Differential Opioid Tolerance and Opioid-induced Hyperalgesia: A Clinical Reality.

Anesthesiology, V 124 • No 2 483 February 2016 O PIOIDS are highly effective analgesics and as such form the mainstay of pain management after surgery. However, they are associated with a formidable array of side effects, some of them potentially lethal. Also, the opioid signaling system has a remarkable ability—possibly unequaled by any other receptor system in the body—for tolerance development. Although not all patients necessarily develop profound tolerance,1 in many cases doses have to be increased over time to maintain analgesic benefit. Physicians have not typically been overly concerned about inducing opioid tolerance in the perioperative period. In the first place, it is assumed that the development of tolerance takes time and that the duration of the perioperative period is too short for significant tolerance to develop. In the second place, even if tolerance develops, it can be overcome by administering more opioids, and the drugs are inexpensive. Finally, it is generally assumed that increased tolerance to the analgesic effects of opioids is associated with increased tolerance to side effects as well, and therefore, even if larger doses have to be given, this would not entail any greater risk to the patient. Unfortunately, these arguments are probably wrong, at least to some degree. The perioperative period may be relatively short, but we now know that opioid tolerance can develop in a shorter time frame, possibly within hours when patients are exposed to high doses (i.e., a phenomenon that classically is referred to as tachyphylaxis). More importantly, many patients are already using opioid drugs for pain control before surgery and, therefore, are tolerant before they even arrive in the operating room. As to the development of tolerance to side effects, we now know that not all opioid targets develop tolerance at the same rate and to the same degree. This differential tolerance can put patients at significant risk. In addition, recent studies have made it clear that continued exposure to opioids induces more than tolerance. It also induces a degree of hyperalgesia. Whereas, in principle, tolerance can be overcome by increasing opioid dose, hyperalgesia is made worse in the long run by increasing the opioid administration. In this article, we will describe the clinical concepts of differential opioid tolerance and opioid-induced hyperalgesia (OIH) and discuss the role they may play in our management of patients in the perioperative setting. It should, however, be realized that these issues are relevant not just only to the perioperative period but also to all settings where opioids are administered. We will focus on the clinical setting; a substantial amount of mechanistic information on these processes is available and has been reviewed recently.2,3