Narcotics through time: exploring historical origins, synthetic advances, and clinical progress

ABSTRACT

Pain management has remained one of the most critical challenges in clinical medicine over the past several decades, with narcotics continuing to play a central role in controlling moderate to severe pain. Originating from natural sources such as Papaver somniferum, these compounds have evolved significantly from plant-derived alkaloids to highly potent synthetic opioids. However, despite their therapeutic effectiveness, long-standing concerns such as addiction, tolerance, and life-threatening side effects remain major obstacles. This review presents a comprehensive overview of the historical development of narcotics and recent progress in synthetic pain-relief agents. A broad literature survey was conducted, encompassing peer-reviewed articles, clinical trial data, and historical records, complemented by an independent SAR analysis based on the chemical structures of some of the most potent synthetic derivatives reported to date. Key transitions from traditional opioids to synthetic compounds such are explored, alongside novel clinical advancements like Oliceridine (TRV-130), NKTR-181, and Cebranopadol, which demonstrate promising analgesic efficacy with fewer adverse effects. Additionally, recent preclinical studies on synthetic mu-opioid receptor agonists and dual-receptor targeting compounds are discussed for their therapeutic potential. Overall, ongoing research into safer and more effective synthetic opioids offers a hopeful path forward in advancing analgesic therapy.

GRAPHICAL ABSTRACT

1. Introduction

Natural resources like plants, animals, and microbes have been essential in discovering pharmacologically active compounds, with many modern analgesics derived from phytoconstituents [1]. Pain management has remained one of the most critical challenges in clinical medicine over the past several decades. It is a protective mechanism defined as an “unpleasant sensory and emotional experience” by the International Association for the Study of Pain, has historically been managed with drugs like aspirin and morphine [2]. The isolation of morphine from Papaver somniferum in the 1800s revolutionized pain management by targeting opioid receptors (mu, kappa, delta) to alleviate pain and induce sedation [3,4]. However, opioid-based therapies, while effective, present addiction risks, as seen with derivatives like heroin, contributing to an opioid epidemic in recent decades [5]. In the past two decades, evolving healthcare regulations and enhanced pain management protocols introduced by JCAHO have significantly contributed to the increased use of opioid analgesics. In 2011, hydrocodone alone accounted for over 136 million prescriptions, with total opioid prescriptions exceeding 238 million, reflecting their essential role in modern pain management. The rising demand highlights the growing clinical reliance on opioid derivatives for effective control of both acute and chronic pain [6]. This review explores the evolution of pain management strategies, emphasizing recent innovations in both opioid and non-opioid therapeutics aimed at improving efficacy and safety, while addressing the growing public health challenges linked to opioid misuse and treatment limitations.

1.1. Historical evolution of narcotics and synthetic painkillers

The opium poppy has been cultivated since antiquity for both medicinal and ritualistic purposes. Its dried latex, rich in alkaloids like morphine, codeine, thebaine, and noscapine, was historically used to relieve pain, cough, and diarrhea [7]. In Ayurveda, opium is believed to balance the doshas Vata, Pitta, and Kapha [8]. Prior to modern anaesthetics, opium derivatives such as laudanum served as primary analgesics, as documented in the Ebers Papyrus (1552 BCE). By the 18th century, poppy-based preparations were commonly used for postoperative pain relief. Morphine, isolated by Friedrich Serturner in the early 19th century, became commercially available by 1820 [9]. Opioids exert their effects by acting on specific receptors in the brain and spinal cord. Ancient Iranian texts recognized a spectrum of pain-relieving agents, including Mokhadir (anaesthetic), Monavim (sedative), Mosabbit (hypnotic), and Mosakkin (analgesic) [10,11]. Despite legal cultivation in some regions, illegal opium production is still a health and law issue [12]. In 19th-century India, the Koeri community developed advanced poppy cultivation techniques, with poppy seeds valued for their richness in fats, amino acids, and proteins, and their use in food products [13]. Despite its therapeutic value, opium’s potential for abuse poses major health and social concerns [14]. Legal use for pain management co-exists with misuse and addiction [15,16]. The 20th century marked the rise of semi-synthetic and synthetic opioids like meperidine, methadone, and fentanyl, offering varied potency and onset profiles. While these drugs advanced pain care, over prescription and illicit fentanyl analogues contributed to today’s opioid crisis, defined by soaring addiction and overdose rates. Recently, non-opioid alternatives like suzetrigine (Journavx) have emerged, offering effective pain relief without activating traditional opioid receptors [17].

