDs work primarily by inhibiting the activity of 
the COX-1 and COX-2 enzymes, which are subsets of the 
calcium-dependent kinases mentioned earlier19. This inhibition leads to 
reduced prostaglandin expression, resulting in analgesic effects and 
decreased inflammation. However, a significant drawback of NSAIDs is the 
increased risk of cardiovascular issues and gastrointestinal complications. 
NSAIDs are responsible for 30% of adverse drug reactions such as strokes, 
heart attacks, renal damage, and bleeding. Common examples of NSAIDs 
include aspirin, ibuprofen, and naproxen. The other common drug, 
acetaminophen, commonly recognized as Tylenol, operates similarly to 
NSAIDs. However, unlike NSAIDs, it does not interfere with the COX 
pathway in the peripheral nervous system; instead, its effects are limited to 
the central nervous system. As a result, Tylenol effectively alleviates pain 
perception and reduces fever but lacks efficacy in diminishing inflammation. 
When used in appropriate doses, Tylenol is generally considered safe. 
However, prolonged or excessive usage can lead to liver damage, occasionally 
fatal.  

Adjuvant analgesics include most non-opioid drugs that are not classified as 
acetaminophen and NSAIDs. Adjuvant analgesics refer to medicine that 

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was originally engineered for purposes other than pain management; 
popular agents include antidepressants and anticonvulsants. Because of the 
nervous system’s interconnectedness, drugs that operate in the nervous 
system for conditions such as depression or convulsions affect pathways 
involved in pain reception. Specifically, their effects on the spinal cord and 
dorsal horn overlap. Antidepressants suppress neuropathic pain by 
enhancing noradrenaline influx in the spinal cord20. This neurotransmitter 
binds to α2-adrenergic receptors, initiating downstream signaling cascades 
that inhibit calcium channel activity in the dorsal horn and dampen 
neurotransmitter transmission, thereby inhibiting hyperalgesia and 
allodynia. 

Additionally, antidepressants hold therapeutic effects on the locus 
coeruleus, a brain region rich in noradrenergic nerve cells. Following injury, 
the locus coeruleus releases noradrenaline in response to noxious stimuli, 
contributing to nociceptive analgesia. However, with prolonged injury, this 
response diminishes, compromising the descending noradrenergic 
inhibitory system. Antidepressants intervene by restoring locus coeruleus 
function and increasing noradrenaline levels21. Moreover, they elevate levels 
of brain-derived neurotrophic factor (BDNF), crucial for AMPA 
receptor-mediated activation in the locus coeruleus, further promoting 
analgesic effects. Another common class of adjuvant analgesics, 
anticonvulsants, exert their analgesic effects by modulating 
neurotransmission to prevent seizure activity. The drug acts on the brain to 
serve its primary pharmaceutical purpose, which also inhibits 
neurotransmission in pain reception. Though the listed adjuvant analgesics 
manage pain well, they do have side effects; headaches, decreased alertness, 
and bleeding are just some of the problems that can arise. 

2.2 Opioid Drugs  

The most hazardous class of medications is opioids. Among the commonly 
known opioids are morphine, oxycodone, codeine, dihydrocodeine, and 
loperamide, some of which are available over the counter without 
prescriptions. Despite the wide array of opioid-based drugs available, they all 
share a common mechanism of action, targeting the mu, kappa, and delta 
receptors in the nervous system. In the context of pain medicine, the mu 

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receptor is of interest for its ability to elicit analgesic effects. Opioids bind to 
the mu receptor, decreasing the excitability of nociceptors and the release of 
pro-inflammatory peptides22. However, this is not all the drug does. The 
kappa receptor induces the commonly known drug effects, like euphoria 
and depression of bodily function. The addictiveness of the euphoria makes 
this combination especially dangerous. As depressants, opioids effectively 
slow down bodily functions, including respiration, which can lead to 
respiratory depression and neuronal damage. The unreliability of this drug 
makes it undesirable as a pain medicine. Nanoparticles, which will be 
discussed further on, hold promise for providing synergistic effects with 
opioids, making them safer to use. 

Additionally, it is important to note that many of the commonly used 
opioids do not act on all of the opioid receptors. Although the majority of 
them act mainly on the mu receptor, they do not act on the other two 
receptors. For example, oxycodone, codeine, and loperamide are all opioids 
that are agonists on the mu receptor. Morphine affects each of the receptors 
but binds mainly to the mu receptor. When morphine binds with these 
receptors it leads to an activation of the descending inhibitory pathways of 
the central nervous system resulting in reduced nociceptive signal 
transmission23. Although morphine has been shown to decrease blood 
pressure and heart rate, it has some unfavorable effects such as constipation, 
nausea, depression, and vomiting. Pentazocine is not as commonly used at 
present but is a synthetic opioid used as an agonist on the kappa (κ) 
receptor24. Pentazocine does have the chance of common adverse effects of 
opioids such as nausea, respiratory depression, vomiting, and constipation. 
The final opioid receptor, the delta receptor, is known to associate with the 
drug named buprenorphine. Buprenorphine is also known to be a partial 
agonist to mu receptors and a weak antagonist at kappa receptors, but its 
effects on delta receptors are also weak . It is a synthetic opioid that is used 
for pain treatment and opioid use disorders (OUD). It acts differently from 
normal opioids by exhibiting slow dissociation kinetics, allowing for fewer 
adverse effects. 

