Opioids are strong analgesics for the treatment of moderate to severe pain. However, paradoxical opioid-induced hyperalgesia (OIH) has become a significant clinical issue that reduces the effectiveness of opioid therapy and contributes to prescription opioid addiction and abuse. Despite significant progress in defining clinical features (markers) of OIH, no effective pharmacotherapies are currently available to prevent and reverse OIH. For years, supervised opioid dose reduction or opioid rotation has been proposed to manage suspected OIH. However, a major clinical challenge in implementing this strategy is the need to maintain adequate pain relief while opioid dose is reduced. Centrally acting alpha2-adrenoreceptor (alpha2-AR) agonists have long been known to improve opioid tolerance and dependence. Recently, alpha2-AR agonists also have been suggested to be useful to improve OIH. Among FDA-approved alpha2-AR agonists (e.g., clonidine, dexmedetomidine, tizanidine), guanfacine possesses a stable cardiovascular side effect profile, is used in a single daily dose regimen, and has been used (off-label) for the treatment of attention deficit hyperactivity disorder. Our preliminary data has shown that alpha-2AR agonist effectively reduces OIH in a preclinical model and maintains the opioid analgesic effect in chronic pain patients. In this application, we propose to conduct two double-blind, randomized, and placebo-controlled clinical studies in order to examine the effectiveness of guanfacine in the prevention and reversal of OIH. In the first study (Aim 1), we will recruit chronic pain subjects who currently ar experiencing unsatisfactory pain relief with non-opioid treatment to assess whether guanfacine can prevent the development of OIH as they commence opioid therapy. In the second study (Aim 2), we will recruit chronic pain subjects who experience moderate to severe pain despite having taken opioid for at least three months and demonstrate signs of OIH to assess whether guanfacine can reverse OIH. Methodologically, we will use both quantitative sensory testing (QST including assessment of temporal summation and diffuse noxious inhibitory control) and clinical (visual analog scale of pain intensity and affect;subcutaneous needle stick test) markers of OIH to assess the effectiveness of guanfacine. We expect that the proposed prospective human studies will yield important and timely clinical data regarding a novel and practical approach to managing OIH. Since OIH decreases the overall effectiveness of opioid therapy, developing this novel pharmacotherapy for OIH treatment will help reduce unnecessary opioid dose escalation, improve clinical outcome of opioid therapy, and diminish the liability of prescription opioid addiction and abuse related to chronic pain management.

Public Health Relevance

Opioid therapy for chronic pain management is often complicated by the presence of opioid-induced hyperalgesia, a clinical condition contributing to the reduced opioid analgesic effect and prescription opioid addiction and abuse. The outcome of this study will help improve the overall effectiveness of opioid therapy by offering a novel therapeutic approach to managing opioid-induced hyperalgesia and reducing the liability of prescription opioid addiction and abuse related to chronic pain management.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Hampson, Aidan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Maher, Dermot P; Chen, Lucy; Mao, Jianren (2017) Intravenous Ketamine Infusions for Neuropathic Pain Management: A Promising Therapy in Need of Optimization. Anesth Analg 124:661-674
Zhang, Shuzhuo; You, Zerong; Wang, Shuxing et al. (2016) Neuropeptide S modulates the amygdaloidal HCN activities (Ih) in rats: Implication in chronic pain. Neuropharmacology 105:420-433
Lee, Cheng-ting; Vo, Trang T; Cohen, Abigail S et al. (2016) Profiles of Urine Drug Test in Clinical Pain Patients vs Pain Research Study Subjects. Pain Med 17:636-43
Mao, Jianren (2015) Clinical Diagnosis of Opioid-Induced Hyperalgesia. Reg Anesth Pain Med 40:663-4
Jamison, Robert N; Mao, Jianren (2015) Opioid Analgesics. Mayo Clin Proc 90:957-68
Zhang, Yi; Ahmed, Shihab; Vo, Trang et al. (2015) Increased pain sensitivity in chronic pain subjects on opioid therapy: a cross-sectional study using quantitative sensory testing. Pain Med 16:911-22
Chen, Lucy; Sein, Michael; Vo, Trang et al. (2014) Clinical interpretation of opioid tolerance versus opioid-induced hyperalgesia. J Opioid Manag 10:383-93
Chen, Kelly Yan; Chen, Lucy; Mao, Jianren (2014) Buprenorphine-naloxone therapy in pain management. Anesthesiology 120:1262-74
Lim, Grewo; Kim, Hyangin; McCabe, Michael F et al. (2014) A leptin-mediated central mechanism in analgesia-enhanced opioid reward in rats. J Neurosci 34:9779-88