1.2. Exploring the therapeutic potential of medicinal plants in pain management

Cannabis sativa L. holds historical, cultural, and medical significance in India and is widely utilized for managing chronic pain, chemotherapy-induced nausea, PTSD (Post-Traumatic Stress Disorder), and reducing opioid dependence [18]. Additionally, postpartum use of cannabis has been associated with reduced stress, improved sleep quality, and enhanced relaxation among mothers [19,20]. Kratom (Mitragyna speciosa), native to Southeast Asia, exhibits opioid-like analgesic, sedative, and stimulant effects. Its major alkaloid, mitragynine as discussed in Figure 1, interacts with mu-opioid receptors, offering the potential for pain management, addiction treatment, and psychiatric care [21,22]. However, its growing recreational use raises safety concerns, particularly related to misuse and liver toxicity [23,24]. Corydalis yanhusuo (YHS), a perennial herb used in traditional medicine for over 1,100 years, exhibits potent analgesic effects in inflammatory and neuropathic pain without tolerance [25]. Key alkaloids, such as dehydrocorydaline (DHC) and levo-tetrahydropalmatine (l-THP), mediate its effects through dopamine receptor inhibition, opioid receptor activity, and microglia modulation [26]. Table 1 compiles the data of key phytoconstituents of these plants responsible for their therapeutic potential. Wild lettuce (Lactuca serriola L.), or prickly lettuce, has traditional uses for headaches, insomnia, and respiratory issues. Key compounds like lactucin and lactucopicrin provide sedative, analgesic, and antioxidant effects, supporting spasmolytic and bronchodilator activities [34]. Salvia divinorum, a herb from the Lamiaceae family used by the Mazatec people, contains salvinorin A, a potent, non-nitrogenous hallucinogen. Found in the leaves, it acts as a selective kappa-opioid receptor agonist with minimal activity at serotonin, dopamine, NMDA, or mu-opioid receptors, offering a unique pharmacological profile [35,36].

Figure 1.

Major phytoconstituents of key narcotic plants alongside representative plant images.

Table 1.

Phytoconstituents and their percentages in key narcotic plants, showcasing natural sources of bioactive compounds.

Narcotic plants	Phytoconstituents	% Composition	Reference
Papaver somniferum L.	Noscapine	4–5%	[27]
	Codeine	1–3%
	Papaverine	1–3%
	Thebaine	1–3%
	9-Octadecynoic acid	30.72%
	9-Tetradecen1-ol	24.02%
	Epoxyoctadecan-1-ol	7.43%
	9,12-Octadecadienoic acid	7.82%
	Undec10-ynoic acid	4.36%
Nicotiana tabacum L.	1-Butyl (dimethyl)silyl oxy propane	1.187	[28]
	Silane, diethoxy dimethyl	1.992
	Ethanol, 2-(2- ethoxy)	1.083
	D- Galactonic acid, ɤ-lactone	1.313
	Phenylethyl alcohol	1.710
	Pyridine,3-(1-methyl-2-pyrrolidinyl)-(s)	37.574
Cannabis sativa L.	Tetrahydrocannabinol (THC)	5–10%
	Α- terpinolene	7.0–16.6%	[29]
	Α-humulen	6.1–8.7%
	Myrcene	21.1–35.0%
	Limonene	16%
	Α- Pinene	7.2–14.6%
	Linalool	5–15%
	Trans-Caryophyllene	12.2–18.9%
Mitragyna speciosa L.	Mitragynine	66%	[30]
	Paynantheine	9%
	Speciogynine	7%
	7-Hydroxymitragynine	2%
Wild lettuce L.	lactucerin	50%	[31]
	lactucin	0.2 %
Corydalis yanhusuo L.	Corydaline	3.55%	[32]
	Tetrahydropalmatine	3.13%
	Coptisine	2.79%
	Palmatine hydrochloride	2.24%
	Dehydrocorydaline	13.11%
	(R)-(+)-corypalmine	2.37%
	Protopine	2.71%
	Glaucine	14.03%
Salvia divinorum L.	Salvinorin A	49%	[33]
	Salvinorin C	32%
	Salvinorin D	13%

