Nanomedicine in the Use of Opioids: Enhancing Analgesia, Mitigating Harm

Abstract

Opioids represent one of the oldest classes of drugs in medicine and remain central to pain management to this day. However, their use is limited by a series of adverse effects, and they are notorious for their addiction potential and for contributing to the opioid epidemic in the US. Nanomedicine, the branch of nanotechnology that utilizes materials at the nanoscale for drug delivery, provides a unique platform that can potentially revolutionize conventional opioid treatment. The aim of this literature review is to summarize the latest research on opioid nanoformulations and their potential to increase analgesic efficacy while minimizing associated risks. Preclinical studies have already demonstrated that both liposomal and dendrimer-based opioid formulations allow for extended release and, consequently, more prolonged and stable analgesia. Moreover, nanoemulsions are currently being investigated for the delivery of opioid compounds, offering formulation versatility and improved bioavailability while maintaining an improved safety profile. At the same time, the use of nanomedicine for vaccines against opioids may enable novel therapeutic strategies to be developed for individuals with opioid addiction. However, several barriers need to be overcome for the promise of nanomedicine to be fulfilled, including the lack of clinical trials, difficulties in mass production of several nanoparticles, toxicity concerns, and regulatory issues.

1. Introduction

The use of opioids by humankind dates back to the ancient Sumerians, when opium was extracted from Papaver somniferum. Nevertheless, it was not until the 19th century that the active ingredients were isolated, leading to the discovery of morphine and codeine [1]. Opioids represent a broad class of drugs primarily used for the management of acute and chronic pain of various etiologies (pain due to malignancy, arthritis, or other causes).

Among the wide range of opioids that have been developed, morphine, fentanyl, tramadol, codeine, hydromorphone, and oxycodone are the most commonly administered opioids across a wide spectrum of settings that can range from perioperative care to malignant and nonmalignant chronic pain [2,3]. The different types of opioids differ significantly with respect to their potency, onset, and duration of action. For instance, fentanyl is 100 times more potent than morphine, and due to its high lipophilicity, it exerts a faster onset with a shorter duration compared to the latter, which is considerably more hydrophilic [4].

Although four opioid receptors have been described (mu, kappa, delta, and nociceptin receptors), current knowledge supports that it is the mu receptor that mediates the majority of both the desired and adverse effects of opioids, which include analgesia, sedation, euphoria, constipation, and respiratory depression. However, the kappa receptors also promote analgesic effects and cause sedation and dyspnea in patients [5].

In parallel, opioids are notorious for their addictive properties, with the opioid epidemic representing a major crisis in the public health system of the USA. It should be noted that drug overdose represents the leading cause of accidental death in the USA, and most deaths involve opioids [6]. According to the CDC, of the 105,000 people who died due to drug overdose, almost 80,000 were due to opioids in 2023 [7].

In this context, nanomedicine, a branch of nanotechnology employing materials at the nanoscale [8], aims to address several of the currently unmet needs in pain management. Although no single universally accepted definition of nanomedicine exists, the European Science Foundation defines it as “the science and technology of diagnosing, treating, and preventing disease and traumatic injury, of relieving pain and of preserving and improving human health, using molecular tools and molecular knowledge of the human body” [9]. This definition explicitly includes pain management and thus positions nanomedicine as a highly relevant and promising field for the optimization of opioid-based therapies.

Indeed, nanomedicine can contribute to the safer and more effective use of opioids in a variety of ways. These can include, among others, nanoformulations that can favorably alter the pharmacological/pharmacokinetic characteristics of different opioids. By tailoring pharmacokinetics and release profiles, nanoparticle formulations can maintain analgesia while reducing peak-related adverse effects, such as respiratory depression. Such formulations currently include liposomes, dendrimers, and other types of nanoparticles (NPs) and hold the potential to optimize opioid clinical profiles while reducing undesired effects. At the same time, the use of nanomedicine-based vaccines could be applied in the treatment of opioid addiction, while nanoformulations of naloxone could produce prolonged opioid antagonism.

This review aims to summarize current research on nanoparticle-based analgesics and to investigate the role of nanomedicine in mitigating the adverse effects associated with opioids.

2. Methods

This narrative review was conducted to evaluate the role of NPs in opioid-based analgesia and in mitigating the harms associated with opioid use. A targeted literature search was performed across PubMed, Web of Science, and Google Scholar for articles published up to December 2025. Primary search terms included “nanoparticles,” “nanomedicine,” “opioids,” “nanovaccines,” “liposomal morphine,” “liposomal fentanyl,” “liposomal naloxone,” “dendrimer opioids,” “solid lipid nanoparticles opioids,” “opioid hydrogels,” “inorganic nanoparticles opioids,” “addiction nanoparticles,” and “systems biology nanomedicine.”

Eligible studies included basic science experiments, animal models, translational studies, systematic and narrative reviews, and clinical reviews. Case reports and correspondence articles were excluded. Articles were screened for relevance, with emphasis on mechanistic insights, pharmacokinetic and pharmacodynamic findings, safety profiles, and translational potential.

3. Liposomes as Carriers of Opioids

Liposomes represent a class of self-assembled lipid-based vehicles that can serve as drug delivery systems. Their basic structure is composed of a bilayer that encapsulates an aqueous core compartment, while their dimensions can vary greatly from the nano- to the micrometer scale [10]. The hydrophobic nature of the bilayer and the hydrophilic nature of the core give them the ability to act as carriers for both hydrophilic and hydrophobic drugs [11]. Of the different nanosystems that are available, liposomes hold a special value due to their high degree of clinical translation [12]. Importantly, their regulatory familiarity and scalable manufacturing make liposomes the most clinically mature nanoformulations among the various opioid delivery systems [13,14].

