Nanotechnology application for pain therapy

Abstract

Prolonged delivery of analgesic drugs at target sites remains a critical issue for efficient pain management. The use of nano-carriers has been reported to facilitate applicable delivery of these agents to target sites with a reduced level of systemic toxicity. Different analgesics have been loaded onto various nano carriers, including those that are natural, synthetic and copolymer, for various medical applications. In this review, we will discuss the concept of nano-formulated carriers for analgesic drugs and their impacts on the field of pain management.

Keywords:

• Analgesic drugs
• nano-carriers
• pain
• toxicity

Introduction

Pain is defined by the International Association for the Study of Pain as an unpleasant sensory and emotional experience associated with potential tissue damage [1]. Pain is documented as a major medical issue and is considered ineffectively treated most surgical procedures [1]. The peripheral and the central nervous system are involved in the perception of pain, with the spinal and supraspinal components of the central nervous system (CNS) playing important roles [2]. Analgesic drugs have several effects on the peripheral and CNS (Figure 1), these drugs include acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) opioid drugs like morphine. NSAIDs are the most generally used therapeutic drugs and are effective at controlling release applications [3]. They have potent anti-inflammatory, analgesic and antipyretic properties, but also cause several adverse effects with the risk of toxicity.

Figure 1. Showing pain pathway. This figure was culled from [4].

Targeted drug delivery offers effective, accurate, and non-toxic therapeutic interventions for treatment of various disease states, by reducing or limiting toxic side effects and as well as increasing drug action. Effective drug targeting relies on numerous factors that related to either the carrier or target. According to Koning et al., drug carrier must be stable biologically, possess the capabilities of protecting the carried drug from degradation, protect the host body from toxic side effects and possess the ability to deliver the loaded drug precisely to the target cell population in vivo [5]. Many different approaches using various nano-formulated biomaterials have been proposed and investigated, materials like liposomes, nano-particles, nanofibres hydrogel, to deliver anaesthetic drugs. Nanotechnology is a multidisciplinary science field involving the design and engineering of physical objects less than 500 nanometres in size. Over the last two decades, nanotechnology has offered a diverse range of nanoscale tools specially fabricated for therapeutic use in medicine. For analgesic drug-delivery systems, nanotechnology has been demonstrated to have the potential to enhance drug delivery and reduce side effects of these analgesic drugs. Recently, application of novel nanotechnology-based techniques and methods, such as implantable drug delivery devices, and transdermal and transmucosal delivery systems for delivery of different types of drug for cancer, anaesthetics, etc. This review will give a summary of available study about the different applications of nanotechnology in pain therapy both in clinical and experimental cases.

Nano-carriers for pain therapy

Drug delivery systems have been applied in pain therapies to improve toxicity profiles by targeted delivery to specific places in the body, increase bioavailability, and to provide longer period of drug release. As reported by [6] the delivery of opioid-based compounds to specifically target peripheral opioid receptors in an injured tissue to stimulate analgesic and anti-inflammatory activity is an area of great interest in pain therapy. Nanosystems used for delivering compounds intended for pain therapies, such as local anaesthetics [7] or NSAIDs. The encapsulation of local anaesthetics into nano-formulated materials like liposomes, nano-particles, nanofibres etc. allows slow and controlled release, prolonged duration of action, decreased plasma concentrations and reduced toxicity to the body systems. There have been several pre-clinical studies to investigate the efficiency of encapsulated local anaesthetics, such as bupivacaine or lidocaine, into numerous nano-formulated biomaterials at different pH combinations [7]. There have been several reports stating an increased duration of anaesthesia and sensory nerve blockade. This area of research of applying targeted drug delivery and the use of nano-carriers like liposomes, nano-particles and nanofibres in the management of pain is a novel area of research, with potential clinical benefits.