2. Tracing the path of pain relief: from natural opioids to synthetic derivatives

The discovery of morphine from opium by Sertürner in 1805 marked the beginning of opioid-based pain management. Soon after, codeine- a methylated form of morphine was introduced for mild to moderate pain and showed antitussive and antidiarrheal effects [37]. In 1874, heroin was synthesized from morphine. Initially used medically, it later became widely abused, leading to serious health concerns [38]. During the early 1900s, oxycodone (1916) and hydrocodone (1920), both derived from thebaine, were developed to treat chronic and post-surgical pain. Hydrocodone also served as a cough suppressant [39,40]. Hydromorphone (1921) became important in cancer pain therapy. In 1960, fentanyl, developed by Paul Janssen, brought a major shift with its high potency and fast-acting formulations, including patches [41]. Other developments included levorphanol (1953) for neuropathic pain and nalbuphine (1978) for moderate pain with fewer side effects [42,43]. Buprenorphine, developed in 1966 as a potent analgesic, is also used in opioid dependence treatment due to its partial agonist profile and safety aspect [44]. Naloxone, introduced in 1960, is widely used to reverse opioid overdoses and remains an essential therapy in managing the opioid crisis [45]. Figure 2 depicts the chemical structures of opioids derived from morphine, as well as the synthetic narcotic drugs.

Figure 2.

Chemical structures of opioids derived from morphine and synthetic narcotic drugs.

2.1. Pharmacological and translational considerations in opioid and non-opioid analgesics

Opioid and non-opioid analgesics differ markedly in their pharmacological properties, influencing efficacy, safety, and clinical utility. Opioids act on mu-opioid receptors and vary in CNS penetration, therapeutic index, and metabolism [46]. Traditional agents like morphine and codeine show moderate CNS entry and metabolic variability, while semi-synthetic opioids such as oxycodone and heroin exhibit faster penetration but greater abuse potential. Synthetic opioids, including fentanyl and methadone, offer high potency and longer duration but require cautious dosing due to narrow therapeutic windows and complex pharmacokinetics [47,48]. Non-opioid agents such as tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and anticonvulsants modulate pain through neurotransmitter regulation or neuronal excitability suppression, effective in chronic and neuropathic pain, they carry minimal abuse risk and fewer systemic side effects, with broader applicability in pediatric, geriatric, and comorbid populations [49]. When used in multimodal regimens, they synergize with opioids or NSAIDs to enhance analgesia, reduce opioid requirements, and mitigate adverse effects. Despite these advantages, real-world application is hindered by regulatory constraints, limited trial generalizability, and persistent opioid stigma [50]. Stigma rooted in fear and misperception discourages prescribing and adherence, even when clinically appropriate. Addressing these barriers is essential for advancing safe, individualized, and evidence-based pain management [51].

