Honokiol and analgesia: A mechanistic review on the current capacities and challenges

Abstract

Pain is an unfavorable subjective sensation influencing 20% of the public population, giving rise to substantial health and economic issues. Several categories of pain, such as acute and chronic pain, have been determined according to factors like pathophysiological mechanism, etiology, and anatomical locations. The current analgesic drugs are the cornerstone of pain management; however, some challenges, such as short-term relief and concerns about addiction, dependence, and side effects, warrant alternative choices for pain alleviation. In the recent decade, the importance of polyphenolic compounds, particularly honokiol, has increased due to their diverse therapeutic and biological features like anti-cancer, anti-inflammatory, anti-oxidative, anti-bacterial, anti-viral, and immune regulatory properties. Also, some documents have accentuated the striking role of honokiol in exerting analgesic effects in conditions such as inflammatory pain, neuropathic pain, and gouty arthritis. Ergo, the current literature review aimed to discuss the analgesic potential of honokiol in the mentioned conditions with a mechanistic insight.

Introduction

According to estimates, pain affects over 20% of the universal population, causing considerable health and financial problems. ¹ The International Association for the Study of Pain (IASP) has introduced pain as a distasteful emotional and sensory experience linked to potential or actual tissue damage. ² The mechanism of how pain is felt has attracted physicians and philosophers for ages. ³ In the 17th century, Rene Descartes was one of the first subjects to speculate that actual pain perception stems from the transmission of peripheral pain stimulus to the brain. ⁴ For the time being, there is enough evidence showing that pain-sensing nerve fibers recognize detrimental stimuli at the damage site and relay this information to the brain, making it processed and triggering a suitable motor reaction. ⁵ Also, it is well-understood that pain induces a coordinated response involving different pain-associated pathways. This response occurs at the cortex levels where pain is consciously comprehended, such as the thalamus, insular cortex, primary motor cortex, and supplementary motor cortex. ⁶ There are several classifications for pain based on factors like pathophysiological mechanism, etiology, and anatomical location. Two main subcategories related the pain include acute and chronic pain. ⁷ Acute pain typically acts as a warning signal against life-threatening conditions. It usually takes from a few days to 12 weeks and is caused by tissue injury, which often improves over time. ⁸ Chronic pain is described as recurring or persistent pain that continues for more than 3 months. Dissimilar to acute pain, it does not serve a protective function and is often maintained by mechanisms distinct from the primary cause, for example, central sensitization, neuroimmune interactions, and changed pain modulation. ⁹ Analgesic medications are considered the cornerstone of pain management and confer short-time effectiveness. Notwithstanding that, remarkable worries have been raised concerning addiction, pharmacological dependence, and the risk of side effects.^10,11 Also, analgesic overuse is among global concerns about these medications. Despite expansive efforts, the current interventions are still insufficient to improve the life quality of subjects with high and long-time-effectiveness and minimum side effects. ¹ These years, the analgesic potential of polyphenolic compounds, especially honokiol, in different models of related diseases has been in the spotlight of scientific communities more and more.^12,13 Honokiol, a natural polyphenolic compound derived from the bark of Magnolia species, has recently gained attention due to its promising analgesic potential. Unlike conventional analgesics, honokiol exhibits multifactorial mechanisms of action, including inhibition of inflammatory mediators (TNF-α, IL-1β, IL-6), modulation of nociceptors such as P2Y and TRPV1, and suppression of oxidative stress. Studies show that honokiol can reduce various forms of hyperalgesia (mechanical, thermal) and allodynia in both acute and chronic inflammatory pain models without apparent toxicity. Additionally, honokiol’s analgesic effects appear comparable or superior to some existing agents in specific pain models, with the advantage of lower associated risks of dependence and side effects.^14–16 Moreover, honokiol's ability to cross the blood-brain barrier and its neuroprotective, anti-inflammatory, and antioxidant properties differentiate it from many traditional analgesics. Its multifaceted action on pain pathways, including central nervous system modulation and peripheral anti-inflammatory effects, positions honokiol as a promising alternative or adjunctive analgesic, potentially filling gaps left by current therapies.^17–19

Hence, this literature review intended to review and summarize the analgesic capacity of honokiol in related conditions to provide suitable insight for anesthesiologists and researchers to make better decisions on its application in the clinical setting.