 

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Though current drugs on the market have proven their use over the years, 
there are many avenues of innovation in the field of medicine that can 
elevate the current drugs on the market as well as provide alternate 
approaches to pain remedies. 

3. Pharmaceutical Remedies Advancements 

3.1 Nanoparticles 

In contrast to the pharmaceutical remedies mentioned earlier, nanoparticles 
demonstrate therapeutic effects stemming from the emerging field of 
nanotechnology. The wide attributes and modifications for nanoparticles 
enable treatment for a diverse spectrum of diseases, as well as an avenue to 
the next age of precision medicine. This review article will explore the 
various avenues and types of nanoparticles that are relevant in a 
pharmaceutical context. 

3.2 ZnO & MgO NP 

Starting with zinc oxide, its wide range of capabilities places it at the 
forefront of scientific research. Zinc, recognized as an essential trace 
element, plays a crucial role in pain perception modulation, proving its 
ability to analgesia through various pathways25. Zinc ions have been shown 
to inhibit the release of glutamate, a previously mentioned neurotransmitter 
by producing more GABA, an inhibitory neurotransmitter. Furthermore, 
zinc ions noncompetitively inhibit the NMDA receptor, which diminishes 
the activation of the central nervous system, the perception pathway for 
pain. What differentiates the nanoparticle from the microparticle form is the 
penetration efficiency; nanoparticles are three orders of magnitude smaller, 
contributing to their greater motility through various tissues26. As a result, 
smaller doses of zinc oxide are required to induce saturation.  

Furthermore, zinc oxide demonstrates photocatalytic capabilities, due to the 
high reactivity of surface oxygen atoms. It has proven to oxidize stimulants 
on peripheral receptors, and various tumors in cancer therapy. Magnesium 
oxide serves a similar role, as it is another vital cation in the human body 
that offers promising avenues for pain relief. By preventing the calcium ions 
from entering cells through blocking NMDA receptors, it serves as another 

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analgesic agent. One study27 was conducted to test this reaction on mice. 
Varying doses of zinc oxide nanoparticles were injected into rats (0, 1, 5, 10, 
20 mg/kg) and the latency in pain was measured. As shown in Figure 1, the 
latency period was longest at about 10 mg/kg, meaning pain was delayed for 
about 90 minutes. Just like zinc, magnesium reduces the need for relaxant 
drugs, intraoperative anesthetics, and morphine. 

Figure 1. Results from Zinc Oxide Nanoparticles on Rats 

3.3 Magnetite Nanoparticles 

Magnetic metal oxides represent a distinct class of nanoparticles. 
Ferromagnetic compounds, including magnetite (Fe3O4), have shown 
ferromagnetism, meaning that they readily interact with applied external 
magnetic fields. Similar to zinc and magnesium oxide, magnetite has 
demonstrated potential in directly alleviating pain. Therapeutic effects that 
the nanoparticle possesses were revealed by a study that concluded 
diminished macrophage activity and diminished expression of inflammatory 
biomarkers with the treatment of ferromagnetic particles. However, the 
most intriguing aspect of magnetite is unveiled by its name: magnetism. It 
has been widely used as a nanocarrier because of its capability to control the 
vesicle externally through magnetic fields. The strong interaction between 
the nanoparticle and the external magnetic fields enhances the targeting 
efficacy of this method, contributing to precise delivery. Just like zinc oxide 
nanoparticles, the nanoparticles themselves hold therapeutic effects.  

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In a mice study28, iron oxide nanoparticles were injected, and the prevalence 
of biomarkers was checked. These biomarkers include reactive oxygen 
species, CD68, and MPO (a neutrophil marker). Pain levels were also 
measured through von Frey filaments, a band that measures mice’s paw 
withdrawal response, an indicator of pain perception. After the injection of 
treatment into inflamed tissue, there were signs of suppressed expression of 
the previously expressed proinflammatory biomarkers. Further taking 
advantage of the magnetic properties of magnetite, they are currently being 
studied in the field of nanoparticle-induced magnetic hyperthermia. 
Bioactive glass doped with magnetite nanoparticles can generate heat in the 
presence of an alternating magnetic field29. When the magnetic field 
alternates, the magnetism of the nanoparticle also alternates, but at a delay, a 
phenomenon called magnetic hysteresis. As a result, heat is capable of being 
generated in a highly specific area. 

3.4 Gold Nanoparticles 

Another metallic nanoparticle worth covering is gold nanoparticles. 
Currently, at the forefront of cancer research, gold nanoparticles boast a 
myriad of conformations and high membrane customizability. One of its 
most notable features is the surface plasmon resonance (SPR), a 
phenomenon that occurs when electron oscillatory frequencies align with 
the frequency of incoming light, allowing the generation of a magnetic 
field30. Though showing great promise, its toxicity must be considered when 
evaluating its efficacy. Gold nanoparticles can alter DNA function and 
bioaccumulate. Depending on the intended application, coatings added 
onto these nanoparticles, such as folic acid, polyacrylamide, 
polyvinylpyrrolidone, and polyacrylic acid can serve to either mask their 
cytotoxicity or exploit it when targeting cancer cells for treatment. For 
instance, in a study31 that tested the absorption of gold nanoparticles, 
antibody-modified gold nanoparticles demonstrated a 600% increased 
retention to tumor cells, allowing greater release of cytotoxicity into the cell.  