3.1. Liposomal Morphine

Morphine encapsulated in liposomes has been investigated in several studies. In a 2019 study, which used a mouse model [15], free morphine was compared to liposomal morphine. The multilamellar vesicles tested showed an encapsulation efficiency of nearly 90% with a drug loading capacity of approximately 18%. Following intraperitoneal administration, the studied nanoformulations achieved an extended-release drug delivery, with morphine being detected in circulating blood up to 25 h post-injection. This is an important finding since conventional morphine typically exhibits plasma detectability for only a few hours [16].

It should also be noted that only the presence of morphine was analyzed. Metabolite profiling was not performed, although the authors commented that their metabolites are expected to be detected after longer periods of time when liposomes are used. An interesting finding of this study was that encapsulated morphine showed a reduced duration of reward and aversive memories. This observation suggests that liposomal encapsulation could alter engagement of central reward circuitry, potentially by reducing rapid peak brain concentrations. Such pharmacokinetic behavior is particularly relevant since rapid brain peak concentrations have been strongly associated with abuse liability [17]. However, the absence of metabolite profiling and addiction-related behavior endpoints represents an important limitation that prevents definite conclusions from being drawn.

Interestingly, liposomal morphine for epidural use has also been researched. In an animal study conducted by Bethune et al. [18], epidurally administered liposomal morphine showed a sustained-release preparation, which prolonged the presence of morphine in three compartments: plasma, epidural, and intrathecal space. It should be mentioned that the research group used a microdialysis pig model. Liposomal sufentanil was also investigated, and no significant prolongation of the drug in any of these compartments was observed.

Moreover, the study concluded that liposome composition not only changes the rate of the drug’s epidural bioavailability but also influences its distribution between different compartments. This study highlights a critical difference between opioid lipophilicity and carrier composition since only morphine—and not sufentanil—showed prolonged compartment retention. Interestingly, of all the opioids tested, sufentanil had the greatest encapsulation efficiency (100%). This finding underscores that encapsulation efficiency alone cannot predict performance in vivo. The conclusion that can be drawn from this is that nanoformulation benefits are drug-specific and should not be generalized across opioids. Therefore, the molecular properties of opioids (such as membrane affinity and molecular size) seem to be key determinants of the nanoformulation performance.

3.2. Liposomal Fentanyl

Fentanyl is a member of the piperidine family and a potent synthetic agonist of the mu-opioid receptor. Compared to morphine, it exhibits a considerably increased potency (being 50 to 100 times more potent). It represents a routinely used drug for both analgesia and anesthesia [19,20]. For highly lipophilic drugs, as in the case of fentanyl [20], formulations based on liposomes display two clinically important characteristics: prolonged drug delivery (and consequently prolonged analgesic effect) and reduced maximum plasma concentrations [21]. Together, these properties may widen the therapeutic window by preserving analgesia and reducing respiratory depression risk at the same time.

In a 2025 study [21], liposomal fentanyl nanoformulations were developed and characterized using AI-assisted methods for their analgesic efficacy in a rat model. The encapsulation efficiency of these liposomal preparations was reported to be 85%. The presented nanoformulation showed prolonged drug release over a period of 12 h and, compared to conventional fentanyl, a statistically significant prolonged anesthesia without respiratory depression. In particular, the group of rats (n = 10) that received standard fentanyl (1 mg/kg) showed respiratory depression (3/10) and sedation (5/10). In contrast, the liposomal fentanyl group (n = 10, dosage 1 mg/kg) showed neither respiratory depression nor sedation. Mortality was not observed in either group.

However, detailed pharmacokinetic concentration–time curves, particularly regarding brain distribution, were not fully reported. As a result, quantitative safety assessment remains limited. At the same time, the use of an AI model allowed for optimized formulation development, a key component for every nano-based system.

In another study that dates to 1995, the nasal administration route was employed, and liposomal fentanyl was tested for its analgesic efficacy in healthy volunteers [22]. The rationale of this study was to offer a noninvasive approach, to avoid first-pass metabolism by the liver, and to achieve sustained plasma concentration. After administration, approximately 12% of the administered fentanyl was absorbed following inhalation, and it was assumed that the rest was metabolized by the lungs, lost into the gastrointestinal tract, or lost in the form of aerosol.

Interestingly, the researchers addressed the issue of fentanyl contamination due to aerosols. Blood samples were collected and analyzed from volunteers who sat 1 m away from the nebulizer of the studied subjects, and no fentanyl was detected. However, there were important limitations of the study, including the unknown fate of fentanyl that could be deposited in the oral cavity and the tracheobronchial tree. Thus, despite its noninvasive nature, intranasal liposomal fentanyl lacks the dose predictability required for reliable clinical analgesia.

4. The Unique Properties of Dendrimers

Dendrimers represent another type of nanoparticle that has been widely studied in the field of nanomedicine. Their structure consists of an initiator core with multiple layers that spread radially from it, while terminal groups are found on the surface. They owe their name to their resemblance to the architecture of a tree [23]. From a chemical perspective, dendrimers can form covalent bonds with drug molecules, thus granting enhanced stability, while they present increased structural homogeneity and have shown satisfactory pharmacokinetic reproducibility [23,24].