Methodology

Literature search strategy

To comprehensively review the current knowledge on honokiol and its analgesic effects, a systematic literature search was performed across multiple scientific databases, including PubMed, Scopus, and Web of Science. The search encompassed all articles published up to August 2025 to ensure the most up-to-date information was included.

Search Terms and Strategy: The following search terms and Boolean operators were used in various combinations to capture relevant studies: (“Honokiol” OR “magnolia extract”) AND (“analgesia” OR “pain” OR “antinociceptive” OR “pain management” OR “neuropathic pain” OR “inflammatory pain” OR “gouty arthritis”). Specific Boolean operators (AND, OR) were used to combine keywords, and filters for animal or human studies were applied where appropriate.

Inclusion criteria

Studies were considered eligible for inclusion if they met all of the following criteria:

• Original research articles (in vitro, in vivo, or clinical) focusing on the analgesic effects or mechanisms of honokiol.

• Published in peer-reviewed scientific journals.

• Articles written in English.

• Studies providing clear experimental methods and outcomes related to pain, analgesia, or nociception.

• Publications released up until August 2025.

Exclusion criteria

The following were excluded:

• Review articles, meta-analyses, commentary pieces, letters, and conference abstracts.

• Studies not directly focusing on honokiol’s analgesic or antinociceptive activities.

• Articles without accessible full texts or lacking sufficient experimental data.

• Non-English language publications.

Honokiol: Structure and pharmacological and biological benefits

Honokiol (5,3′-diallyl-2,4′-dihydroxybiphenyl) is a bioactive agent with a small molecular weight (226.334 g/mol) found in Magnolia plants.^20,21

This biphenolic compound, with the molecular formula C₁₈H₁₈O₂, naturally co-exists with its structural isomer magnolol.^22,23 It is also known as a phenylpropanoid agent pertaining to the neolignans, which is structurally defined by the ortho-, para-C-C coupling of a para-allyl phenol and an ortho-allyl phenol (Figure 1). ²⁰

Figure 1.

Chemical structure of honokiol.

Several pharmacological and biological features of honokiol have been demonstrated, including antinociceptive, ²⁴ anti-neoplasia, ¹⁸ anti-inflammatory, ²⁵ anti-oxidative, ²⁶ anti-bacterial, ²⁷ anti-viral, ²⁸ anti-fungal, ²⁹ immune regulatory ³⁰ effects. These benefits encourage scientists to explore its therapeutic potential against a broad range of diseases in in vitro and in vivo models.

Honokiol and pharmacology: Features and challenges

Honokiol, thanks to its strong lipophilic nature, can easily pass through the blood-cerebrospinal fluid (CSF) and blood-brain barrier (BBB) barrier. ³¹ However, there are some pharmacological challenges, comprising low hydrophilicity and stability, high oxidation, and poor bioavailability, that hamper its wide clinical applications. ³² Pharmacokinetically, honokiol is mainly metabolized in the liver, where it undergoes bio-transformation. The key metabolic pathways related to honokiol include glucuronidation and sulfation, converting it into sulfated mono-hydroxy honokiol and mono-glucuronide honokiol prior to elimination. ³³ Honokiol displays biphasic kinetics described by early fast distribution phase followed by a slower elimination phase. Subsequent to its intravenous use at a 10 mg dose, its elimination half-life is 56.2 min, and at a 5 mg dose, its half-life is 49.2 min in rats.^34,35 Animal studies have shown that honokiol administration orally to rats leads to fast distribution in different organs, and the brain, kidney, and liver are among the organs with the highest concentrations of this bioactive compound.^36,37 It is worth mentioning that the potential risks related to honokiol should not be overlooked since its therapeutic application is still understudied, making its side effects obscure. It has been stated that the excessive administration of honokiol could give rise to neurotoxicity and increased risk of bleeding. ³⁸ An experimental study, with the purpose of inspecting of toxicity (acute and sub-chronic) of honokiol microemulsion, showed that the median lethal dose (LD₅₀) of the microemulsion in mice was 50.5 mg/kg following intravenous use. In this work, honokiol microemulsion up to 500 μg/kg was considered safe once applied intravenously for 1 month in animals. Higher doses conferred vascular irritation at the injection site without causing systemic toxicity. ³⁹ The drug interaction of honokiol with drugs metabolized by cytochrome P450 enzymes, such as cytochrome P450 2C9 (CYP2C9), CYP1A2, CYP2C8, and CYP2C19, has also been clarified. ⁴⁰

Honokiol and analgesia

The analgesic potential of honokiol in different conditions, including inflammatory pain, neuropathic pain, and gouty arthritis, has been examined, and promising results have been expressed (Figure 2 and Table 1).