Looking into the therapies driven by gold nanoparticles, photothermal and 
radiofrequency therapy stand as promising candidates. As previously 
mentioned, the ability of nanoparticles to absorb and scatter 
electromagnetic radiation has captured significant interest in the realm of 

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photothermal therapy. The application of this phenomenon has been 
studied in localized hyperthermia, as well as radiofrequency therapy, as its 
great specificity and morphology control have contributed to great levels of 
localization. Its impact has also been seen in neurodegenerative disorders, 
such as Parkinson’s Disease, Multiple Sclerosis, and Lou Gehrig’s Disease. 
The commonality amongst these painful illnesses includes the decline of the 
NAD+/NADH ratio in the brain. Reversing this energy deficit promises 
slower neurodegenerative decline and even partial recovery. In the phase 2 
clinical trial conducted in 202432, gold nanoparticles demonstrated their 
capability to improve this NAD+/NADH balance. 11 participants with 
relapsing Multiple Sclerosis and 13 with Parkinson’s Disease were the 
subjects of this clinical trial and took CNM-AU8 (the gold 
nanoparticle-based therapeutic agent) for 12 weeks. The result included an 
average of 10.4% improvement in NAD+/NADH ratios. Further validated 
testing was performed to test the motor skills of these patients and improved 
motor skills were demonstrated by the patients. Without diagnosing any 
adverse effects of this treatment, the gold nanoparticles have cemented 
themselves as a promising candidate for neurodegenerative disorders. 

The next class of nanoparticles this review article will be covering includes 
nanocarriers, one of the most active areas of research in nanotechnology. 
The capability to fine-tune the solubility and mimic human cells grants 
them easy entry into specific cells, while their ability to vary delivery 
mechanisms based on environmental factors ensures controlled and precise 
drug release. By doping the nanoparticles with various membranes or 
certain receptors, there are many ways to specify the targeted location of the 
cell. Beyond their ability to precisely target cells, their modifications enhance 
drug stability and cellular compatibility. With high modification potential, 
nanocarriers hold immense promise for personalized medicine and 
theranostic applications. We will be taking a look at a few nanocarriers that 
are currently being researched in the field of nanotechnology33. 

3.5 Liposomes 

Liposomes are mainly composed of cholesterols and phospholipids, 
boasting great biocompatibility, biodegradability, high loading capacity, and 
permeability. Over the past decades, liposomes have gradually been 

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improved to localize more precisely, with improved responsiveness to pH 
and temperature as conditions, though they still encounter issues. Some of 
its applications have been heavily explored in co-morbidities with chronic 
pain, including cancer. In a clinical study34 conducted in 2022 on the 
efficacy of liposomes in children’s anticancer therapy 74 trials were 
conducted with 70 being intervention trials and 4 being observational trials, 
with 28.6% being in Phase 3 trials, 30.0% in Phase 1 trials, and 24.3% in 
Phase 2 trials. In total, 17 liposomal drugs for 123 types of cancer were 
investigated, consisting mainly of organic chemicals. Of these cancers, the 
highest proportion was leukemia (15.4%), followed by lymphoma (9.8%) 
and ovarian cancer (8.9%).  

It is worth noting that accurate statistical masking is required to produce 
accurate results, and only 30% of the data collected was properly masked. 
Ultimately, many challenges were found to be associated with this treatment 
modality. Leakage, uncontrollable drug release, instability in storage, and 
difficulty in drug loading limited the use of liposomes in cancer therapy. 
However, they did demonstrate high loading capacity for hydrophobic 
substances. Ultimately, liposomes are still an active area of research for 
scientists and possess many challenges that must be overcome. 

3.6 Solid Lipid Carriers and Nanostructured Lipid Carriers 

Solid lipid nanocarriers have been around for decades and have been 
extensively researched. Many versions of this nanoparticle have been 
produced. A solid lipid nanocarrier, at its core, is a solid lipid (lipid that is 
solid at room temperature) that is commonly composed of triglycerides, 
fatty acids, waxes, and phospholipids35. These lipids form a matrix of 
crystalline structure that encapsulates the drug to be delivered. Surrounding 
this solid lipid nanocarrier core exists a surfactant layer. In chemistry, 
surfactants decrease the surface tension between adjacent surfaces and are 
amphiphiles. The hydrophilic portion of the surfactant faces outward 
toward the aqueous environment, while the lipophilic portion interacts 
with the lipid core, which acts as a stabilizer for the solid lipid core, 
preventing aggregation or coalescence. The first generation of this 
nanocarrier was used as a vesicle to deliver topical anti-inflammatory drugs. 
Great success was found in the controlled release of the drug, allowing for 

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bioaccumulation in the stratum corneum, the outermost layer in the 
epidermis. It has also served as an effective nanocarrier for various pain 
drugs.  

Epalrestat36, a treatment for streptozotocin-induced diabetic neuropathic 
pain, was delivered with solid lipid nanocarriers, and the effect was measured 
in a rat-modeled study. The study tested the efficacy of epalrestat 
encapsulated nanoparticles at varying concentrations (0.25, 0.50, 1, and 5 
mg/kg) on streptozotocin-injected rats. The various parameters linked with 
peripheral neuropathy were subsequently measured. The results were 
promising. Solid lipid nanoparticles demonstrated a large encapsulation 
efficacy at 88 ± 2%. Analyzing the results, the tail-flick latency time and hot 
plate response time, improved linearly with greater doses of solid lipid 
nanoparticles. 

