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Opioid-induced hyperalgesia

Dumont, H.*; Guntz, E.*; Sosnowski, M.*; Talla, G.*; Roman, A.; Segers, B.

European Journal of Anaesthesiology: February 2007 - Volume 24 - Issue 2 - p 205–207
doi: 10.1017/S0265021506001700

*Department of Anesthesiology, Centre Hôspitalier Universitaire Saint-Pierre, Université Libre de Bruxelles, Brussels, Belgium

Department of Intensive Care Unit, Centre Hôspitalier Universitaire Saint-Pierre, Université Libre de Bruxelles, Brussels, Belgium

Department of Vascular Surgery, Centre Hôspitalier Universitaire Saint-Pierre, Université Libre de Bruxelles, Brussels, Belgium

Correspondence to: Emmanuel Guntz, Department of Anesthesiology, Centre Hôspitalier Universitaire Saint-Pierre, Université Libre de Bruxelles, Rue Haute, 322, 1000 Brussels, Belgium. E-mail:; Tel: +322 535 35 94; Fax: +322 535 40 70

Accepted for publication 9 July 2006

First published online 11 October 2006


There is evidence to suggest that acute administration of opioids results in analgesia and delayed induced hyperalgesia [1]. N-methyl-d-aspartate (NMDA) receptors play a critical role in the development of hyperalgesia and opioids are known to activate or potentiate these receptors through different mechanisms [2,3]. The analgesic effects of fentanyl are known to be followed by a dose dependent decrease in pain threshold and morphine following fentanyl enhances this induced hyperalgesia [4].

A 62-yr-old man, ASA Grade III, 72 kg, 165 cm, was scheduled for revascularization of the right femoral artery. He had undergone an aorto-bifemoral bypass 9 yr before and suffered again from lower limb claudication. Relevant medical history included essential hypertension, ischaemic heart disease (stenting of the anterior interventricular artery 1 yr before), non-insulin dependant diabetes mellitus, chronic lymphoid leukaemia, oesophagitis, alcohol addiction, depression and chronic pain related to the arteritis of the lower limbs. Smoking was stopped 6 months ago. Daily treatment included: amlodipine 10 mg, carvedilol 25 mg, lorazepam 2.5 mg, amitriptyline 50 mg, metformin 1700 mg and artovastatin 20 mg. The analgesic treatment included: tramadol 150 mg, paracetamol 3 g per day and a 75 μg patch of fentanyl every 3 days. The fentanyl patch had not been changed for 2 days prior to the operation.

The placement of a new aorto-femoral bypass from the previous prothesis to the deep femoral artery was performed without complications. Anaesthesia was induced with 150 mg propofol, 100 μg remifentanil and 14 mg cisatracrium and maintained with continuous administration of propofol, remifentanil and cisatracrium. The patient received a total dose of 6.3 mg remifentanil during the 5 h operative time period. He was intubated with an 8.5 mm tracheal tube (Portex, Keene, NH, USA) and extubated at the end of the surgery. Two grams of proparacetamol and 10 mg of piritramide were given respectively 30 and 10 min before the end of surgery. Continuous monitoring included electrocardiography, pulse, oxygen saturation, end-tidal carbon dioxide, invasive arterial pressure and central venous pressure.

Once admitted to the intensive care unit, the patient complained of intense epigastric pain and therefore received 2 mg of morphine. This injection dramatically increased the pain. A second injection induced a similar result. He then received a bolus of 5 mg ketamine that markedly reduced his pain. Consequently, ketamine, 60 mg per day was continuously infused over 3 days with additional bolus of 5 mg ketamine if required.

This case report of opioid-induced hyperalgesia illustrates the putative role of opioids as activators of both a pronociceptive and an antinociceptive pathway [4].

In rats fentanyl dose-dependently decreases the nociceptive threshold and reduces morphine-induced analgesia. Moreover, morphine enhances for several days fentanyl-induced hyperalgesia. This effect is described as related to the activation of pronociceptive pathways by morphine administration and is prevented by repeated boluses of ketamine [4,5]. Ketamine inhibition of opioid-induced hyperalgesia underlines the involvement of NMDA receptors in the activation of pronociceptive pathways.

Remifentanil has also been involved in promoting hyperalgesia. Guignard and colleagues described this effect as an acute opioid tolerance prevented by the administration of ketamine [1,6]. Two recent electrophysiological studies showed that remifentanil is able either to activate NMDA receptors or to potentiate their activity [2,3]. The potentiation of NMDA receptors by opioids is related to the activation of an intra-cellular pathway triggered by the activation of μ-opioid receptors [3].

This report suggests that the fentanyl patch induced hyperalgesia subsequently enhanced by the postoperative boluses of morphine. We assume that intra-operatively remifentanil activated the pro- and antinociceptive pathways. The potency of remifentanil allowed surgery but as soon as it was stopped, the antinociceptive μ pathway was ineffective whereas the pronociceptive NMDA pathway remained active and sensitive to the administration of morphine. As described in rats by Laulin and colleagues, morphine is able to enhance opioids induced hyperalgesia and not potent enough to blunt it [4]. The analgesic-hyperalgesic equilibrium is unbalanced in favour of the pronociceptive pathways and is restored by ketamine.

The administration of ketamine decreased after 12 h. This length of time corresponds to the time required for the fentanyl release from the patch to be active. It implies that during 12 h the blockade of the pronociceptive pathway by ketamine was efficient enough to relieve the patient from his pain. Secondly, morphine did not relieve pain as expected but worsened the pain which is unusual. Since the patient had been using a fentanyl patch for a long period of time, we postulate that the down-regulation left less receptors available. Remifentanil and fentanyl have a high potency than morphine [7]. Thus the morphine that remained active on the pronociceptive pathway became inactive on the antinociceptive pathway whereas fentanyl would have, probably, been active on both pathways, as shown by the progressive antinociceptive effect of fentanyl.

This report describes an unusual situation that can be encountered when a patient is treated with opioids for a long period of time undergoes surgery. Although opioids remain the gold standard for postoperative analgesia, in this type of case morphine must be used with caution. We suggest to favour the use of a high efficacy agent (remifentanil) in association with ketamine.

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Work attributed to Department of Anesthesiology, Centre Hôspitalier Saint-Pierre, Université libre de Bruxelles (ULB), Rue Haute, 322, 1000 Brussels, Belgium.

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