As the use of opioid medications for treatment of chronic noncancer pain has increased, there have been both intended and unintended consequences. Importantly, access to analgesic medications, including opioids, has risen. However, abuse of prescription opioids, with its associated morbidity and mortality, has concurrently increased, reaching epidemic levels in the United States [1
]. Additionally, there has been increasing evidence for unintended pronociceptive consequences of long-term use of opioids. Worsening pain sensitivity without a new injury or exacerbation of an old injury in a person chronically exposed to opioids is termed opioid-induced hyperalgesia (OIH). This pain often can be diffuse, of a different quality, and unassociated with previous tissue damage. However, there remain many unanswered questions for OIH regarding its molecular mechanisms, pathophysiology, opioids with the highest risk for OIH, and the time frame involved from first use of an opioid to signs of clinically significant hyperalgesia.
OIH first was described in the peer-reviewed literature in 1943 [2
], but has garnered increasing attention over the past two decades. Controlled preclinical experiments have defined OIH in animals as a decrease in pain threshold from baseline after chronic administration of opioids [3••
]. There still is no accepted operational definition of OIH amongst researchers in human clinical trials; hyperalgesia is defined either as decrease in pain threshold or pain tolerance after chronic opioid exposure. Pain threshold is the first experience of pain from a given stimulus, and pain tolerance is the amount of pain from a given stimulus a person can handle before seeking relief (eg, the amount of time before stopping an experimental pain procedure due to pain, or amount of time before seeking pain-relieving therapy). Threshold and tolerance are two different constructs with, potentially, two different psychophysical mechanisms. Given the lack of consensus definition of OIH amongst pain researchers, it can be difficult to compare results across studies and draw firm conclusions.
Additionally, OIH often is confused with opioid tolerance, allodynia, and withdrawal-associated hyperalgesia (WAH). These three syndromes can manifest similar symptoms, but need to be clinically differentiated from OIH due to differing effective interventions. offers a guideline for practitioners in the diagnosis and treatment strategies for all of them. Opioid tolerance occurs when increasing amounts of opioids are required to produce the same desired effect; an increase in opioid dose would be the intervention when opioid tolerance is associated with decreased analgesic efficacy. Allodynia is the experience of pain from a benign stimulus (eg, persons suffering from temporomandibular joint disorder will feel excruciating pain from light touch or cold foods). It can be treated with opioids, nonopioid analgesics, or surgical intervention. Finally, WAH is the experience of diffuse joint pain and body aches, which occur when detoxifying from chronic opioid use or skipping/missing scheduled doses; it is time-limited and can be treated with NSAIDs, clonidine, controlled taper of an opioid (if desired), or strict schedule of opioid dosing.
Diagnosis and treatment strategies for opioid-induced hyperalgesia, opioid tolerance, allodynia, and withdrawal-associated hyperalgesia. NMDA N-methyl D-aspartate; QST quantitative sensory testing
It is not yet known what changes in the peripheral or central nervous systems cause OIH. Given that OIH is associated with chronic administration of opioids, it is theorized that neural plasticity in one or more aspects of the nervous system occurs before the onset of hyperalgesia. Likely neural candidates underlying OIH include the μ-opioid receptor, glutamate receptor, other excitatory neuropeptides, or the descending inhibitory pathway. This review explores recent research in OIH, looking at important preclinical and clinical experiments that are assisting scientists and clinicians in understanding this phenomenon. Additionally, important individual differences that impact on the experience of OIH are discussed. Finally, there will be a balanced discussion on the diagnosis, treatment, and clinical significance of OIH.