 

Figure 2. The formation of solid lipid nanocarriers. 

The second generation of this nanocarrier saw the advent of nanostructured 
lipid carriers (NLCs). The main differentiating factor between these 
nanocarriers and solid lipid nanocarriers lies in the liquidized lipid core37. 
The oils in the core function by decreasing the crystallinity of the lipid core, 
preventing drug expulsion from the matrix, enhancing drug loading 
capacity, and stability, and ensuring long-term physical and chemical 
stability. As a result, its loading capacity saw an increase, and its 
encapsulation rate rose to 99.5%. Now solving many of the problems that 
plagued the solid lipid nanocarrier, one of its applications was the delivery 
enhancement of topical therapeutic agents like butyl-substituted 
benzocaine analog butamben, a local anesthetic. It proved to decrease 

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toxicity and improve analgesic effects. Building off of all the applications of 
solid lipid nanoparticles, it has been explored in the delivery of gene therapy, 
chemotherapy, and other treatments. 

3.7 Hydrogels 

Hydrogels in their simplest form are networks of water-absorbing polymers. 
Some commonly used polymers include Polyethylene glycol (PEG), 
Poly(acrylic acid) (PAA), Polyvinyl alcohol (PVA), Hydroxypropyl 
methylcellulose (HPMC), Alginate, Collagen, and Chitosan; some of these 
hydrophilic polymers are naturally forming polymers. In the world of 
anesthetics, the brief lifetime of the anesthetics and toxicity has been at the 
center of focus when attempting to engineer effective therapeutics. 
Hydrogels have demonstrated great promise in combination therapy with 
traditional anesthetics in blocking peripheral nerve blocks. A study38 tested 
the logistics of polycaprolactone (PCL) hydrogels in delivering topical 
agents. The study determined that drugs enriched in a PCL core and 
chitosan shell demonstrated a steady release of drugs. They also tried 
determining the optimal ropivacaine (RPV) and dexamethasone (DEM) 
nanoparticle composition and determined that RPV/DEM CH-PCL NPs-3 
delivered the best effects, the mix with the largest nanoparticle size.  

Hydrogels have also been extensively researched in the field of oncology, as a 
result of their impressive biodegradability and biocompatibility39. 
Specifically, it has shown great promise in the field of immunotherapy. With 
difficulties arising in the delivery of monoclonal antibodies (immune 
checkpoint inhibitors), hydrogels serve as the perfect transport vesicle. (Li et 
al., 2023)40 reported that the alginate hydrogel with protoporphyrin IX 
(PpIX)-modified iron oxide (Fe3O4) nanoparticles demonstrated high 
control over the performance of photodynamic and chemodynamic 
therapies41. Another study conducted by Li et al., 2021) demonstrated how 
a hybrid peptide hydrogel of melittin (RADA-320, titanium, and 
doxorubicin (DOX) controlled the release of 

therapeutics-that activated immune cells, depleting the M2-like 
tumor-associated macrophages, effectively reshaping the 
immunosuppressive tumor microenvironment42. Altering the 

Berkeley Pharma Tech Journal of Medicine | 16 



 

microenvironment of melanoma gives promise to the capability to alter 
other tumor microenvironments present in other cancers. 

Figure 3. Hydrogel into a Cell 

3.8 Micelles 

In its simplest form, micelles are aggregates of amphiphilic molecules that 
have self-assembled into a spherical geometry. They are formed by 
submerging common amphiphiles, like surfactants, in an aqueous solution, 
where the hydrophilic heads shield the hydrophobic tails from the polar 
aqueous environment. This structure mirrors that of the phospholipid 
bilayer of cells, as there exists a hydrophilic head with hydrophobic tails. 
When applied to the field of therapeutics development, micelles can 
encapsulate drugs in their inner compartment. What differentiates micelles 
from other nanocarriers is their minute size, being sub 50 nanometers in 
size. Combined with their cell-like coatings, these particles have accessibility 
to deeper tissue locations, increasing the range of drug delivery distance. 
Micelles are also easily manufactured, increasing their accessibility relative to 
the previously discussed nanocarriers. Though there are many benefits to 
this nanocarrier, a major drawback includes instability in fluctuating 
environments. As a result, it may disintegrate in variable environments, like 
the bloodstream, thereby reducing therapeutic effectiveness of the 
nanocarrier. Current research efforts are investigating the possibility of 
crosslinking various structures to prevent premature release of therapeutic 
agents43. Like any other nanocarriers, micelles are currently being 
investigated for their role in delivering therapeutic agents to tumors. Their 
small size allows them to permeate well through certain systems, like the 
kidney, and evade elimination by the liver or spleen. Their minute size 
allows precise localization in certain tissues, improving therapeutics delivery. 

Berkeley Pharma Tech Journal of Medicine | 17 



 

By modifying the surface of micelles with ligands that can specifically 
recognize and bind to receptors overexpressed on the tumor cells, a targeting 
modality is established. This is evident in approved polymeric nano 
micelle-based drugs on the market for cancer treatment44. 

