Background
The clinical landscape of substance use among patients managing chronic pain has shifted considerably in recent years, driven by regulatory tightening around traditional opioids and the parallel emergence of unregulated or loosely regulated alternatives. Kratom, novel synthetic opioids (including nitazenes), designer benzodiazepines, misused gabapentinoids, xylazine-adulterated supplies, and ketamine have each entered this population through distinct pathways — self-treatment, diversion, or adulteration of the illicit drug supply — creating new diagnostic and management challenges for clinicians and pharmacists.
Objective
This presentation examines the pharmacology, clinical presentation, and risk profile of these six emerging substances specifically within the context of chronic pain management, with attention to drug interactions, toxicology screening limitations, and implications for prescribing and monitoring practices.
Discussion
Each substance class presents unique detection and management challenges: kratom's dual opioid-agonist/stimulant pharmacology complicates standard toxicology interpretation; novel synthetic opioids' extreme potency and structural diversity outpace routine immunoassay screening; designer benzodiazepines carry unpredictable potency and duration; gabapentinoid misuse frequently escapes clinical suspicion; xylazine contributes to non-opioid-responsive overdose presentations and severe wound complications; and ketamine's growing off-label and recreational use raises distinct dependence and diversion concerns.
Conclusion
Clinicians and pharmacists managing chronic pain populations must maintain current awareness of this evolving substance landscape to support accurate risk assessment, appropriate monitoring protocols, and informed clinical decision-making.

Frank Breve, PharmD, MBA, CCP, has been the owner and president of Mid Atlantic PharmaTech Consultants, LLC since 1990. He is also President and CEO of a 501(c)(3) non-profit corporation, Opioid Consulting Educational Solutions. His activities include Treasurer for the New Jersey Joint Board for Certified Consultant Pharmacists and Advisory Board member for the Institute for Safe Medication Practices. He is past president of the New Jersey Pharmacists Association, the New Jersey Academy of Consultant Pharmacists, and the New Jersey Society of Health-System Pharmacists-Southern Chapter.
Dr Breve is adjunct faculty with Temple University School of Pharmacy and the University of Colorado Skaggs School of Pharmacy. He is a consultant for Baxter Healthcare Renal Division and Cardinal Health Medical Products and Services. He has authorised over 50 publications and is active in numerous professional organisations, including the National Association of Drug Diversion Investigators, the National Association of State Controlled Substances Authorities, and the Association of Healthcare Internal Auditors.