Application of liposomes in pain therapy

Liposomal formulations of local anaesthetics have been shown to provide significantly sustained pain relief after surgical procedures and in chronic cancer [7]. Avnir and co-workers, in their study, reported the use of long-circulating PEGylated liposomes containing methylprednisolone or betamethasone to treat Lewis rats with adjuvant-induced arthritis (AIA) both at early and late stages of the disease [8]. Non-steroidal anti-inflammatory drugs have also been demonstrated as an analgesic and anti-inflammatory agent; however, they have been reported to be related with several interactions with other medications and thereby causing serious toxic effects to the body systems [9]. Several nano-formulations have been successfully demonstrated in preclinical studies [10–13] to improve the efficacy and decrease the toxicity of NSAIDs by targeted delivery to the site of inflammatory pain. Dong et al. reported that celecoxib-loaded liposomes encapsulated in hyaluronate gel was more potent than either single agent in pain control and cartilage protection in a rabbit knee osteoarthritis model after intra-articular injection [14].

Gorfine and colleagues in their clinical study compared the magnitude and duration of postoperative analgesia from a single dose of bupivacaine extended-release injection with placebo administered intraoperatively via wound infiltration in 184 patients undergoing haemorrhoidectomy. They concluded in their report that the results showed that the liposomal formulation significantly and effectively decreased pain over 3 days and reduced the need for opioid compared to placebo [15]. In another similar clinical study, Lafont et al. reported the efficiency of liposomal bupivacaine formulation in reducing prolonged pain in a patient with chronic cancer that lasted for 11 h after its administration compared to 4 h for plain bupivacaine [16]. Furthermore, Puglia and colleagues demonstrated the use of indomethacin-loaded liposomes incorporated into hydrogels in UVB-induced erythema on healthy human volunteers. They concluded in their report that the results provided a more prolonged anti-inflammatory effect in comparison to a gel formulation containing free drug, allowing a sustained release of the drug [17].

Application of nano-particles in pain therapy

Hua and Cabot also reported the use of targeted nanoparticles to deliver opioids, in particular, loperamide HCl, specifically to peripheral opioid receptors to stimulate analgesic and anti-inflammatory actions for use in painful inflammatory conditions [18]. Ward et al. also reported other sustained engineered release systems to extend the duration of action of opioid analgesics [19]. Liu and colleagues in their report demonstrated that endomorphin-1, adsorbed onto the surface of butyl- cyanoacrylate nanoparticles and coated with polysorbate 80 could be administered intravenously as an analgesic agent [20]. Furthermore, Tosi and co-worker investigated the antinociceptive efficacy of peptide-derivatized nanoparticles loaded with loperamide HCl in an in vivo experiment for delivery to central opioid receptors. They concluded that there was a peak percentage of possible effect of 60% at 4 h and a significant continued release effect for 6 h after the administration of 0.7 mg of loperamide HCl in Wistar rats [21]. In addition, Chen et al. reported that nanoparticles made up of loperamide and PLGA-PEG-PLGA triblock copolymer coated with poloxamer 188 or polysorbate 80 enhanced penetrations across the blood–brain barrier in comparison to PLGA-PEG-PLGA nanoparticles and PLGA nanoparticles.

Application of nanofibres in pain therapy

There have been reports of the application of nanofibres with loaded analgesics for various clinical applications. Grewal and colleagues in their report fabricated a biodegradable polycaprolactone (PCL) transmucosal patches for delivering diclofenic sodium to treat toothaches. They concluded in their report that the results were superior in terms of patient compliance, safety and therapeutic efficacy [22]. Shen and co-worker demonstrated the use of Eudragit L 100–55 nanofibres loaded with diclofenac sodium exhibited pH-dependent drug release profiles and had a sustained and complete release at pH 6.8. They finally concluded that their results recommended that drug-loaded Eudragit L 100–55 nanofibres could potentially serve as an oral colon-targeted drug delivery systems [23]. Table 1 gives a summary of the potential applications of nanofibres in pain relief.

Table 1. Showing various applications of nanofibres for pain relief. Culled from [4].