2.2. mechanisms of action and receptor pathways

Narcotic agents exert their therapeutic effects by modulating various molecular targets within the central and peripheral nervous systems. Traditional opioids like morphine primarily activate MORs (mu-opioid receptors), leading to inhibition of adenylyl cyclase, reduction in cAMP and PKA activity, and subsequent downregulation of CREB-mediated gene expression (Figure 3) [52]. This action is complemented by increased K⁺ efflux and decreased Ca²⁺ influx, resulting in neuronal hyperpolarization and suppressed release of excitatory neurotransmitters such as glutamate and substance P, thereby reducing pain transmission [4]. Non-opioid agents utilize alternative mechanisms. Cocaine blocks monoamine transporters (DAT, SERT, NET), increasing synaptic neurotransmitter levels and producing stimulant effects. Ketamine antagonizes NMDA receptors, limiting calcium and sodium entry and dampening glutamatergic activity, which contributes to both its anaesthetic and antidepressant properties [53]. Salvinorin A, a plant-based compound, selectively activates k-opioid receptors (KORs), through a distinct pathway, producing short-lived analgesic and dissociative effects. Figure 4 summarizes the key pathways through which both opioid and non-opioid drugs influence CNS activity and pain signaling [54]. Emerging targets such as NOP, DOR, S1R, and TRPV1 offer promising alternatives to traditional opioid pathways. NOP and DOR provide potent analgesia with reduced risk of addiction or respiratory depression, while S1R and TRPV1 expand the scope to non-opioid mechanisms, particularly relevant for neuropathic and inflammatory pain [55–57]. However, the clinical translation of these targets remains limited. Further studies are essential to refine receptor selectivity, map signaling pathways, and establish predictive SAR models to optimize their therapeutic potential.

Figure 4.

(Continued).

Figure 3.

Depicting the mechanism of action of opioids at the μ receptor in suppressing pain signals through neurotransmitter inhibition and cellular hyperpolarization.

Figure 4.

Structural advancements in synthetic opioid and non-opioid derivatives emphasizing improved receptor selectivity and reduced side effects.

3. Advancements in synthetic opioid derivatives with enhanced potency and receptor selectivity

Fentanyl is a potent, highly lipophilic synthetic opioid that first synthesized by Janssen Pharmaceuticals in the 1960s, has inspired the development of numerous analogues with improved potency and receptor selectivity [58]. Cittern P. reported that cis-3-methyl Fentanyl (21) synthesized in 1973, exhibits eight times the potency of Fentanyl [59]. Bertha C.M. et al. developed derivatives with improved δ-opioid receptor selectivity to minimize side effects caused by µ-opioid receptor binding, notably finding that the compound (22) with levo-10-methoxy substitution showed substantial selectivity for the δ receptor [60]. Schütz J. et al. synthesized 18,19-dehydrobuprenorphine (23), demonstrating 25-fold higher potency than morphine and a strong affinity for the μ-opioid receptor [61]. Abalo et al. evaluated Fentanyl analogues and found that substituting its phenyl ring with a 1-phenylpyrazole moiety (compound 24) increased analgesic activity beyond morphine [62]. IVANOVIĆ M. D. et al. synthesized (±)-2,3-seco-Fentanyl analogues, reported compound (25) as 5–6 times more