Figure 4. Loading of a micellar nanocarrier 

Genexol-PM, a micelle-based drug, has been approved for the treatment of 
breast cancer, non-small-cell lung cancer, and ovarian cancer. It is also 
undergoing clinical trials for a variety of cancers. In a Phase II study of 
Genexol-PM in patients with locally advanced or metastatic pancreatic 
cancer, common side effects were comparable to those of Taxol in a dose of 
300 mg/m2 every three weeks. The general reaction rate was 6.7%, with 1 
patient in complete reaction and 2 patients in halfway reactions, and the 
infectious prevention rate was 60%. The median PFS was 2.8 months, and 
the median overall survival was 6.5 months. Neutropenia (40.0%), fatigue 
(17.8%), infection (13.3%), dehydration (13.3%), neuropathy (13.3%), and 
abdominal pain (11.1%) were the most common grade 3 toxicities. 
Genexol-PM had sufficient antitumor activity as second-line chemotherapy 
in patients with urothelial cancer after Gemcitabine-Platinum failure in a 
Phase II study in 37 patients with advanced urothelial cancer who had 
previously received Gemcitabine and Platinum combination 
chemotherapy45. Of 34 evaluable patients, the general reaction rate was 21%, 
with 1 patient in complete reaction. The median PFS was 2.7 months, and 
the median overall survival was 6.5 months. Grade 3/4 non-hematologic 
poison levels included neutropenia (14.7%) and contamination (5.9%). 
Hematologic toxicities of grade 3/4 were observed in only one patient. The 
low rates of high-grade toxicities give promising results prospects for 
micelles in the field of oncology. 

3.9 Dendrimers 

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Dendrimers are large branched molecules that are composed of generation 
zero (the core molecule) with branched polymer chains synthesized onto the 
central molecule. Drugs can be integrated into the various branches of this 
molecule through reactions. Their differentiating characteristics from other 
nanocarriers include hyperbranching, well-defined spherical structure, and 
high compatibility with biological systems. Beyond operating as a 
nanocarrier, dendrimers can also be used to enhance drug solubility and as a 
stabilizing agent for various drugs. These two attributes are synergized when 
finding applications of dendrimers. The most well-known dendrimers 
incorporate poly(amidoamine) (PAMAM) dendrimers, polypropylene 
dendrimers, polyesters, and triazines. Dendrimers can be conjugated to 
various molecules in addition to the functional groups that are found on 
their external surface. Dendrimers are a productive solvency enhancer of 
NSAIDs, which is enhanced by weak hydrogen bonds provided by branch 
units, and electrostatic action from surface groups.  

Koc et al. investigated the solubility of PAMAM dendritic macromolecules 
loaded with NSAIDs (ketoprofen, ibuprofen, and diflunisal) in a buffer 
solution46. The outcomes showed that the solvency improvement execution 
of hydrophobic medications in PAMAM dendritic atoms was several times 
greater than ethylenediamine-cored PAMAM dendritic macromolecules 
because of their original polypropylene oxide cores. As a result, dendrimer 
carrier optimization and application have significant potential for 
pain-induced inflammation treatment. 

3.10 Poly(Lactic-co-Glycolic Acid) NPs (PLGA) Nanoparticles 

PLGA nanoparticles are synthesized from lactic and glycolic acids, with 
customizability deriving from the myriad of lactic and glycolic acid 
concentrations. The differentiating factor of this nanocarrier lies in its 
simple preparation, biodegradability, and high drug-loading capacity. It also 
demonstrates great control over drug release. A study conducted on the 
release of ketamine through PLGA nanoparticles was conducted by Han et 
al; biocompatible and biodegradable ketamine-loaded polyethylene-glycol - 
PLGA nanoparticles were tested in pain treatment in the context of pain 
medicine47. The results demonstrated a 41.8% drug loading, with 
preservation of the drug for up to 7 days and controlled release for up to 21 

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days. Furthermore, the decay of ketamine below the lower limit of 
quantitation rose to ~103 hours and ~80 hours with PLGA in comparison 
to only 24 hours when injected intravenously without a nanocarrier. 
Further optimization of drug distribution in the polymer matrix as well as 
PLGA composition is being performed to better formulate drugs with 
broader and more effective applications. 

3.11 Other Nanocarriers 

There remains a multitude of nanocarriers currently being explored for their 
therapeutic applications. To list a few, thermogels, emulgels, various films, 
and silicon nanoparticles are currently being researched. It is important to 
note the limitations when it comes to nanotechnology, including stability, 
cytotoxicity, and solubility, as they pose great barriers to delivering many 
drugs. 

4. Pharmaceutical Remedies Advancements 

4.1 Myofascial Release 

Myofascial release is an external method that refers to the manual 
application of a low-load, long-duration stretch of the myofascial complex. 
Its objective is to restore the ideal length of the fascial tissue to decrease 
perceived pain and enhance mobility. This method targets fascia tissue and 
other associated soft tissues. Fascia tissue is considered connective tissue and 
it is not just the muscular aspect but the connective tissue that also 
surrounds organs48. Overall fascia tissue goes under a lot of stress from the 
body and may become increasingly rigid over time. In addition, fascia tissue 
can be elastic and go in and out of the normal shape, but over time the 
overuse may gradually deform the tissue, allowing the rigidness to take 
place49. Tissue rigidity or deformity may contribute pain for an individual. 
The method of myofascial release is to target those tightened points of fascia 
tissue and either the individual or clinician will add pressure to the pain 
point and hold the pressure until there is no longer any resistance 

from the tissue50. When myofascial release is used by the individual, the tools 
commonly used are a foam roller and roller massager51. Variety of motions 
and movements used with each of these tools target specific painful areas. 