It should also be noted that the globular shape of these NPs allows the presence of void spaces within dendrimers. These internal cavities can host drugs or other functional molecules in a protected environment. At the same time, the higher dendrimer generations (the most distant layers from the core) allow the attachment of functional groups that influence both the loading capacity and the chemical diversity of the molecules that can be introduced. This property enables the design of multifunctional dendrimers that have distinct molecules ranging from antibodies to vitamins and sugars. It should be highlighted that the use of ligands on dendrimers can enable targeting of specific tissues in vivo [25]. Although it is evident that dendrimers exhibit superior structural precision compared to liposomes, this advantage comes at the expense of a complex synthetic process and unresolved concerns regarding long-term biocompatibility [26,27].

Dendrimers and Morphine for Prolonged Anesthesia

Ward et al. [28] investigated the potential of PAMAM dendrimers complexed with morphine prodrugs to produce prolonged anesthesia. The researchers employed PAMAM dendrimers (poly(amidoamine dendrimers)), which were complexed with two different morphine prodrugs. The process did not require salt, and the prodrugs used allowed for a controlled morphine release. As a result, analgesia was extended from approximately 2 h in the control group to nearly 6 h in the two animal models used (guinea pigs and rats).

It should be noted that the release of the prodrugs was rapid in the plasma of both animal models. However, the secondary release of free morphine from these prodrugs showed differences in the time to reach a plateau, which was attributed to the difference in plasma esterase activity. The toxicity screening tests, which involved blood, urine, and histopathology specimens, did not reveal significant drug-related findings in either animal population. Indeed, the suggested nanoplatform showed promise, and it could also be tested for other opioids and analgesia-related pharmacological compounds.

5. Other Nanoformulations

NPs represent a vast category of materials, and although liposomes are currently the most common type to be clinically translated, several other NPs have been investigated, although to a lesser degree. These include nanoemulsions, polymers, lipids, and metal NPs. It should be noted that metal NPs such as gold NPs [29] and carbon nanotubes [30] have been studied predominantly in the context of identification of opioids, but these applications are outside the scope of this review.

5.1. Solid Lipid Nanoparticles

Solid lipid nanoparticles (SLNs) are composed of a solid lipid (from which they receive their name) at body temperature, and they hold the advantage of being able to bind different types of molecular cargos. At the same time, they can be administered via different routes, and they are reported to have increased stability, low material cost, and ease of production [31].

In 2021, Khanna et al. [32] intranasally loaded intranasal SLNs with nalbuphine (a synthetic opioid) and subsequently tested their analgesic efficacy. TEM microscopy revealed that the prepared SLNs had a spherical shape and an average size of 170 nm. Their safety profile was evaluated in vitro using HEK293 cells. No toxicity was observed on the MTT assay, with unaffected cell viability up to a nalbuphine SLN concentration of 500 μM. In parallel, an animal study (a rat model) using gamma scintigraphy showed that the formulation had reached the brain, which was the target tissue. It should be mentioned that this formulation had a high encapsulation efficiency (surpassing 90%). Its efficacy was evaluated using the hot plate assay, showing an action onset at 10 min post-administration with a peak effect at 1 h. While the encapsulation efficiency represents a major advantage, comparative pharmacokinetic studies against free nalbuphine were not provided.

Spadaro et al. [33] also evaluated SLNs as carriers for LP2 (an opioid peptide that binds to both mu and delta opioid receptors). This in vitro investigation showed that the production of this nanoformulation exhibited several desired characteristics, including low polydispersity index, sufficient stability, and small particle size. However, the absence of in vivo validation limits the assessment of both toxicological and analgesic relevance. These characteristics make the suggested SLNS promising for both parenteral and transdermal administration. Nevertheless, in vivo experiments are essential for evaluating toxicity and analgesic efficacy.

5.2. Polymeric NPs

Polymeric NPs represent an appealing type of NPs with potential in drug delivery and considerable advantages compared to conventional systems due to their biocompatibility, their ability to encapsulate a plethora of pharmacological molecules, and their controlled release properties [34].

Hoseinifar et al. investigated the efficacy of polymer NPs (composed of three different polymers (hydroxypropyl methylcellulose, carbopol, and ethyl cellulose)) loaded with morphine in achieving a sustained release of morphine. The authors reported a drug loading capacity that reached nearly 60%, with NP dimensions ranging from 25 to 30 nm. This study, which employed fibroblast cells, showed no signs of cytotoxicity. Sustained morphine release was observed for up to 6 h. Thus, the researchers introduced a novel formulation to be studied for oral morphine administration that could bypass first-pass metabolism [35].

A different approach to polymeric NPs in the context of opioid analgesia was investigated by Shen et al. [36]. In this study, the researchers created stable suspensions of nano-curcumin to counter morphine’s low bioavailability when administered per os, along with other undesired pharmacokinetic characteristics (high rates of metabolism and clearance). All the polymers tested had a drug loading capacity of approximately 45%, while encapsulation efficiency surpassed 90%. However, this study (conducted in mice) showed that when the formulations were administered orally to mice tolerant to opioids, morphine anti-nociception was largely restored, as shown by the tail-flick and hotplate assays. Notably, this effect was not observed with free curcumin.

5.3. Nanoemulsions

Nanoemulsions represent a class of emulsions with droplet sizes typically ranging from 100 to 400 nm. They are characterized as colloidal dispersions containing at least two immiscible phases, and they are produced using sonication or microfluidization techniques [37,38]. These nanoformulations also hold the potential of serving as systems that can achieve prolonged release systems of pharmaceutical molecules and can be prepared using a variety of oils and surfactants, which are typically considered safe [39,40]. Studies in opioid nanoemulsions are extremely limited. Most of the nanoemulsion studies regarding analgesic efficacy have been conducted using NSAIDs and other non-opioid drugs [41].

