Colorado Anesthesia Services Group

Non-Conventional Opioids for Analgesia

Managing pain effectively while minimizing harm presents one of the greatest challenges in modern medicine. Clinicians have long relied on conventional opioids such as morphine, oxycodone, and fentanyl to treat moderate to severe pain. However, these medications carry significant risks, including respiratory depression, addiction, and death [8]. To address these concerns, researchers and clinicians have developed and adopted non-conventional opioids as alternative approaches to analgesia. These medications engage different receptor pathways and mechanisms than traditional opioids, offering potential advantages in efficacy, safety, and tolerability. Among them, buprenorphine, tramadol, and tapentadol have emerged as leading options for managing both acute and chronic pain [2, 11].

Non-conventional opioids provide effective analgesia while targeting different receptor pathways and mechanisms than traditional opioids. Buprenorphine, tramadol, and tapentadol stand out as leading options for managing both acute and chronic pain [11]. Clinicians use these agents to maintain analgesic efficacy while reducing the risks of respiratory depression, tolerance, and misuse seen with classic opioids. As the opioid crisis reshapes prescribing practices, non-traditional formulations offer a practical path toward safer, more individualized pain management.

One non-conventional opioid, buprenorphine, is gaining widespread clinical use due to its unique pharmacological profile and favorable safety characteristics [6]. Buprenorphine is a semi-synthetic thebaine derivative that acts as a partial agonist and antagonist [1]. In clinical practices, buprenorphine can provide strong pain relief with a reduced risk of fatal respiratory compromise and is less likely to cause euphoria even as doses increase, unlike full agonist opioids [1, 6]. It is FDA-approved for both acute and chronic pain and can be administered intravenously or sublingually in acute settings and through transdermal patches or buccal films for long-term pain control [6]. Notably, research has found that buprenorphine is particularly effective for neuropathic pain and may offer a safer analgesic option for older adults and individuals with renal impairment [1]. In recent years, clinicians have increasingly turned to buprenorphine when conventional opioids pose heightened risks or fail to provide adequate relief. Its versatility across formulations and patient populations makes it a valuable tool in modern pain management [7].

Tramadol is a non-conventional opioid often used for moderate pain or as a bridge between non-opioid analgesics and stronger opioids [3]. It works through a dual mechanism: weak μ-opioid receptor binding and inhibition of serotonin and norepinephrine reuptake, which enhances descending pain modulation [5]. It is not typically used alone for severe acute pain but can be effective in multimodal regimens or when stronger opioids are not appropriate [5]. Tramadol’s side effects include nausea, dizziness, sedation, and constipation, which limit its tolerability [5]. Its monoaminergic effects also pose unique risks, including seizures at high doses and serotonin syndrome when combined with other serotonergic drugs [5]. While tramadol carries a lower abuse potential than Schedule II opioids, misuse remains a concern [4]. Overall, it fills a niche as a centrally acting analgesic that provides multimodal pain relief with fewer respiratory risks but only moderate efficacy and some atypical adverse effects.

Tapentadol combines moderate μ-opioid receptor agonism with norepinephrine reuptake inhibition, allowing it to target both nociceptive and neuropathic pain [10]. Unlike tramadol, it has minimal serotonergic activity and carries a lower risk of serotonin syndrome [9]. Clinical studies have shown that tapentadol provides analgesia comparable to oxycodone for acute and chronic pain, with significantly fewer gastrointestinal side effects and a lower potential for misuse. These qualities make it a strong and more tolerable option for patients who do not respond well to conventional opioids or who experience mixed pain mechanisms [12].

Buprenorphine, tramadol, and tapentadol illustrate how targeted innovations in opioid pharmacology can address pain management needs that traditional opioids often fail to meet. Together, these non-conventional opioids offer clinicians flexible options to provide analgesia in complex pain scenarios with greater precision and fewer risks.

References

  1. Dalal, S., Chitneni, A., Berger, A. A., Orhurhu, V., Dar, B., Kramer, B., Nguyen, A., Pruit, J., Halsted, C., Kaye, A. D., & Hasoon, J. (2021). Buprenorphine for chronic pain: A safer alternative to traditional opioids. Health Psychology Research, 9(1), 27241. https://doi.org/10.52965/001c.27241
  2. Dey, S., Sanders, A. E., Martinez, S., et al. (2025). Alternatives to opioids for managing pain. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK574543/
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  7. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Committee on Pain Management and Regulatory Strategies to Address Prescription Opioid Abuse. (2017). Pain management and the opioid epidemic: Balancing societal and individual benefits and risks of prescription opioid use. National Academies Press. https://www.ncbi.nlm.nih.gov/books/NBK458653/
  8. Regina, A. C., Goyal, A., & Mechanic, O. J. (2025). Opioid toxicity. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK470415/
  9. Roulet, L., Rollason, V., Desmeules, J., & Piguet, V. (2021). Tapentadol versus tramadol: A narrative and comparative review of their pharmacological, efficacy and safety profiles in adult patients. Drugs, 81(11), 1257–1272. https://doi.org/10.1007/s40265-021-01515-
  10. Tzschentke, T. M., Christoph, T., & Kögel, B. Y. (2014). The mu-opioid receptor agonist/noradrenaline reuptake inhibition (MOR-NRI) concept in analgesia: The case of tapentadol. CNS Drugs, 28(4), 319–329. https://doi.org/10.1007/s40263-014-0151-9
  11. Webster, L., & Rauck, R. L. (2021). Atypical opioids and their effect on respiratory drive. Journal of Opioid Management, 17(7), 109–118. https://doi.org/10.5055/jom.2021.0648
  12. Zavaleta-Monestel, E., Anchía-Alfaro, A., Villalobos-Madriz, J., Munich, A., García-Montero, J., Quesada-Villaseñor, R., Arguedas-Chacón, S., Hernández-Ortiz, A., & Rodríguez-Miranda, R. (2024). Tapentadol: A comprehensive review of its role in pain management. Cureus, 16(11), e74307. https://doi.org/10.7759/cureus.74307