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Figure 5. Fascia Tissue Normal vs Abnormal shape 

A clinical, double-blind, parallel sham-controlled trial with a balanced 
randomization trial performed in 2021 investigated the magnitude of 
myofascial release’s relief on chronic lower back pain (CLBP)52. In this trial, 
fifty-four participants between the ages of eighteen and sixty years old 
diagnosed with nonspecific CLBP for at least three months were chosen. 
These participants were then divided into two groups: myofascial release 
(n=27) and sham (n=27) with a random number generator. Patients’ pain 
was measured through the Short Form McGill Pain Questionnaire 
(SF-MPQ) and visual analog scale (VAS) and disability was measured with 
the Roland Morris Questionnaire. The trial showed a significant 
improvement in pain, as displayed with the SF-MPQ compared to the sham 
group while showing no significant difference in VAS. 

4.2 TENS 

Transcutaneous electrical nerve stimulation (TENS) is an external 
non-invasive treatment used to treat neuropathic and nociceptive pain53. 
TENS, in practice, is an inexpensive mode of electrically stimulating 
targeted tissues that excite a neuronal complex. The most common form of 
TENS can be found as a small battery-run device that can be 
self-administered, with the dosage of electrical currents being delivered 
through electrical pads that are attached to the skin. In addition, there are 
three different techniques of TENS that are used with this type of device to 
evoke different nerve fibers to treat different types of pain. The three 
different techniques are conventional TENS, acupuncture TENS, and 
intense TENS. 

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Conventional TENS is the most commonly used technique and is 
characterized by a low-intensity and high-frequency stimulation54. The 
overall purpose of this approach is to target afferents (A-beta fibers) that are 
connected to the central nervous system and are related to pain. 
Conventional TENS stimulation affects a broader neural area and can 
inhibit nociceptive transmission55. Acupuncture TENS (AL-TENS) is 
considered a high-intensity low frequency technique used for 
hyperstimulation. AL-TENS targets a smaller area and aims for higher 
threshold peripheral afferents (A-delta). During this technique, patients 
may have painless muscle twitches because of the placement of the electrode 
pads. Intense TENS is viewed as a high intensity high frequency technique 
that is used as a “counter-irritant” to stop nociceptive transmission in the 
peripheral nerves before it reaches the central nervous system. This 
technique is different compared to the other two because this method can 
only be used for a small amount of time compared to the conventional 
method, which can be used as long as the patient desires. 

The overall method of TENS affects the surrounding area by reducing the 
transmission of nociceptive neurons. TENS can also activate 
extra-segmental areas including the midbrain and the medulla. The 
activation in the midbrain and medulla complexes then triggers descending 
inhibitory systems which reduces hyperalgesia, an increased sensitivity to 
pain, or an extreme response to pain. Although the main intent of TENS is 
through electrical stimulation, some neurochemicals help further the effects 
of TENS. Low frequency stimulation has demonstrated the involvement of 
the mu opioid receptor and high frequency has displayed the use of the delta 
opioid receptors. TENS is still being researched and garnering more 
information but has shown promising results in multiple clinical trials. 

 

 

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Figure 6. Common TENS device 

A heat application studied in clinical trials garnered positive effects56. When 
applying TENS and heat stimulation in a 2021 clinical trial, the results 
showed a significant improvement in average pain experienced by those 
affected by chronic lower back pain. The clinical trial was a randomized, 
double-blinded controlled trial to test the early intervention of TENS for a 
spinal injury. A treatment of 30 minutes of TENS therapy twice a week for 
8 weeks or a sham TENS therapy was supplied as a placebo (n=26). There 
were 4 pads applied, 2 located paraspinally to the spinal injury and the other 
2 located ventrally within the dermatome of the injury. The overall end 
showed one patient from the TENS treatment and 2 from the sham 
treatment having adverse reactions related to the study.  

With many clinical trials showing promising results, they have also shown 
some complications with interactions with pre-dispositioned illness. People 
with epilepsy, who are pregnant or have a pacemaker have been shown to 
have more risk of complications. In addition, there have been negative 
effects due to inappropriate positioning of the electrode pads. Current 
common errors in placement of the pads include over the chest near the 
heart, eyes, and internally unless specified for internal use. Overall the use of 

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TENS has been shown to be safe with little to no side effects for most 
people. 

4.3 Photobiomodulation  

Photobiomodulation is an external treatment that uses laser and LED light 
to affect the action potentials of the pain pathway. The method uses 
low-intensity red or near-infrared light that is brought near the surface of 
the skin, relative to other energy densities in laser therapy used for ablation, 
cutting, and the thermal coagulation of tissue57. It interferes with the 
stimulation of action potentials within the mitochondria by initially 
interacting with the peripheral nerves and having the electrons join part of 
the photoreceptor on the skin. These photoreceptors stimulate membrane 
potential and cause extra absorption into the potassium and sodium 
channels. This increases the reabsorption power of sodium and potassium 
which keeps the action potential from crossing the threshold needed. The 
electron transfer by photons in the visible and near-infrared light spectrum 
through the modulation of cytochrome c-oxidase activity, increasing ATP 
production, modulation of redox states, and inducing transcription 
factors58. Due to limited understanding of its effects on the molecular, 
cellular, and tissular mechanisms, photobiomodulation has not been widely 
accepted in clinical settings. In recent years, the effects of 
photobiomodulation have been further studied59. 