Wang et al. [40] investigated the feasibility of using water-in-oil nanoemulsions to create sustained-release platforms for morphine and morphine propionate (morphine’s ester prodrug) in rats. The in vitro study showed a gradual release of morphine for up to 36 h; among the different oils used, soybean oil emulsion released significantly more morphine compared to sesame oil emulsion. An interesting observation was that the prodrug delivery was slower than morphine delivery, likely due to differences in lipophilicity. It should also be noted that the subcutaneous route was also shown to be effective since it produced plasma concentration like that of intravenous administration and showed peak concentration at 15 min. The authors also concluded that morphine’s analgesic effect could be prolonged up to 3 h by using nanoemulsions that contained Span 80 or Tween 80, which function as surfactants.

Taken together, the mentioned studies are indicative of the breadth of nanotechnology-based platforms, which have profound pharmacological advantages over conventional opioid (non-nanomedicine-based) treatments. The main findings of these studies are summarized in

Table 1. Overview of nanoparticle-based opioid formulations and their major findings.

Nanoparticle	Size (nm)	Route of Administration	Opioid	Experimental Model/Approach	Main Finding/ Limitations	Ref.
Liposomes	120 ± 45	Intraperitoneal	Morphine	In vivo (mouse)/pharmacokinetic analysis	Extended release: morphine was detected in circulating blood 25 h post-injection/Only plasma morphine concentration was investigated, not brain concentration or kinetics	[15]
Liposomes	Not reported	Epidural	Morphine	In vivo (pig)/ microdialysis model	Prolonged presence in plasma, epidural, and intrathecal space/No assessment of long-term analgesic effect, toxicity, or repeated dosing.	[18]
Liposomes	Not reported	Epidural	Sufentanil	In vivo (pig)/ microdialysis model	Unlike epidural morphine, prolonged presence was not observed/No assessment of long-term analgesic effect, toxicity, or repeated dosing.	[18]
Liposomes	120.4 ± 10.2	Intravenous	Fentanyl	In vivo (rat)/AI-assisted pharmacokinetic protocol	Prolonged drug release without respiratory depression/Short-term rodent pain model may not fully predict clinical efficacy and safety in humans.	[21]
Dendrimers	Not reported	Intravenous	Morphine prodrugs	In vivo (rats and guinea pigs)/pharmacokinetic analysis	Extended release of morphine prodrug, no apparent toxicity/Small sample size (3 rats and 3 guinea pigs).	[28]
SLNs	Multiple formulations ranging from 85.61–426.55	Intranasal	Nalbuphine (intranasal)	In vivo (HEK293 cells) and in vivo (Sprague-Dawley rats)/Gamma Scintigraphy	High encapsulation efficiency, the formulation reached target tissue (brain)/No brain/plasma ratios reported.	[32]
SLNs	29.79 ± 2.06	-	LP2 (opioid peptide)	In vitro/physicochemical characterization	Low polydispersity index, sufficient stability, and small particle size/No in vivo pharmacokinetic validation.	[28]
Polymeric NPs	25-30	-	Morphine	In vitro (fibroblast cells)/cytotoxicity assessment	Continuous morphine release, no cytotoxicity observed/No in vivo pharmacokinetic Validation.	[33]
Nanoemulsions	82.7 ± 1.7 106.7 ± 2.1 41.1 ± 0.7 43.9 ± 0.7 196.7 ± 1.5 51.8 ± 2.9	Subcutaneous	Morphine, morphine propionate	In vivo (rat)/physicochemical characterization and analgesic evaluation	Morphine release can be achieved for up to 36 h; surfactants Span 80 and Tween 80 can prolong analgesia in vivo/Brain morphine levels were not quantified.	[40]

.

5.4. Hydrogels

Gels represent soft and viscoelastic materials composed of three-dimensional polymeric chains within an aqueous or non-aqueous solvent. Hydrogels represent a subclass of such materials characterized by their property to retain large quantities of water (such as biological fluids) without losing their structural integrity. Due to their biocompatible nature and responsiveness to a variety of stimuli (including pH), they have a wide variety of potential applications, both therapeutic and diagnostic [42]. Their main clinical use is in wound dressings, but they can also be used in lubricants and contact lenses [43].

The rationale for using morphine hydrogel is the increased concentration locally (on the skin) with reduced side effects from distal targets. At the same time, patients reported high satisfaction when applying medications directly to the site of pain [44]. Mateus et al. [45] developed hydrogels containing morphine for topical applications in the context of pain elicited from wounds. The prepared hydrogels showed efficacy with respect to morphine release in vitro, while the gels were odorless, translucent, homogenous, and stable for a period of sixty days. The sterility of these formulations is of utmost importance since they can be applied to burnt or otherwise non-intact skin. The preservatives of choice—methylparaben and propylparaben—exhibited activity at pH values between 4 and 8. Regarding morphine hydrochloride release, it was reported that approximately half of the drug had been released in a time period of 6 h. The most important aspect of this formulation is that even after 70 days, morphine hydrochloride was not affected in the tested batches, and no significant pH changes occurred. Toward that direction, Jansen et al. [46] prepared a morphine-containing poloxamer 407 thermoreversible hydrogel with a reported sterility duration even after 20 months following preparation and initial sterilization. The contribution of this study is the proposed method, which allows for the preparation of a morphine-containing hydrogel that can be compounded in any pharmacy, thus improving its availability.

Despite these important advantages, to date, hydrogels remain limited to localized or superficial pain conditions and have not been sufficiently investigated for systemic analgesic needs.