Materials	Nanofibres	Analgesic	Route	Application	References
Polycaprolactone	∼120 nm	DS	Trans-mucosal	Oral patch toothache	[22]
Eudragit L 100–55	441 nm	DS	Trans-mucosal	Oral–colon target	[23]
Polyvinyl alcohol	121 ± 11 nm	Meloxicam	Trans-dermal	Analgesic patch	[24]
Poly(lactic-co-glycolic acid)	285–641 nm	DS	Membrane	No specific	[25]
Poly(maleic anhydride-alt-2-methoxyethyl vinyl ether	100 nm–10 μm	DS	Membrane	No specific	[26]
Poly(3-hydroxybutyrate-co3-hydroxyvalerate)	500 nm	DS	Membrane	No specific	[27]
Polyvinyl alcohol	∼160 nm	Ketoprofen	Membrane	No specific	[28]
Poly (lactic acid)	∼170 nm	IBU	Membrane	No specific	[29]
Poly(l-lactide-co-epsilon-caprolactone)		Indomethacine	Nano-scaffold	Tracheal stent	[30]
Poly(95 epsilon-capro/5 d,l-lactide)	130 nm	DS	Nano-scaffold	No specific	[31]
Zein/Eudragit S 100	50–200 nm	Aceclofenac(Z)/pantoprazole(E)	Oral	Gastric ulcer treatment/prevention	[32]
Zein	670–940 nm	IBU	Membrane		[33]
Cellulose acetate/poly-(vinyl pyrrolidone)		IBU	Trans-dermal	Analgesic patch	[34]
Eu 3+/Tb 3 + (MBG) + hydroxyapatite	100–120 nm	IBU			[35]
Poly(lactic acid) and poly(lactic-co- glycolic acid)	610–1010 nm	Acetaminophen	Membrane	No specific	[36]
Poly (lactic-co-glycolic acid)	230–710 nm	Lidocaine	Epidural	Central analgesia	[37]
Polyvinyl-pyrrolidone	300–800 nm	Acetaminophen	Oral	Solid dispersions	[38]

All nanofibres were manufactured via electrospinning. DS: Diclofenac sodium; IBS: Ibuprofen.

In another report by Tseng et al., where they fabricated a biodegradable lidocaine embedded poly([d,l]-lactide-co-glycolid) nanofibres for delivering analgesics to the epidural space of rats receiving laminectomies. They concluded in their report that the lidocaine-loaded nanofibres successfully provided a prolonged release of lidocaine for more than 2 weeks [37]. Finally, Yu and co-workers reported that the use of electrospun nanofiber-based solid dispersions (SDs) demonstrated an improved dissolution compared with other SDs; which is as a result of the large surface area and high porosity that resulted from the web structure of the electrospun nanofiber-based SDs and the more homogeneous analgesic (acetaminophen) distribution in the nanofiber matrix [38].

Nanofibres in wound pain relief

In a recent study by Chen and colleagues, they demonstrated that electrospun PLGA/collagen nanofibrous membranes loaded with vancomycin, gentamicin and lidocaine successfully accelerated the healing process of the wound and also, was efficient in the sustained release of the loaded lidocaine thereby reducing the wound pain [39,40]. In another study by Wang et al., they fabricated a chitosan nanoparticle/PCL composite electrospun nanofibres with a core-sheath structure loaded with rhodamine B and naproxen. They concluded in their report that the results demonstrated required controlled release of the two agents, providing a new method to obtain programmed or temporal release of multiple agents [41] (Table 2).

Table 2. Showing application of nanofibres in wound pain relief. Culled from [4].

Material	Analgesic	Concurrent Medication	Structure	Function	Fabrication	References
Poly(lactic acid)	Ibuprofen		Membrane (bandage)	Anti-inflammatory	Electrospun	[29]
Chitosan polycaprolactone	Naproxen	Rhodamine B	Core-sheath	Analgesia/infection	Electrospun	[42]
Poly(lactic-co-glycolic acid)	Lidocaine	Vancomycin	Sandwich	Analgesia/infection control Accelerate wound healing	Electrospun	[43]
Poly(epsilon-caprolactone)	Curcumin		Membrane	Anti-inflammatory/anti-oxidant	Electrospun	[44]
Phe-Phe	Naproxen		Hydrogel	Analgesia	Self-assembly	[45]