Figure 2.

The mechanisms by which honokiol exerts analgesic effects in conditions such as inflammatory pain, gouty arthritis, and neuropathic pain.

Table 1.

Analgesic effects of honokiol in conditions, including inflammatory pain, gouty arthritis, and neuropathic pain based on experimental studies.

Condition	Dose/concentration (s)	Target (s)	Findings (s)	Ref.
Acute and chronic inflammatory pain	0.1, 5, and 10 mg/kg	NF-κB/Nrf2 pathways	• Elevating paw withdrawal thresholds • Decreasing paw licking reaction in hot plate • Attenuating pro-inflammatory cytokines (i.e., IL-6, TNF-α, and IL-1β) and VEGF • Promoting antioxidant factors (i.e., Nrf2, HO-1, and SOD2)	(12)
Inflammatory pain	5 and 10 mg/kg	NMDA receptors and eicosanoid	• Decreasing licking time • Reducing formalin-caused c-Fos in spinal dorsal horn • Mitigating central sensitization in the spinal cord	(41)
Inflammatory pain	5 and 10 mg/kg and 0.1–1.0 µg/paw	mGluR5, NMDA receptor, and c-Fos	• Decreasing licking time and thermal hyperalgesia • Attenuating nociception by decreasing inflammatory factors (i.e., PGE₂ and substance P)	(24)
Inflammatory pain	10 mg/kg	NMDA receptor, GABA receptor, NF-κB pathway, c-Fos (landmark for neuronal activation)	• Decreasing paw-licking/flinching behaviors • Preventing thermal hyperalgesia • Promoting exploratory behavior and memory	(42)
Neuropathic pain	MOE: 1–60 mg/kg Honokiol: 0.1–10 µg/mL	Notch signaling and CB1	• Attenuating mechanical allodynia in the spared nerve injury by MOE • Attenuating LPS-caused neuroinflammation in BV2 microglia by honokiol	(43)
Gouty arthritis	10, 20, and 40 mg/kg	Voltage-gated proton channels	• Ameliorating inflammatory reaction and mechanical allodynia dose-dependently • Normalizing Hv1 channel activity	(13)

Inflammatory pain

Inflammatory pain is related to the elevated sensitivity of perception and emotional reaction to detrimental stimuli, resulting from an inflammatory response following tissue injury. ⁴⁴ Khalid et al. have investigated the antinociceptive potential of honokiol, its action mechanism, and pharmacological interactions in animal models of acute and chronic inflammatory pain, established by carrageenan (100 µL/paw) and complete Freund’s adjuvant (CFA; 20 µL/paw), respectively. ¹² Behavioral tests in this work were paw edema, thermal hyperalgesia, and mechanical allodynia/hyperalgesia. This research team observed that honokiol (10 mg/kg) can considerably decrease paw edema, allodynia, and mechanical/thermal hyperalgesia in both acute and chronic inflammatory pains. Molecular analyses showed that this phenolic compound can exert suppressive role in inflammation, as evidenced by downregulated pro-inflammatory cytokines (e.g., interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF)) and suppressed the nuclear factor kappa B (NF-κB) signaling and elevating role in antioxidant defense system, as demonstrate by elevated expression of antioxidant agents, including superoxide dismutase 2 (SOD2; an antioxidant enzyme converting superoxide radical to O₂ and hydrogen peroxide), heme oxygenase-1 (HO-1; an antioxidant enzyme catalyzing heme degradation), nuclear factor erythroid 2-related factor 2 (Nrf2; A transcription factor modulating antioxidant gene expression), and decreased oxidative stress.^12,45–47 Another action mechanism of antinociceptive effects of honokiol was related to gamma-aminobutyric acid (GABA) and opioid pathways, given that the administration of a GABA antagonist (flumazenil) and an opioid antagonist (naloxone) in this study reversed somewhat honokiol’s influences, offering their involvement. ¹² Overall, this research accentuated the antinociceptive effects of honokiol on inflammatory pain by affecting signaling pathways related to inflammatory occurrences, oxidative stress, and GABA and opioids. It has also been stated that honokiol can ameliorate inflammatory pain models by formalin without affecting acute thermal pain, possibly by repressing central sensitization in the spinal cord. ⁴¹ Another research paper implicated that the intraperitoneal (IP; 5–10 mg/kg) or intraplantar (0.05–1.0 µg/paw) administration of honokiol and magnolol mitigated thermal hyperalgesia and N-methyl-D-aspartate (NMDA)-and-glutamate-caused nociception in animal models of inflammatory pain. Also, honokiol had more ability to alleviate NMDA-conferred pain, whereas magnolol was more capable of acting against 2-Chloro-5-hydroxyphenylglycine CHPG-caused hyperalgesia. Moreover, these two compounds derived from the bark of Magnolia officinalis could decrease inflammatory mediators related to hyperalgesia and nociception (i.e., substance P and prostaglandin E2 (PGE₂)) and diminish glutamate-induced c-Fos expression in the spinal cord, implicating the suppression of neuronal activation. Taken together, this investigation accentuated the suppressive role of honokiol and magnolol in glutamate receptors (metabotropic glutamate subtype 5 (mGluR5) and NMDA) and inflammatory factors (e.g., substance P and PGE₂), justifying their antinociceptive influences. ²⁴