5.5. Inorganic NPs

This class of NPs includes metal NPs (including noble metals such as gold and platinum), their oxides (such as zinc oxides), mesoporous silica, and magnetic NPs (MNPs).

Despite their potential, there is currently a major lack of clinically investigated nanoparticle formulations [47]. Studies involving opioids and inorganic NPs are extremely limited. Nevertheless, there are a few promising studies that suggest an enhanced analgesic effect when inorganic NPs are used in combination with morphine. A 2020 study [48] showed that green-synthesized Cu NPs not only showed anti-nociceptive properties in a mouse model, but when co-administered with morphine, they resulted in superior analgesic effects.

In a conceptually similar experiment, Chiguvare et al. [49] found that silver NPs from a plant extract had important analgesic properties. In the Swiss albino mouse model used, the researchers showed significant pain inhibition compared to aspirin. The analgesic effect was evaluated based on the number of paw licks, and administration of 200 mg/kg of silver NPs inhibited this behavior successfully (inhibition values between 73 and 98%). However, the mechanism that mediates this effect was not investigated. Although further research is needed, especially on the pharmacology of the analgesic mechanisms that mediate the effect of these NPs, their promise as potential components of multimodal analgesia is clear. It remains to be determined whether their combination with opioids could enable dose reduction while maintaining efficacy. Given that the underlying mechanisms are poorly understood, effects unrelated to classical opioid receptors could be a potential source of unpredictable pharmacologic outcomes.

Keshmati et al. [50] investigated the potential analgesic effects of ZnO NPs and explored their underlying mechanisms in adult male Wistar rats. Interestingly, the researchers showed that ZnO NPs co-injected with morphine increased latency time to pain stimulus compared to either conventional (non-nanoparticle-based) ZnO or saline. The analgesic effect of ZnO NPs is proposed to derive from the release of Zn and their subsequent inhibitory effects on NMDA receptors. Lastly, mesoporous silica-based NPs were used as ropivacaine carriers and prolonged sciatic nerve block in mice. However, minor neurotoxicity and myotoxicity were observed [51]. Overall, inorganic NPs appear more suitable as adjuncts rather than primary opioid carriers.

Magnetic NPs

Surprisingly, the literature is lacking research on magnetic NPs as opioid carriers. The absence of opioid-based magnetic NP systems is indicative of a translational gap rather than a lack of conceptual feasibility. Many inorganic substances can act as magnetic nanoparticles (MNPs). Due to stability and toxicity concerns, the most extensively studied ones are magnetite (Fe₃O₄), hematite (Fe₂O₃), and SPIONS (superparamagnetic iron oxide NPs) [52]. They have been extensively studied in many aspects of nanomedicine, including cancer hyperthermia [53] and imaging [54], but also in the field of analgesia. Santi et al. [55] demonstrated magnetic-field-responsive MNPs coated with thermoresponsive polymer that acted as a reservoir of capsaicin. Release was possible via exposure to alternating magnetic fields in a rat model, showing no signs of toxicity. Similar efforts have been made with magnetite NPs with bioactive glass–naproxen coating, which exhibited anti-inflammatory effects in vitro [56]. These approaches represent paradigmatic studies that investigate the efficacy of MNPs as opioid carriers that can release opioids effectively to ensure adequate analgesia and can even be stimulus responsive, as in the case of using alternating magnetic fields for cancer treatment. Across the discussed platforms, a recurring limitation is the absence of standardized pharmacokinetic and toxicological/safety evaluations. While SLNs and polymeric NPs have shown promising release profiles, translational readiness remains inferior to liposomal systems. Figure 1 provides a schematic of representative nanocarrier classes, highlighting their pharmacokinetic profiles and clinical implications.

6. Using Nanomedicine to Improve the Efficacy of Naloxone

Naloxone, a pure antagonist of the μ-opioid receptor (MOR), has been approved by the FDA since 1971 and plays a major role in clinical practice [57]. This antagonist is used to reverse the effects of opioids and has been used for more than 50 years. Furthermore, its use extends well beyond the hospital settings. Naloxone is widely administered by law enforcement personnel, first responders, and caregivers due to its life-saving properties as an opioid antidote [58,59]. Naloxone is typically administered intravenously or intramuscularly, and oral administration is limited due to its extensive first-pass metabolism. A nasal spray represents a novel formulation for naloxone delivery. However, only a fraction of the administered dose is absorbed, necessitating higher doses to achieve therapeutic efficacy [60].

To overcome this issue, lipid NPs loaded with naloxone have been developed for intranasal administration [58]. In a rat model, high drug entrapment efficiency was achieved. In vivo and ex vivo studies using dialysis and nasal membranes showed satisfactory results. In parallel, the conducted histopathological investigation of the brain of the subjects did not reveal signs of toxicity. Another promising finding is that the pharmacokinetic investigation revealed a prolonged deposition of the formulation, which is necessary for the sustained release of naloxone. Figure 2 illustrates the intranasal naloxone spray approach.

This feature is important since naloxone has a short elimination half-life. As a result, repeated dosing may be required to prevent recurrence of opioid-induced respiratory depression. To counter this challenge, long-acting naloxone nanoformulations have been developed [60]. In one study, researchers formulated a poly(lactic-co-glycolic acid) polymer covalently bound to a naloxone chain end. The produced nanoformulation showed several advantageous characteristics.

The polymer served as a stable and reproducible carrier for naloxone. The elimination half-time was increased by at least six-fold longer compared to naloxone in a mouse model. Most importantly, these formulations successfully reversed the effects produced by the administration of fentanyl (including respiratory depression). The antagonist effect persisted for up to 48 h. Further investigation of this formulation could result in a more efficient form of naloxone that extends naloxone’s short elimination half-time and reduces the necessity for repeated administration.