active than morphine [63]. Figure 4 illustrates structural advancements in the opioid and non-opioid analogues discussed herein. Spetea M. et al. developed a 6-amino substituted derivative of 14-O-methyl oxymorphone, which showed strong μ-receptor binding (compound 26) despite limited CNS penetration [64]. Crooks P.A. et al. assessed binding affinities of several opioids and found that morphine-3-O-propionyl-6-O-sulfate (27) exhibited fourfold higher affinity than morphine [65]. Hiebel A. et al. synthesized enantiomeric C9-Substituted 5-(3-Hydroxyphenyl)-N-phenylethylmorphans, finding compound (28) to be a potent μ-agonist with 500-fold greater activity than morphine [66]. Premkumar L S. emphasized the need for non-opioid analgesic alternatives for chronic pain to avoid typical opioid-related adverse effects [67]. Holtman J. R et al. reported that morphine-6-O-sulfate (29) showed superior analgesic activity across pain types [68]. Váradi A. et al.synthesized 3-O and 6-O sulfate esters of morphine and codeine, offering peripheral analgesia without CNS side effects [67]. Lackó E. et al. synthesized 14-O-methylmorphine-6-O-sulfate, which exhibited improved μ-receptor binding and agonist potency [69]. Spetea M. et al. evaluated diphenethylamine derivatives as selective k-opioid receptor (KOR) agonists with strong antinociceptive activity [70]. Ylidirir Y. et al. synthesized novel thebaine derivatives with analgesic potential [71]. Ansari M. I. et al. developed UMB246 (30), a novel opioid with reduced tolerance and dependence [72]. Wang Y. H. demonstrated that dezocine acts as a partial agonist at both μ and κ receptors [73]. Ummah M. developed N-Desethyl isotonitazene (31), which is 20 times more potent than Fentanyl [74]. Hsu T. et al. synthesized enantiomeric opioids, identifying compound (32) as highly selective for the μ-receptor [75]. Huang H et al. designed piperidine derivatives with high μ-receptor affinity [76]. Zádor F. et al. found 14-methoxycodeine-6-O-sulfate (33) more effective than codeine-6-O-sulfate [77]. Jevtic I. I. et al. synthesized Fentanyl analogues and reported that cis-4 analogue (34) was 180 times more potent than the trans-4 isomer due to steric interactions [78]. Blanckaert synthesized isonitazene (35), reporting higher potency than hydromorphone [79]. Garcia M. et al.García M. et al. synthesized propionamide derivatives (36) as dual MOR agonists and σ₁ receptor antagonists, showing strong analgesia with minimal GI effects and no tolerance development [80]. Hedrick S. L. et. al. evaluated naltrexone analogues, identifying compound (37) as a promising fentanyl antagonist with favourable in vivo properties [81]. Vandeputte synthesized N-desethylisotonitazene (38) as more potent than nitazene [82]. Borowiecki P. et al.developed a chemoenzymatic iso-moramide analogue (39) targeting KORs [83]. Vandeputte M. M. et al. evaluated N-pyrrolidino etonitazene (40), noting significantly higher potency than both fentanyl and morphine [84]. Wang L. et al. synthesized SW-WL-2 (41), a dual MOR/DOR agonist with potent antinociceptive action [85]. Paulino R. P. et al reported fentanyl triazole derivatives (42) with strong affinity for MOR and σ₁ receptors [86]. Vu L Y. et al. identified atoxifent (43), a potent MOR agonist that minimized respiratory depression while preserving analgesia [87]. Guo Y. et al. synthesized and evaluated novel biased mu-opioid receptor agonists (44) [88].

