The Evidence for Opioid-Induced Hyperalgesia Today

Research Article

Austin J Anesthesia and Analgesia. 2014;2(4): 1024.

The Evidence for Opioid-Induced Hyperalgesia Today

David A Edwards and Lucy Chen*

Department of Anesthesia, Critical Care & Pain Medicine, Harvard University, USA

*Corresponding author: Lucy Chen, Department of Anesthesia, Critical Care & Pain Medicine, Massachusetts General Hospital, Harvard University, Boston, MA, USA.

Received: March 14, 2014; Accepted: April 24, 2014; Published: April 28, 2014


Hyperalgesia is an increased response to painful sensation. Opioid–induced hyperalgesia occurs after sustained opioid exposure and⁄or following abrupt cessation of opioid. At the cellular level, adenylyl cyclase superactivation and elevated cAMP levels lead to PKA–mediated enhanced neurotransmitter release. Spinal glutamate, substance P, and CGRP enhance pain through NMDA, NK–1, and CGRP receptors respectively. Non–opioid receptor mediated OIH may be caused by M3G activation of TLR4. In controlled human experiments OIH is evident to cold pain, but less consistently found with pain caused by other modalities such as heat, electricity, or pressure. Hyperalgesia detected in response to cold pain can be reduced by the NMDA antagonist ketamine. Patients on methadone maintenance also show an increased sensitivity to nociception between doses. Multi–modal analgesia may be the best strategy fortreatment of OIH in the clinical setting.

Keywords: Hyperalgesia; Opioid; Nociception; Ketamine


Nearly all clinicians know that when they prescribe opioid medications to treat their patient’s pain, they are balancing against the risk of tolerance and addiction, overdose and death. What they know less about is that high–dose opioids, as an intra–operative infusion or as an oral home dose, could make the pain worse under certain conditions. This latter situation is called Opioid–Induced Hyperalgesia (OIH) and is defined as an increased response to a painful stimulus caused by exposure to opioids. The paradox of potentially doing harm when trying to provide relief is antithetical to a clinician’s sworn oath, so if real, must be recognized and avoided.

Is OIH real in humans, and if it is real, is it relevant? After 3 decades of research, the question is still being asked [1]. Since the early observation that patients on morphine had a lower threshold for pain [2,3], in vitro cell studies and in vivo animal studies have proceeded to uncover the potential mechanisms. Case reports and clinical studies of OIH are appearing with increased frequency. Models to empirically measure OIH in humans have been developed, and are used to detect hyperalgesia in these controlled situations. Still, what is its relevance in the clinic?

Clinically OIH may occur with chronic oral opioid consumption or after intra–operative intravenous infusions of opioid. In methadone aintained populations the threshold for pain sensation is decreased. After remifentanil infusions, post–operative hyperalgesia is presumed due to increased pain scores and opioid requirement. In either scenario, what are the clinician’s options? Withholding pain–relieving opioids is not the complete answer, but opioid–sparing techniques may be at least part of it.

It seems more obvious that the chronically treated patient may be subject to a relatively increased disservice by the prescription of opioids compared to the surgical patient that is given an intraoperative infusion. If methadone–maintained patients are more sensitive to pain, preventing ongoing suffering or managing perioperative pain becomes a challenge. Compare this to the patient exposed intra–operatively to a remifentanil infusion who is requiring more morphine in the recovery room. A transient increased use of morphine to become comfortable seems to be an appropriate measure and trade–off for preventing intra–operative severe surgical pain, especially if there are no long–term downsides. On the other hand, if there are options that can prevent hyperalgesia and also provide equal relief from pain then we are obligated to use them.

This review provides an overview of the evidence for OIH. First, in vitro cell models and in vivo animal models are reviewed followed by up–to–date evidence from human trials. Reference tables were created to show all human trials published to date. Several good reviews have been published on this topic that deal with the potential mechanisms in great depth [4,5]. This review emphasizes the evidence for OIH in humans in order to serve as a reference for clinicians.


Hyperalgesia is an increased response to a painful stimulus. The injured organism is more sensitive to pain and thereby is encouraged to guard against further injury while the healing occurs. Chronic pain is the pathological extension of allodynia or hyperalgesia beyond the normal healing period.

The establishment of hyperalgesia is known to have a central mechanism. Peripheral injury may directly damage nerve and surrounding tissue inducing the release of an inflammatory milieu that facilitates transmission of pain. Continual pain stimulus results in plastic changes in the dorsal horn of the spinal cord that decrease the threshold to pain sensation for surrounding neural inputs. Descending pain–inhibiting pathways are themselves inhibited. Over time, as the wound heals and the barrage of peripheral pain stimuli decreases, hyperalgesia lessens and disappears. On the other hand, a continuous exogenous stimulus may cause hyperalgesia to persist. Continued delivery of exogenous opioids induces downstream mechanisms that result in opioid tolerance and hyperalgesia.

In vitro studies of the cellular mechanism of opioid–induced hyperalgesia

In vitro studies of OIH have used mammalian cell cultures or acute tissue preparations to reveal several potential underlying mechanisms (Table 1). Prolonged opioid exposure causes changes in opioid–receptor mediated, and opioid–receptor independent downstream second messenger systems that may persist beyond the duration of opioid exposure. Mechanisms underlying hyperalgesia may involve both primary neurons as well as changes in glia. We first look at the opioid receptor–mediated mechanisms.