Nanotechnology and cancer pain

One-third of every cancer patients experienced from moderate to severe pain after receiving active therapy. Nanotechnology has demonstrated a significant advancement in the management of pain in cancer patients over the past two decades and its most notable applications is in development of a novel drug-delivery system. Oral transmucosal fentanyl citrate (OTFC) is the first medication formulated specially for the treatment of pain, and via a microfabrication nanotechnology, it delivers its most active constituent, fentanyl, in a unique oral transmucosal delivery system [46]. The OTFC delivery system combines nanoparticle technology for the enhancement of transmucosal transport of fentanyl. This delivery method gives a simple, tolerable and patient-compliant administration of fentanyl for prompt onset of opioid analgesia specifically for pain episodes related with cancer. According to Csaba et al., the success of high surface-volume ratios of nanosized drug boosts drug–mucosal interactions and thus increases the bioavailability of fentanyl compared with the drug administered in larger particles [47]. There have been several studies that demonstrated the use of OTFC for the management of pain in adult patients with cancer. Examples like Christie and colleagues in their two randomized, double blind, dose titration studies of OTFC demonstrated that in 74% of their patients, they were able to identify a safe and applicable dose of OTFC. They further reported that the mean successful dose of OTFC in their study was approximately 600 μg. They also stated that no correlation was recorded between the successful dose of OTFC and the total daily dose of around-the-clock opioid in their study, denoting that the optimal dose of OTFC cannot be predicted by the total daily dose of fixed-schedule opioid. Additionally, OTFC was reported to be efficient in producing a greater analgesic effect, global satisfaction and a more rapid onset of action than the usual pain medication [48] Similarly, Portenoy and co-worker were able to pinpoint a safe and effective dose of OTFC in 76% of their patients in a randomized, double-blind, dose titration studies of OTFC [49].

In another clinical study by [50], they investigated the efficacy of OTFC in a randomized, placebo-controlled trial and one randomized comparative study with immediate-release morphine sulphate (MSIR) using 93 patients, who successfully finished the titration phase and proceeded to the randomized, double-blind phase. Each patient was administered 10 sets of medication (five contained OTFC + placebo capsules; five contained placebo units + MSIR capsules). The patient consumed a full set of study medication at each episode of pain, with all 10 doses to be taken within two weeks period. They concluded in their report that in the primary efficacy analysis OTFC was statistically significantly efficient to the MSIR in regards to pain intensity and pain relief at each time point, and global performance rating.

Furthermore, in another open-label study by [51], investigation of long-term safety and tolerability of OTFC in ambulatory cancer patients with pain was carried out. Briefly, 41,766 units of OTFC were administered to 155 patients to treat 38,595 episodes of pain. Patients averaged 2.9 pain episodes per day. They concluded in their report that about 92% of episodes were successfully treated with OTFC and they recorded no trend towards reduced efficiency with increase in time, they also stated that the global satisfaction ratings were constantly above 3 showing a very good to excellent relief.

However, there were reports of common adverse events related with OTFC like somnolence, constipation, nausea, dizziness and vomiting as well as a report about six patients that withdrawn from the therapy because of an OTFC-related adverse event. Finally, they concluded that OTFC was administered safely and effectively during long-term treatment of pain in cancer patients. Burton and colleague in their clinical study evaluated the effectiveness of OTFC in the outpatient management of severe pain in cancer patient. Before the OTFC treatment, the mean pain intensity for all patients was recorded at 9.0. After OTFC treatment, the mean pain intensity for all patients reduced to a value of 3.0, signifying reduction in pain intensity. In conclusion, Burton and colleagues suggested that OTFC could be an effective alternative over intravenous opioids to rapidly titrate analgesia in selected opioid-tolerant cancer patients experiencing severe pain [52].

Conclusion

Nano-formulated biomaterials have attracted increasing attention for use in biomedical applications such as controlled drug delivery. The use of drug-loaded nano-particles would be promising for several of acute and chronic pain conditions. Various analgesics have been loaded onto different nano-formulated and has exhibited potentials to improve therapeutic efficiency. In addition, nano-formulated materials loaded with analgesics have been demonstrated to relief cancer pain. Their application will lead to improved efficacy, prolonged duration of action and improved side effect profile of analgesic therapeutics. However, more clinical and experimental studies should be done to investigate more the efficacy of nano-based therapeutics to target and treat pain.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.