7. Nanoparticle-Based Vaccines Against Substances of Abuse

Drug abuse and addiction pose a major public health concern with a worrisome increase in the number of affected individuals on a global scale [61]. Opioid use disorder affects more than 16 million individuals worldwide, with more than 2 million in the USA. Recreational use of opioids peaked in 2010 and has declined since. However, up to 50% of patients receiving chronic opioid treatment meet the criteria for opioid use disorder (OUD) [62]. OUD encompasses several opioids, including but not limited to morphine, diacetylmorphine, and fentanyl, among others.

Treatment of OUD requires an interprofessional approach that includes pharmacological and non-pharmacological strategies aiming to reduce withdrawal syndromes, relapse, and/or overdose [63]. Unfortunately, relapse rates remain high, with the FDA reporting a relapse rate as high as 70% in 2020 [64]. In a quest to decrease these devastating numbers, anti-opioid immunotherapy emerges as a novel tool in the clinician’s armamentarium. Although the nanoparticle-based vaccines against opioids are primarily developed to prevent addiction, they hold important implications for opioid analgesia. By generating opioid-specific antibodies, these vaccines may reduce the risk of dependence in patients who receive long-term opioid therapy for pain management. According to a systematic review by Mathieson et al. [65], approximately one in three patients with chronic pain (not due to malignancy) has been prescribed opioids. Thus, opioid vaccines may evolve into a complementary strategy to improve the safety profile of opioid analgesics. If translated into clinical practice, nanotechnology will have fulfilled the promise of not only achieving improved drug delivery but also mitigating adverse outcomes of chronic opioid use.

Vaccines against opioids typically use the covalent conjugation of several copies of molecules analogous to opioids with a carrier protein holding immunogenic properties. One example in this category is the widely used protein tetanus toxoid (TT) and toll-like receptor agonists (TLR agonists) to trigger innate immunity [66,67].

7.1. A Fentanyl Vaccine Based on Lipid NPs Could Grant Anti-Fentanyl Immunity

In a 2025 study [66], fentanyl was used as a hapten (a term referring to a molecule that can elicit an immune response only when combined with a larger carrier [68]). In this work, a nanovaccine based on LNPs was developed utilizing a non-covalent assembly approach of fentanyl haptens, an epitope, and a TLR7/8 agonist. In an in vitro investigation, efficient cellular uptake by a dendritic cell (murine in origin) was confirmed, while the activation of immune cells was also confirmed. The same research group used a mouse model to show the presence of fentanyl-specific IgG antibodies, while IgM and IgA antibodies were also detected, although to a considerably lesser extent. Furthermore, the neutralization potential of the produced antibodies was also tested employing a hot plate assay. During this procedure, mice received increasing doses of fentanyl, and the latency response to thermal stimuli applied to the paws was evaluated. Only immunized mice failed to exhibit increased pain tolerance following administration, a finding consistent with the effective neutralization of fentanyl molecules in vivo [67].

7.2. A Nanovaccine Yielding Anti-Morphine Immunity

Fentanyl is not the only opioid that has been explored in the context of addressing opioid addiction. Interestingly, morphine, in addition to its addictive properties, has also been found to hinder the immune response to vaccines by impeding the activation of T-cells and the production of antibodies [68,69]. In a recent study conducted by Nanda et al. [70], a nanovaccine was developed consisting of Acr1 NPs (alpha-crystallin-related protein, a heat-shock protein derived from Mycobacterium tuberculosis [71]), onto the surface of which morphine and a TLR-2 agonist (Pam3Cys) were conjugated.

In female mice, this formulation induced high titers of anti-morphine antibodies (IgG). Efficient clearance of morphine from both the brain and blood was observed. Importantly, prior morphine exposure did not have any effect on the efficacy of the vaccine. Of note, the studied vaccine prevented the inhibition of the expression of several inflammation-related molecules, including TNF-α and IFN-γ. However, several aspects of this nanovaccine require further preclinical evaluation before clinical translation. Long-term safety, durability of antibody responses, and potential off-target immune effects must be thoroughly assessed. [71]. A conceptual workflow for an opioid nanovaccine is illustrated in Figure 3.

8. Clinical Translation of Nanomedicine-Based Opioids

Nanomedicine represents a paradigm shift in healthcare. The emergence of nanomedicine in clinical practice goes back to 1995, when the FDA approved Doxil (liposomal doxorubicin), the first nanodrug [72]. Although its initial impact was rather modest, nanomedicine gained far wider recognition decades later during the COVID-19 pandemic. This was largely driven by the successful clinical use of lipid-nanoparticle-based mRNA vaccines [73].

Despite these meaningful contributions, clinical translation of nanomedicine has faced considerable barriers across multiple potential applications in medicine. This issue has been explicitly highlighted in the literature, questioning why an extensive research output has resulted in so few approved drugs, particularly in the field of cancer nanomedicine [74].

8.1. Currently Available Nanomedicine-Based Formulations

Although very limited, there are already some nanoformulations for clinical use in the field of pain management. DepoDur represents a morphine sulfate liposome-based formulation, the composition of which includes DOPC and DPPG (two types of phospholipids), cholesterol, and uriolein [12]. This formulation acts as an extended-release morphine compound and has been found to result in considerably decreased intravenous patient-controlled fentanyl use when compared to conventional epidural morphine in a randomized double-blind study [75]. However, its clinical utilization remains limited [76].