Parallel development in non-opioid analgesics has also accelerated over the time. Draper-Joyce C. J. et al. synthesized A₁ receptor allosteric modulators, identifying MIPS521 (45) as a neuropathic pain candidate [89]. Bibi H. et al. reported isoxazole-4-carboxamide derivatives, particularly compound (46), as promising alternatives [90]. Chartier et al. designed macrocyclic NTS2 ligands, with compound (47) showing efficacy without NTS1-linked side effects [91]. Masaud S M. et al. developed a ketamine derivative (48) targeting NMDA receptors with substantial analgesic activity [92]. Eremina et al. discovered compound (49), a hexaza-isowurtzitane analogue, as a potential non-narcotic pain modulator [93]. Khan A. et al. synthesized Schiff base derivatives, finding compound (50) effective in opioid receptor-mediated analgesia, suggesting new scaffolds for safer therapeutic design [94].

3.1. Structure-activity relationship (SAR) of synthetic opioid derivatives evaluated in preclinical studies

The structural modifications in compounds 21 to 44 demonstrate significant advancements in opioid pharmacology. Compound 21 (cis-3-methyl fentanyl) achieves 8× the potency of fentanyl through methyl substitution at the C₃ position, enhancing μ-opioid receptor binding. Compound 22 employs methoxy substitutions to improve δ-receptor selectivity, reducing μ-receptor side effects. Compound 23 (18,19-dehydrobuprenorphine) increases rigidity in its scaffold, leading to 25× morphine potency. Compound 24 replaces fentanyl’s phenyl ring with a pyrazole group, enhancing analgesic activity. Compound 25 introduces seco-fentanyl analogues, achieving 5–6×morphine potency via scaffold modifications. Compound 26 utilizes amino substitutions in 14-O-methyloxymorphone to enhance μ-receptor binding while limiting CNS penetration, reducing central side effects. Compound 27 (morphine-3-O-propionyl-6-O-sulfate) improves solubility and μ-receptor affinity through sulfation, with 4× binding over morphine. Compound 28 features hydroxyl groups in a C9-substituted scaffold, achieving 500× morphine potency by optimizing μ-receptor agonism. Compound 29 (morphine-6-O-sulfate) shows broad analgesic efficacy with an improved potency ratio. Compound 30 enhances receptor selectivity and potency via structural refinements, while Compound 31 (N-desethyl isotonitazene) demonstrates 20× fentanyl potency through specific nitrogenous modifications. Compounds 32 to 34 incorporate stereoisomeric or methoxy modifications, optimizing receptor binding and reducing adverse effects. Compound 36 enhances lipophilic interactions for improved μ-receptor targeting. Compound 39 & 40 features a nitrogenous framework that facilitates receptor binding via lipophilicity and ionic interactions. Compound 41 rigid scaffold and polar functionalities ensure optimal μ-receptor binding. Compound 42 enhances hydrogen bonding with hydroxyl groups and ionic interactions via a nitrogenous core. Compound 43‘s hydroxyl and nitrogen groups strengthen receptor affinity through hydrogen bonding and ionic interactions and Compound 44 leverages dual μ- and δ-receptor targeting for synergistic analgesic effects, reducing β-arrestin recruitment and mitigating side effects like respiratory depression. Compound 45 features a thiazole ring linked to a substituted phenyl ring; the thiazole and linker units are crucial for A₁ receptor modulation. Compound 46, an isoxazole-4-carboxamide, shows the presence of isoxazole, and the position of phenyl substituents are key for analgesic activity. Compound 47, a macrocyclic NTS2 ligand, benefits from conformational rigidity and aromatic side chains that enhance receptor selectivity without NTS1-related side effects. Compound 48, a ketamine analogue, retains the aryl cyclohexylamine core, with modifications on the aryl and amine side chains to optimize NMDA receptor activity. Compound 49, a hexaza-isowurtzitane derivative, relies on its cage-like nitrogenous framework for potent analgesia and receptor fit. Lastly, compound 50, a Schiff base, uses a diaryl imine structure where halogenation and the imine nitrogen contribute to its analgesic and opioid-receptor interaction properties.

4. Narcotic derivatives under clinical trials for pain management

Several narcotic derivatives and related compounds are undergoing clinical trials for pain management, psychiatric disorders, and addiction treatment. Oliceridine (TRV-130), a G-protein-biased μ-opioid receptor agonist, has shown reduced side effects compared to traditional opioids and is FDA-approved as Olinvyk® for acute pain in adults [95]. NKTR-181, an oral opioid analgesic with slow CNS entry, minimizes euphoria and misuse risks, targeting chronic low-back pain [96]. Bromadoline (U-47931E), a synthetic opioid with potent analgesic properties, is under investigation for its pharmacokinetics [97]. SLL-039 has demonstrated efficacy and safety in trials, especially where NSAIDs are insufficient [98]. EST73502, currently in Phase I, exhibits antinociceptive properties with an improved safety profile [99]. In neuropsychiatric and cancer contexts, Dexanabinol (HU-211), an NMDA receptor antagonist, has completed Phase I trials for brain cancer and solid tumors without psychoactive effects. MDMA has shown promise in Phase III trials for PTSD, with significant therapeutic outcomes [100]. Psilocybin demonstrates sustainable reductions in depression and anxiety, particularly in cancer patients, while LSD is being evaluated for cluster headaches and anxiety. Other compounds like 5-MeO-DMT and ibogaine/noribogaine, derived from Tabernanthe iboga, are under study for depression, eating disorders, and addiction treatment, particularly opioid use disorder. Cebranopadol, a novel analgesic, targets both opioid and nociceptin receptors. It has shown strong efficacy in pain management with a reduced risk of tolerance and abuse, positioning it as a promising alternative for chronic pain treatment [101]. Figure 5 represents the structures of narcotic derivatives currently under clinical trials for pain and neuropsychiatric conditions.