Figure 7. Photobiomodulation mechanism of action 

A double-armed, randomized, sham-controlled, double-blinded clinical trial 
of photobiomodulation therapy with a 3:4 ratio (n=70) to treatment or 

Berkeley Pharma Tech Journal of Medicine | 24 



 

sham arms was conducive to less neuropathic pain in treating 
chemotherapy-associated peripheral neuropathy. Each patient was given 18 
treatments of 30-minute duration three times a week, which included laser 
exposure to areas of pain which included the legs, feet, cervical spine region, 
and lumbar spine region for anywhere between 3 to 30 minutes, based on 
the severity of the symptoms. The change in mean for the pain score 
between the time of randomization and by the end of the experiment for 
photobiomodulation therapy and sham treatment were -6.8 and 0.2 
respectively. The higher magnitude in a change of mean for 
photobiomodulation therapy demonstrates its efficacy in attenuating 
neuropathic pain symptoms.  

Heat is a limitation in receiving optimal results as the skin surface 
temperature increases, and the effects of photobiomodulation decrease. 
Heat can be generated through the absorption of radiation by cells and 
tissue targeted by the laser. However, this energy transfer from the photons 
produced by the laser that the skin absorbs is allocated to non-targeted 
tissues that surround the targeted tissues, leading to the unwanted 
production of heat that reduces the efficacy of photobiomodulation. 
Absorption of light is a characteristic that is attributed to any material and, 
thus, is impossible to completely eradicate. Therefore, an external procedure 
that decreases the temperature of the surface of the targeted tissue must be 
performed to induce a substantial response toward photobiomodulation.  

Other limiting factors include reflection and scattering60. Reflection of light 
from the targeted tissue implies that the energy provided by the light is not 
being completely absorbed and that energy is erroneously expended towards 
non-targeted tissues. Scattering on the other hand disperses light in different 
directions due to wave-particle interactions. This is significant to 
photobiomodulation efficiency because varying wavelengths of light pertain 
to different scattering properties when penetrating tissue, diffusing 
collimated beams into a cloud of photons. This dilutes the potency of the 
light because rather than focusing on a single area, surrounding non-target 
tissue receives unnecessary treatment. Recent debates on using pulsed waves 
instead of continuous waves to maximize therapeutic efficiency have 
emerged because pulsed waves are less thermally strenuous to irradiated 

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tissues which may improve deep tissue penetration, but this is only 
conjecture since evidence for this hypothesis is scarce. 

Photobiomodulation has also been studied in the context of its promising 
effects on the musculoskeletal system. Due to its cellular activity 
enhancement capabilities, photobiomodulation is often used in recovering 
athletes affected by musculoskeletal-related issues. It has been found that 
when using an 810 nm laser on athletes to observe muscle performance and 
postexercise recovery, 50 J is the optimum dosage. The study only focused 
on three different doses at 10 J, 30 J, and 50 J, which implies that an upper 
limit is still unknown and that a higher dose may be conducive to more 
benefits. Similarly, an 830 nm laser was used on another group of athletes 
before and after exercise divided into three groups: placebo, pre-fatigue laser, 
and post-fatigue laser. This wavelength of light reduced serum lactate and 
creatine kinase levels in both pre-fatigue laser and post-fatigue laser groups. 
However, a more significant reduction was observed in the post-fatigue laser 
group. It has also been found that the source of light is responsible for the 
resulting beneficial effects of photobiomodulation. In a study observing 
musculoskeletal performance and postexercise recovery in healthy males, a 
30 J dose provided the best results by decreasing delayed-onset muscle 
soreness and improving biochemical markers related to musculoskeletal 
damage61. Therefore, maximum musculoskeletal system recovery benefits 
stemming from photobiomodulation therapy are empirically attainable 
through optimizing wavelength, light source, and application during 
fatigue. 

4.4 Passive Treatment  

Capsaicin patch is an effective and accessible treatment for neuropathic 
pain. Capsaicin is a compound that when used topically, attenuates 
cutaneous hypersensitivity to heat and mechanical stimuli through the 
degeneration of nerve fibers. TRPV1, a cationic channel that is activated by 
capsaicin, stimulates the increased movement of sodium and calcium ions 
into sensory cells that depolarize nociceptive neurons and cause action 
potential firing. This creates an analgesic effect that desensitizes the 
nociceptive areas to which the patch or topical treatment is applied to. 

 

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Figure 8. Capsaicin mechanism of action 

Unlike other topical alternatives, patches are unique in their method of drug 
delivery as they can provide extended release of the drug in regulated 
concentrations to prevent overdose and unwanted prolonged effects. 
Neuropathic pain is a type of chronic pain. Therefore, capsaicin effectively 
attenuates pain for longer periods depending on several factors that are 
being researched in recent developments. The duration of the analgesic 
effect is affected by the concentration of capsaicin, capsaicin-induced 
calpain-mediated ablation of axonal terminals, axonal mitochondrial 
dysfunction, and microtubule disorganization62. Calpain is a protease 
activated by the influx of overbearing levels of calcium into the cell which 
cleaves cytoplasmic and nuclear substrates causing cells to end up 
undergoing apoptosis. While calpain enzymes are involved in processes such 
as cell division, differentiation, and migration, their apoptotic response 
allows for protection from other malignant cell lines including 
hepatocarcinoma, prostate cancer, human glioma, breast cancer cells, and 
human gastric cancer. Therefore, even in different contexts regardless of the 
causation of said neuropathic pain, capsaicin appears to be a versatile 
remedy. 