Another liposome-based formulation that was approved by the FDA in 2011 is Exparel. It is composed of liposomal bupivacaine that also has extended release for up to 72 h. It has shown successful prolongation of pain relief postoperatively when applied in the form of a wound infiltrate. Although it holds a potential for use in regional anesthesia, it has not been extensively studied (nor approved for that purpose), while a 2020 study found inconsistent results in a small study group regarding its analgesic properties [77].

Finally, Zynrelef represents yet another liposomal formulation for clinical use. It was approved by both EMA and FDA but was withdrawn from EMA for commercial reasons [78] in 2023. This nanomedicine is a combination of two drugs (bupivacaine and meloxicam) and is used in the surgical incision site for total knee arthroplasty and bunionectomy. As of 2024, its indications have expanded to shoulder and spine open surgical procedures [79]. Although these two nanoformulations are not opioid-based, they are of importance for opioid nanoformulations. This is due to the fact that the used nanocarriers have already made it to the clinic, and thus, they could have potential as opioid carriers in the future.

8.2. Current Patent Landscape

Academic research on nanoparticle-based opioid delivery systems has been extensive and rich. Nevertheless, patent activity in the field remains extremely limited, which is an indicator of the early translational maturity of these formulations. Current patents have focused on polymeric NPs and depot opioid formulations (including with a focus on prolonged release profiles, improved therapeutic index, and safety profiles). Based on a Google Patents search, patent No. US10912772B2 [80] describes a depot precursor formulation for the in situ generation of a controlled-release opioid composition. A second patent, No. US9566241B2 [81], describes stable NP compositions of buprenorphine employing a biodegradable polymer while providing methods of controlling animal pain.

8.3. Barriers to Clinical Translation

These nanomedical-based formulations face considerable challenges in reaching clinical practice. These limitations are not specific to opioid nanomedicines, but they apply to most, if not all, nanoformulations. Nanomedicine has gained global attention due to the unique properties of NPs. However, it is exactly those novel properties that can drastically alter a nanoformulation’s pharmacodynamics and pharmacokinetics when compared to the conventional form of the drug [82]. As a result, toxicity screening and safety evaluation become particularly complex. Nanoparticle translocation to distal tissues or across the blood–brain barrier may raise toxicity concerns that are not present in the conventional drug formulation [83]. Another major issue with the translation of nanomedicines is large-scale manufacturing. Critical quality characteristics, such as particle size, shape, and morphology, can be challenging to assess [84].

Nevertheless, the presence of these barriers should encourage researchers to mitigate these challenges and bring forth novel clinical tools with adequate safety and efficacy profiles. This is particularly relevant in domains of medicine where conventional approaches may have reached their limits [85].

8.4. In Silico Approaches Are Essential for Effective Clinical Translation

It is evident that there are myriads of potential NPs (liposomes, dendrimers, SLNs, inorganic NPs, etc.) that are promising for use as carriers of opioids. Simultaneously, opioids constitute a large class of drugs with multiple members. The combinational complexity of nanoparticle-opioid pairing is therefore substantial. To make matters more complicated, a given NP can vary widely in physicochemical characteristics. For example, a metal NP can exist in different sizes and shapes, surface coatings, and chemical states [86]. Experimentally evaluating all possible combinations is impractical. Time- and cost-efficient in silico approaches are essential.

Beyond combinational challenges, other significant barriers include toxicity concerns, immunogenicity, pharmacokinetic profile, and biodistribution, and of course, having the desirable therapeutic effect. Systems biology holds the promise of achieving holistic insights into the cellular mechanisms, where multiple analyses can be performed in silico [87]. Inversely, the concepts of predictive toxicology and safety-by-design using machine learning approaches could create a desirable nanoplatform that possesses the desired properties a priori [88,89].

Within anesthesiology and analgesia research, systems biology has already been applied to identify pain mediators [90], analyze opioid addiction networks [91], and assess nanoparticle toxicity [92]. Focused interdisciplinary research efforts will be critical to fully realize these advantages.

8.5. Perspective on Promising Nanoparticle Strategies for Opioid Delivery

Among nanoparticle-based opioid delivery platforms, liposomal carriers are still the most clinically advanced and translationally viable option. Liposomes have a long history of clinical success across several therapeutic areas, having a plethora of FDA- and EMA-approved products, with their most well-known application being that of COVID-19 vaccines [93,94,95]. A key advantage of liposomal systems is their excellent biocompatibility. Immunogenicity concerns can be mitigated through polyethylene glycol (PEG) modification, which also enhances circulation time and stability [96]. Sustained drug release remains a critical requirement for opioid-loaded liposomes to ensure effective patient analgesia.

Beyond liposomes, other nanoformulation applications in clinical practice are extremely narrow. Dendrimer studies in the field of opioids have shown promise, as discussed in the corresponding section, and currently, there are very few examples of clinically approved dendrimer-based formulations, such as astodrimer sodium with virucidal activity against respiratory viruses (including SARS-CoV-2) [97]. For dendrimer–opioid formulations, demonstrating long-term safety is a prerequisite for translation. Surface chemistry is particularly important since terminal cationic functional groups can lead to cell membrane disruption, hemolysis, and cytotoxicity. Thus, appropriate surface engineering must incorporate strategies to address these challenges, such as the use of neutral or anionic functional groups [98].

Nanoemulsions are also promising, and interestingly, a nanoemulsion preparation of propofol has been suggested with sufficient chemical stability [99]. Nevertheless, the clinical application of nanoemulsions faces considerable challenges, especially when it comes to their safety profile. Data from animals have shown increased white blood cell count and platelets. Lipid peroxidation in the liver was increased, but paradoxically, reduced glutathione content was not affected. It should be noted, however, that a key parameter of toxicity for nanoemulsions (and any nanoparticle) is the size; typically, smaller sizes offer larger reaction surfaces for damage of subcellular targets, including mitochondria and DNA [100].