Figure 5.

Potential narcotic derivatives undergoing clinical trials.

5. Discussion and future directions

Recent advances in synthetic opioid chemistry have significantly expanded the potential for safer and more effective analgesics. Strategic modifications such as methylation, sulfation, scaffold rigidification, and nitrogen substitutions have been shown to improve receptor selectivity, potency, and metabolic stability. These innovations reflect a shift toward designing opioids that retain strong analgesic activity while reducing risks such as tolerance, dependence, and respiratory depression. Additionally, the emergence of compounds with dual receptor activity (e.g., MOR/DOR or MOR/σ1) and biased agonism offer promising strategies to reduce adverse effects. Emerging targets such as NOP, S1R, TRPV1, and DOR also present novel, non-addictive pathways for pain modulation, expanding the pharmacological landscape beyond classical opioid receptors. The SAR insights discussed herein offer valuable direction for optimizing future analgesic scaffolds. Furthermore, the inclusion of non-opioid agents highlights complementary mechanisms suitable for cases where opioid therapy is limited. Future research should prioritize the development of peripherally acting, multi-target ligands that integrate SAR-driven design, computational modeling, and translational pharmacology to meet evolving therapeutic and regulatory needs.

6. Conclusion

This manuscript provides a comprehensive exploration of the historical significance of narcotic plant sources, emphasizing the enduring importance of opium derivatives in pain management. By tracing their evolution from natural alkaloids to synthetic derivatives, the work highlights the pivotal role of structural advancements in enhancing therapeutic efficacy and safety. An extensive literature review enabled framing the SAR insights for key synthetic derivatives tested in preclinical studies, offering valuable perspectives on receptor selectivity and pharmacological potential. Additionally, the structures of potent narcotic derivatives currently in clinical trials were examined, underscoring ongoing efforts to develop safer and more effective analgesics. Together, these findings bridge historical context with modern advancements, contributing to the evolving narrative of narcotic-based pain management and inspiring future innovations in analgesic therapy.

Funding Statement

This paper was not funded.

Article highlights

• Historical perspective in pain relief highlighting the role of narcotic plants: The therapeutic use of narcotic plants such as Papaver somniferum, Cannabis sativa, and Corydalis yanhusuo in traditional medicine systems, establishing the foundation for modern opioid-based pain management.

• Mechanism of action via opioid receptors: Opioids mediate analgesia through μ-opioid receptor activation, inhibiting cAMP pathways, modulating ion channels, and attenuating nociceptive neurotransmission in the central nervous system.

• Most potent synthetic derivatives in preclinical studies: Compounds like cis-3-methyl fentanyl, de hydro buprenorphine, and C₉-substituted morphans demonstrate ultra-high potency, surpassing traditional opioids in receptor affinity and analgesic efficacy.

• Structure – Activity Relationship (SAR) analysis of potent derivatives: SAR insights emphasize the impact of strategic chemical modifications – such as sulfation, methoxylation, and scaffold rigidification – on potency, selectivity, and reduced central side effects.

• Clinical evaluation of opioids and non-opioids: Agents including Oliceridine, NKTR-181, and Cebranopadol represent a new generation of analgesics with improved safety profiles, while non-opioids like MIPS521 and psilocybin offer mechanistically distinct alternatives.

• Phytopharmacological contributions to analgesic development: Plant-derived compounds such as mitragynine, tetrahydrocannabinol (THC), and dehydrocorydaline continue to inform novel analgesic strategies by leveraging both opioid and non-opioid pathways.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties

Writing assistance

No writing assistance was utilized in the production of this manuscript

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author Contributions/ CRediT Author Statement

Rakesh Chandra Kalita conducted an extensive review of synthetic derivatives and contributed significantly to drafting the manuscript. Shivank authored the historical perspective and introductory sections and prepared the figures using Chem draw and Bio Render. Suman compiled the data on key phytoconstituents present in narcotic plants and molecules currently under clinical trials. Dr. Deepshikha refined and finalized the manuscript and prepared the graphical abstract.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17568919.2025.2527606