Historical Evolution of Understanding

INTRODUCTION The use of opioids is associated with various adverse effects, including the development of dependence, tolerance, addiction and opioid-induced hyperalgesia (OIH).(1,2) Recently, there has been a marked increase in the number of basic and clinical science literature exploring the mechanisms and clinical significance of OIH. Broadly, OIH refers to an increased sensitivity to pain as a result of opioid exposure. It may manifest as hyperesthesia or allodynia, and may also be accompanied by other signs of opioid toxicity such as myoclonus, delirium and seizures. Furthermore, it may present in the clinical setting as worsening pain despite increasing pain medication doses; worsening pain that cannot be explained by progression of the original condition; diffuse pain or pain at anatomically different sites; or excessive pain from surgical procedures.(1,2) Recent interest in OIH has grown, and there have been at least four recent reviews(1-4) that discussed various aspects of its biochemical and molecular basis. However, OIH research to date has been complicated by two main factors: (1) OIH may resemble tolerance in that inadequate pain relief leads to increasing opioid doses, and symptoms may also be confused with opioid withdrawal, particularly in the setting of acute opioid use without a taper or maintenance dose; (2) There appears to be plausible development of hyperalgesia in more than one setting of opioid use − OIH has been described with acute and chronic exposure, at high and low doses, and with different types of opioids and routes of administration. Implicit is that different mechanisms might underlie the phenomenon in each specific circumstance. Specific mechanisms should thus be considered when attempting to generalise the conclusions of one study across the entire OIH spectrum. This concise review aims to discuss the existing literature with respect to these limitations and identify future research directions that would help in the clinical diagnosis and management of OIH. HISTORICAL EVOLUTION OF UNDERSTANDING It has been well known within the medical community that patients suffering from opioid addiction seem to express a decreased tolerance to pain stimulus when compared to healthy subjects.(5) Furthermore, formal experiments on opioid addicts have demonstrated their increased pain sensitivity to objective measurements, such as the cold presser test.(6) Evidence now exists that OIH develops not only in addicts, but also in those who are on long-standing opioid maintenance and even those who have received short courses of opioids in the perioperative period.(7) Recent evidence suggests that contrary to earlier views, OIH is more common than many providers recognise, and is not always limited to high-dose opioid use.(8) The phenomenon of hyperalgesia secondary to opioid administration has been demonstrated under controlled experimental conditions in otherwise healthy adults,(9,10) and is also recognised in patients with a history of narcotic abuse.(11,12)