A randomized clinical trial involving the application of NGX-4010, a 
high-concentration capsaicin patch, to treat painful HIV-associated 
neuropathy areas was conducive to a decrease in the average pain felt by 
participants (n=422)63. The study involved four groups: NGX-4010, 60 

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Minutes (60 min of high concentration capsaicin 640 mcg/cm^2), Control 
Group, 60 Minutes (60 min of low concentration capsaicin 3.2 mcg/cm^2), 
NGX-4010, 30 Minutes (30 min of high concentration capsaicin 650 
mcg/cm^2), Control Group, 30 Minutes (30 min of low concentration 
capsaicin 3.2 mcg/cm^2). The change in mean for the pain score between 
weeks 2-12 of the study period on a scale from 0-10 (0 = no pain, 10 = worst 
pain) for the above groups listed were -32.8, -30.0, -26.2, and -19.1 
respectively. The “NGX-4010, 60 Minutes” group exhibited the largest 
reduction in pain score. This suggests that a higher concentration of 
capsaicin and a longer duration of application is optimal. 

Another common analgesia-induced patch used to treat neuropathic pain is 
through the local anesthetic lidocaine64. Frequently juxtaposed with 
capsaicin, both drugs are mediators for neuropathy, but should not be used 
interchangeably. Their mechanism of action, situational application, and 
analgesic effects differ. Lidocaine works to block nerve signals in the area of 
application by inhibiting the action potentials occurring between nerves 
through interference with sodium channels. It is mainly used in medical 
procedures that require localized analgesia, resulting in a numbing sensation 
in the area due to the blockage of transmission signals. However, both 
lidocaine and capsaicin are effective neuropathic pain relievers that produce 
anti-inflammatory effects, it is believed that lidocaine is more effective short 
term like in cases of dental procedures or minor abrasions while capsaicin is 
more effective long term involving treatment of allodynia and hyperalgesia. 

A double-blinded, placebo-controlled, parallel-group study was conducted 
to observe the development of adverse effects in type 2 diabetics 
experiencing symptoms of peripheral neuropathy (pricking sensations, 
numbness, burning, and aching in feet) for more than 10 years. Only males 
ages 40-60 were chosen as participants for this study (n=273) to avoid 
possible hormonal issues as variables. Patients scored from 0-10 (0 = no 
pain, 10 = worst pain). The study groups are as follows: Group LL (5% 
lidocaine patch 700 mg lidocaine for 60 min), Group LP (placebo patch for 
60 min), and Group LC (8% capsaicin patch 179 mg for 60 min). After 24 
weeks, Group LC displayed significantly reduced pain scores compared to 
Group LP. The average pain scores for the groups are as follows: LL: 6.4 to 
4.9, LP: 6.1 to 5.7, LC: 6.7 to 3.6. 

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Group average satisfaction scores (0 = poor, 4 = excellent) are as follows: LL: 
2.1 to 3.2, LP: 2.2 to 2.5, LC: 2.0 to 4.2. Showing higher and improved 
scores than Group LL in both average pain score and satisfaction score, 
Group LC demonstrates a more potent analgesic effect. 

5. Future Direction/Implications 

The emergence of nanotechnology, external modalities, and passive 
treatments has changed the future of the pain management industry. With 
the status of pain alleviation not curing or fully treating the problem, these 
new developing treatments show promising outcomes. They have shown 
fewer side effects and complications because of their external and 
non-invasive nature. For the side effects, they also showed no addiction, 
respiratory depression, and irregular bowel movements that are common in 
the current treatments such as opioids. 

In addition, the style of these procedures has been demonstrated to be more 
cost-effective when compared to surgical procedures and the repetitive 
prescriptions of ongoing pain medicine. Even with these advantages of the 
treatments, there still needs to be consideration that these are developing 
and still relatively new with more research needing to be done before 
widespread usage. Additionally, more research must be done to make sure 
that each method would address the root causes of pain. Despite these 
treatments still being developed, there would be ethical considerations to 
address during their development. Those ethical considerations include 
obtaining informed consent, ensuring patients understand both the benefits 
and risks, guaranteeing access to treatment without financial or 
insurance-related barriers, and addressing conflicts of interest among those 
promoting the treatments. These therapies have currently optimistic results 
and will change the future of pain treatment. 

6. Conclusion 

As the field of biotechnology continues to grow, the information gained 
here will help influence and promote numerous treatment modalities that 
will help address chronic pain in patients. These modalities would offer 
more options for the large population of individuals who suffer from pain. 
In addition, they would be able to treat chronic pain and relieve it greater 

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than the ongoing treatments. Nanotechnology can effectively work with 
opioids but enhance their safety profile with their controlled delivery and 
high specificity. The non-pharmaceutical and external treatments such as 
myofascial release, TENS, photobiomodulation, and the capsaicin patch are 
non-invasive and give little to no complications and chances of infections. 
Although these treatments require further research, they have shown 
positive outcomes with a good impact on the future of pain management. 
Furthermore, pain treatments will continue to advance and evolve, 
expanding the range of procedures available to patients, ultimately 
improving their wellbeing. 

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