Regarding inorganic NPs, the major clinical applications are limited to the use of SPIONs, with ferumoxytol being the only member of this group to receive FDA approval for treatment of iron-deficiency anemia [101]. Their unique physicochemical properties, combined with the ease of functionalization, make them appealing. However, their use as drug carriers, especially for opioids, remains at an early research stage. Major concerns regarding accumulation, clearance, and long-term toxicity limit near-term clinical translation [102].

Finally, polymeric NPs and SLNs offer considerable advantages, including physical stability, satisfactory drug loading capacity, and the potential of sustained release. At the same time, they have been studied in animal models. Nevertheless, the clinical translation remains limited, with major issues being large-scale manufacturing, regulatory standardization, and formulation complexity [103,104].

Overall, different NPs offer unique advantages but also have unique toxicity/safety challenges. No single toxicity assay is sufficient to fully characterize nanoparticle safety, and many existing assays were not designed specifically for nanomaterials [105]. This characteristic further highlights the key role of in silico approaches and standardized evaluation of NPs with comparable physicochemical characteristics. Based on the preclinical and translational evidence discussed in the previous sections,

Table 2. A summary of the main characteristics of potential nanoparticle carriers for opioids.

Nanoparticle Platform	Key Advantage for Opioid Delivery	Limitations/ Concerns	Current Translational Status	Overall Perspective for Opioid Delivery
Liposomes	High biocompatibility, can encapsulate both hydrophilic and lipophilic opioids, prolonged drug release	Stability variability, active targeting requires	Multiple FDA-approved drugs	Most promising and clinically viable nanoformulation
Dendrimers	Precise molecular architecture and surface functionalization enable targeting	Complex synthesis, potential cytotoxicity of cationic terminal groups	Largely preclinical	Promising but requires extensive safety validation
SLNs	Prolonged opioid release, high drug loading, biocompatible polymers available	Limited toxicological data, long-term safety unclear	Preclinical (cell and small-animal models)	Moderate potential
Polymeric NPs	Sustained and controlled opioid release, high drug loading, and available biocompatible polymers	Manufacturing challenges, limited in vivo data	Preclinical	Moderate–low clinical applicability in the near future
Nanoemsulions	Simple formulations, prolonged release	Size dependent toxicity, limited safety data	Very limited clinical translation	Limited translational readiness
Inorganic NPs	Unique physicochemical properties, potential synergistic analgesic effects	Accumulation and clearance concerns, unpredictable toxicity	Early preclinical	Potential as adjunctive rather than primary carriers
Magnetic NPs	Potential for externally controlled stimulus-responsive opioid release	Absence of opioid-carrier studies	Conceptual	Exploratory research stage

provides a summary of the relative advantages, limitations, and clinical readiness of the major NP platforms with respect to systematic opioid delivery.

9. Conclusions

Nanomedicine-based delivery systems represent promising tools for providing effective analgesia for patients. The diverse range of available nanocarriers allows for both hydrophilic and hydrophobic opioids to be delivered, with liposomes dominating both preclinical studies and formulations that are already clinically approved. These nanoformulations offer the potential for personalized analgesic strategies tailored to each patient’s unique needs.

From a clinical perspective, nanomedicine-based formulations are most likely to be applied in both perioperative and postoperative pain management but also in the chronic pain settings where sustained analgesia is required. This is of particular importance since prolonged release profiles may reduce dosing frequency and improve patient compliance with therapy. Their role in emergency and pre-hospital overdose reversal, as well as the prevention of opioid use disorder via nanovaccines, should also not be overlooked.

Despite the considerable progress in opioid nanoformulations, several critical gaps must be addressed before meaningful clinical translation is reached. Future studies should prioritize systematic head-to-head comparisons between different NPs (for instance, liposomes and dendrimers) using standardized experimental protocols. Such comparative frameworks are of key importance for the identification of platform-specific advantages in the safety profile, drug loading capacity, release kinetics, and analgesic efficacy. At present, the literature remains fragmented, often reporting isolated physicochemical characterization without progression to in vivo validation. This limitation hampers rational nanocarrier selection and comparative evaluation.

In parallel, studies should integrate pharmacokinetic–pharmacodynamic profiling to accurately define therapeutic windows and to detect delayed adverse effects, particularly respiratory depression. Smart or stimuli-responsive nanocarriers, such as magnetic or pH-responsive systems that release their cargo after external activation, represent a promising strategy towards a safe nanoformulation through controlled opioid delivery. Most published studies are preclinical, employing cell lines and/or laboratory animals of different species. These investigations lay the foundations for future applications. However, translation to large-animal models and early-phase clinical trials is essential to validate both analgesic efficacy and safety.

Additional translation issues include large-scale production, toxicity concerns, regulatory aspects, and long-term safety profiles. It is evident that for nanoformulations to become a clinical reality in anesthesia and pain management, early incorporation of manufacturing feasibility and quality control is crucial. These challenges do not make the use of nanomedicine in analgesia impractical; rather, they highlight the need for systematic and coordinated development strategies.

Finally, interdisciplinary collaboration among materials scientists, pharmacologists, anesthesiologists, and regulatory authorities is essential for the establishment of standardized evaluation pipelines for opioid nanoformulations. Only through such coordinated efforts will nanomedicine evolve into a clinically reliable and widely accessible tool for both effective and safe pain management.