Gouty arthritis

Gouty arthritis is a metabolic disorder conferred by increased levels of uric acid and disrupted purine metabolism, causing deposition of monosodium urate (MSU) crystal in the joint areas, activating inflammatory response and tissue degradation. ⁴⁸

According to an experimental scientific project, honokiol can serve as an analgesic agent in an animal model of gouty arthritis established via intra-articular injection of MSU crystals into the mouse hind ankle joint. ¹³ In the work of Miao et al., honokiol was administered orally via gavage. The authors assessed the ankle swelling degree by measuring the joint circumference and examined mechanical pain sensitivity using von Frey filaments. Also, using a patch-clamp, tail current, voltage-gated proton channel (Hv1) current, and electrical activity of dorsal root ganglion (DRG) neurons were measured. The obtained results revealed that honokiol at doses of 10–40 mg/kg ameliorated mechanical allodynia and inflammatory response dose-dependently.

In normal conditions, Hv1 channels in pain-sensing neurons (DRG) are in overactive status during gout, resulting in elevation in transporting pain signals. Using two known Hv1 suppressors (i.e., 2-GBI and Zn²⁺), this investigation approved the channel’s role by curbing its function in normal neurons. MSU crystals conferred hyperactivity of Hv1 channels by day 3, but honokiol could largely normalize Hv1 channel activity, particularly at 40 mg/kg. Moreover, it was found that at the mentioned dose, honokiol shifted the Hv1 activation curve to more positive voltages than MSU treatment and normalized the reversal potential. This bioactive agent also acted against the reduction in the tail current deactivation time constant (τtail). ¹³ On the whole, this study highlighted the analgesic capacity of honokiol in gout by repressing the Hv1 current.

Neuropathic pain

Neuropathic pain is any unfavorable sensation due to damage or disorder related to the somatosensory system that confers symptoms and signs, including the combination of sensory impairment or numbness accompanied by related pain, with or without increased sensitivity in the region of pain. ⁴⁹

The effectiveness of honokiol and Magnolia officinalis extract (MOE) rich in honokiol in improving neuropathic pain in mice has also been examined. Borgonetti et al. utilized male CD1 mice exposed to spared nerve injury (SNI) to establish neuropathic pain and pain thresholds were assessed using behavioral tests including von Frey filaments (mechanical allodynia) and hot plate (thermal pain). Also, locomotor assays were accomplished using hole board and rotarod tests to validate that MOE did not affect motor function negatively. Given that MOE (30 mg/kg), considerably decreased mechanical and thermal hypersensitivity in SNI mice, authors approved the pain relief potential of MOE in a neuropathic pain model. It is worth expressing that the analgesic effects peaked at 45 min following administration and were suppressed by AM251, showing cannabinoid 1 receptor (CB1) receptor dependence. Other results revealed that MOE is able to mitigate spinal proinflammatory parameters (i.e., p-p38, IL-1β, and Inducible nitric oxide synthase (iNOS)) and elevate the anti-inflammatory factor IL-10. On the other hand, honokiol reduced oxidative stress and lipopolysaccharide (LPS)-caused microglial activation. From a molecular standpoint, the capacity of MOE and honokiol in attenuating neuroinflammation and promoting nerve repair was demonstrated by repressing Notch signaling proteins (NEXT and Jagged1) and elevating spinal expression of myelin basic protein (MBP), respectively. ⁴³ Collectively, this study signifies that MOE and honokiol weaken neuropathic pain through CB1-mediated anti-inflammatory and anti-oxidant processes, comprising the Notch pathway pathways regulation.

