History of Opioid-Induced Hyperalgesia
Chronic pain is a significant problem in both the United States and Europe. Research suggests it affects 30 – 40% of the population[1][2] and costs between 100 billion[2] and 635 billion[1] dollars each year. It is most commonly treated with opioid-based medications, which are well characterized in their ability to alleviate pain. However, these compounds also have drawbacks, including the development of tolerance and the significant potential for addiction. Less well described is their potential to actually increase the perception of pain, which has been termed opioid-induced hyperalgesia. While clinical reports have suspected the existence of this hyperalgesia since 1870[3], there remain doubts about the existence of this condition in the human clinical literature as recently as 2015[4]. To address this confusion, studies conducted since about the year 2000 in both animals and humans have attempted to demonstrate the existence of this phenomenon and to characterize what causes it and the mechanisms that underlie it.
Animal Studies of Opioid-Induced Hyperalgesia
Opioid-induced hyperalgesia (OIH) has been studied in animals using traditional animal models of pain. In a model of fracture pain, the analgesic effects of opioids were assessed using the hot plate test, in which the time to remove a limb from a hot plate is measured, and von Frey fibers, which measure the response to mechanical stimulation[5]. It was found that analgesic effect of opiates decreased over time, similar to tolerance, but distinct from this well-characterized phenomenon. However, if the mouse was also treated with ketamine, an antagonist of the NMDA glutamate receptor (more on this later), the effectiveness of the opiates did not decrease[5].
In a study of OIH in a mouse model of postoperative pain, analgesia was evaluated using measurements of both mechanical and thermal hyperalgesia[6]. Mechanical hyperalgesia was assessed through von Frey fibers and the application of pressure to the dorsal surface of the paw until the animal flexed. Thermal hyperalgesia was assessed using an equivalent of the hot plate test. Using these methods, gene knockout mice were used to determine the involvement of the nitric oxide system in the development of OIH[6].
Xu and colleagues[2] used the tail-flick test, which assesses thermal nociception, to evaluate the involvement of the mammalian target of rapamycin (mTOR) in the development of hyperalgesia. This kinase is active in the dorsal horn of the spinal cord following injection of morphine. Blocking the activity of this kinase, which is involved in the mu opioid receptor pathway, prevents the development of hyperalgesia[2]. Other researchers are using a variety of models of pain to study the genetics of this condition[7]. The current trend in this field is to use traditional models of pain in mice and rats combined with gene knockouts to study various neurotransmitter systems and signaling pathways that may be important in the development of OIH.
Mechanisms of Opioid-Induced Hyperalgesia
Studies of thermal and mechanical pain in animals has lead researchers to suggest several biological systems involved in the development of OIH. A complete review of these mechanisms is beyond the scope of this post, but have been extensively reviewed in the literature[1]. Briefly, some of the pathways implicated include NMDA receptors[3][5][8], the cyclooxygenase enzyme[1][9], and descending facilitation of excitatory signaling in the spinal cord[1][9]. These studies have also identified other factors, including the melanocortin receptor, particularly in female subjects, that contribute to the development of OIH[1][10]. Other studies have identified a difference in hyperalgesia to different types of stimulation, with researchers reporting the development of OIH to thermal stimuli but not mechanical stimuli[9]. Some studies have identified OIH in healthy, drug-naïve volunteers[11], while others have found it in drug addicts or patients receiving opioid-based medications for chronic conditions[10]. Together, these results suggest that the effect may be highly specific and only identified if researchers are aware of the condition and are prepared to differentiate it from the development of tolerance.
Clinical Relevance of Opioid-Induced Hyperalgesia
Chronic pain is a condition that affects a large number of individuals. The most common treatment for pain involves the use of opioid-based medications. Physicians have understood that patients develop tolerance to these medications and suffer withdrawal from them for many years, and OIH is commonly perceived as the development of tolerance to the medications[8]. However, as research has explored OIH in animals and human subjects, it has become possible to differentiate between these conditions, based on how patients react to changing the dosage and timing of medications. One important question has become how to prevent the development of OIH. The use of animal models of pain has helped in the development of ways to prevent such hyperalgesia. One route is to block the NMDA glutamate receptor using agonists such as ketamine[5][9]. Small dosages of opioid receptor antagonists have also been proposed to prevent the development of OIH[9]. The results of research involving traditional animal models of pain have helped elucidate the mechanisms of opioid-induced hyperalgesia and will continue to be important in future genetic studies of this condition.
References
- Roeckel, L.A., et al., Opioid-induced hyperalgesia: Cellular and molecular mechanisms. Neuroscience, 2016. 338: p. 160-182.
- Xu, J.T., et al., Opioid receptor-triggered spinal mTORC1 activation contributes to morphine tolerance and hyperalgesia. Journal of Clinical Investigation, 2014. 124(2): p. 592-603.
- Lee, M., et al., A comprehensive review of opioid-induced hyperalgesia. Pain Physician, 2011. 14(2): p. 145-61.
- Eisenberg, E., E. Suzan, and D. Pud, Opioid-induced hyperalgesia (OIH): a real clinical problem or just an experimental phenomenon? Journal of Pain and Symptom Management, 2015. 49(3): p. 632-6.
- Minville, V., et al., Opioid-induced hyperalgesia in a mice model of orthopaedic pain: preventive effect of ketamine. British Journal of Anaesthesia, 2010. 104(2): p. 231-8.
- Celerier, E., et al., Opioid-induced hyperalgesia in a murine model of postoperative pain: role of nitric oxide generated from the inducible nitric oxide synthase. Anesthesiology, 2006. 104(3): p. 546-55.
- Liang, D.Y., et al., A genetic analysis of opioid-induced hyperalgesia in mice. Anesthesiology, 2006. 104(5): p. 1054-62.
- Low, Y., C.F. Clarke, and B.K. Huh, Opioid-induced hyperalgesia: a review of epidemiology, mechanisms and management. Singapore Medical Journal, 2012. 53(5): p. 357-60.
- Leal Pda, C., et al., Opioid-induced hyperalgesia (OIH). Revista Brasileira de Anestesiologia, 2010. 60(6): p. 639-47, 355-9.
- Tompkins, D.A. and C.M. Campbell, Opioid-induced hyperalgesia: clinically relevant or extraneous research phenomenon? Current Pain and Headache Reports, 2011. 15(2): p. 129-36.
- Fishbain, D.A., et al., Do opioids induce hyperalgesia in humans? An evidence-based structured review. Pain Medicine, 2009. 10(5): p. 829-39.