Future perspectives

As mentioned above, honokiol has received much attention in the medical arena thanks to its diverse pharmacological and biological capacities, and among these, its analgesic effects have gained much importance in preclinical studies more and more, which can herald a promising outlook for clinical settings. However, pharmacological limitations, such as low water solubility and stability and poor bioavailability, and the effectiveness of approaches to bypass these obstacles to better use the therapeutic capacities of honokiol should be considered more and more. These days, nanotechnology-based methods have strongly been suggested for solving such barriers. These nano-based strategies possess benefits, such as promoted bioavailability, solubility, prolonged circulation time, and targeted delivery of drugs. ⁵⁰ Up to now, scientists have efficiently encapsulated honokiol within different nanocarriers, for example, nanoparticles, ⁵¹ liposomes, ¹⁸ nanogels, ⁵² polymer micelles, ⁵³ dendrimers, ⁵⁴ and self-microemulsion delivery systems. ⁵⁵

Moreover, the combination of honokiol with other effective drugs or bioactive compounds has been offered as a therapeutic strategy that can be suitable for reaching therapeutic purposes by exerting synergistically curative effects. Interestingly, hopeful results from studies have shown the effectiveness of honokiol when combined with drugs or natural compounds, such as curcumin, resveratrol, and ginger extract, which have demonstrated possible analgesic effects in other research.^56–61

Conclusion

Pain is known as one of the most prevalent symptoms in palliative care that still demands effective analgesic approaches with minimum side effects. One of the strategies for analgesic purposes is harnessing the therapeutic potential of natural bioactive compounds, especially polyphenolic compounds. Among these, several experimental studies have affirmed the analgesic capacity of honokiol as a biphenolic agent with various therapeutic and biological advantages in different conditions, including inflammatory pain, neuropathic pain, and gouty arthritic. In these conditions, honokiol has demonstrated its analgesic effects by elevating paw withdrawal thresholds, decreasing paw licking reaction in hot plate, decreasing mechanical allodynia in the spared nerve injury, normalizing Hv1 channel activity, and mitigating the levels of pro-inflammatory cytokines (i.e., IL-6, TNF-α, and IL-1β). The action mechanism of these effects refers to the ability of honokiol to regulate different molecular pathways or agents related to pain, including NMDA receptors, eicosanoid, CB1, GABA receptor, NF-κB, and Notch signaling pathways. However, some pharmacological considerations should be assumed for more investigation of this bioactive compound (e.g., low water solubility and stability and poor bioavailability), especially in clinical assessments. Therefore, more in-depth studies are required to validate these outcomes.

Limitations of studies

Many studies reviewed are preclinical, predominantly in vitro or animal models, limiting direct extrapolation to human clinical efficacy. Variations in study design, treatment duration, and outcome measures reduce comparability. Some studies have small sample sizes, which may affect statistical power and generalizability. Lack of long-term safety data and follow-up in most studies restricts understanding of chronic treatment effects.

Sample size considerations

Several animal studies involved limited numbers of subjects per group, often fewer than 10 animals, which increases variability and risk of type II error. Clinical studies, if any, tend to have modest sample sizes, emphasizing the need for larger, well-powered randomized controlled trials (RCTs).

Variations in honokiol dosage and formulations

Honokiol dosages varied widely across studies, ranging from microgram per paw doses in localized injections to tens of mg/kg in systemic administration. Differences in honokiol formulations (pure compound vs magnolia extracts) and routes of administration (oral gavage, intraperitoneal, topical) may influence bioavailability and pharmacodynamics.