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How can we prevent opioid induced hyperalgesia in surgical patients?

2016; Elsevier BV; Volume: 116; Issue: 4 Linguagem: Inglês

10.1093/bja/aew050

1471-6771

Dominique Fletcher, V. Martinez,

Pediatric Pain Management Techniques

In this issue of the British Journal of Anaesthesia, Comelon and colleagues1Comelon M Raeder J Stuhaug A et al.Gradual withdrawal of remifentanil infusion may prevent opioid-induced hyperalgesia.Br J Anaesth. 2016; 116: 524-530Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar report that gradual withdrawal of remifentanil infusion may prevent opioid-induced hyperalgesia in volunteers. In this randomized, double-blinded, placebo-controlled, crossover study, nineteen volunteers were administered remifentanil for 30 min, with target infusion 2.5 ng ml−1 with abrupt or gradual withdrawal of remifentanil infusion. Pain was assessed with heat pain test and the cold pressor test at baseline, during infusion and 45–50 and 105–110 min after end of infusion. Forty-five min after the end of infusion there was remifentanil-induced hyperalgesia in the abrupt withdrawal session, with significantly higher pain scores compared with the gradual withdrawal and placebo sessions (both P<0.01), but no hyperalgesia after gradual withdrawal compared with placebo (P+0.93). In the cold pressor test, 50 min after the end of infusion there was hyperalgesia in both remifentanil sessions compared with placebo (gradual P+0.01, abrupt P<0.01). There were no differences between any of the remifentanil sessions compared with the placebo 105–110 min after end of infusion. The study has a clear methodology and supports the beneficial impact of gradual withdrawal on the development of opioid-related hyperalgesia, when tested with the heat pain test. The absence of opioid-induced hyperalgesia prevention detectable in the cold pressure test paradigm, is not clearly explained and may be related to more negative skewness of pain rating. The clinical phenomenon is short lasting as no difference persists at 105–110 min after remifentanil administration. This is shorter than the impact observed on pain intensity and opioid use at 24 h in clinical studies.2Fletcher D Martinez V Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis.Br J Anaesth. 2014; 112: 991-1004Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar This is probably related to the short duration of administration and therefore the limited cumulative dose of remifentanil administered to volunteers. A recent review and meta-analysis on remifentanil and opioid-related hyperalgesia evaluated to what extent the phenomenon occurs clinically, as the literature appeared controversial. This review suggests that high intra-operative doses of remifentanil are associated with small but significant increases in acute pain, lasting 24 h after surgery and a higher postoperative morphine use, estimated to be 18 mg during the same 24 h period.2Fletcher D Martinez V Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis.Br J Anaesth. 2014; 112: 991-1004Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar In this review, the additional morphine use was not associated with increased incidence of opioid related side-effects such as nausea, vomiting or sedation. These clinical data confirm that remifentanil opioid hyperalgesia is detectable in surgical patients but with a limited clinical significance. Interestingly, a subgroup analysis has suggested the protective role of propofol-based anaesthesia compared with inhalation anaesthesia agents against postoperative hyperalgesia.2Fletcher D Martinez V Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis.Br J Anaesth. 2014; 112: 991-1004Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar In some situations, prevention of opioid-induced hyperalgesia may have even more clinical significance.3Martinez V Fletcher D Prevention of opioid-induced hyperalgesia in surgical patients: does it really matter?.Br J Anaesth. 2012; 109: 302-304Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Genetic factors and preoperative use of opioid are two different preoperative factors, influencing potentially the benefit related to opioid-induced hyperalgesia prevention. A clinical study of 43 healthy volunteers, using a painful thermal stimulus, found that individuals homozygous for the met (158) polymorphism of the catechol O-methyl transferase gene, had greater hyperalgesia after remifentanil.4Jensen KB Lonsdorf TB Schalling M Kosek E Ingvar M Increased sensitivity to thermal pain following a single opiate dose is influenced by the COMT val(158)met polymorphism.PLoS One. 2009; 4: e6016Crossref PubMed Scopus (97) Google Scholar Another clinical situation is the potential preoperative use of opioid to treat preoperative pain. This chronic administration of opioid exposes to preoperative hyperalgesia.5Chen L Malarick C Seefeld L Wang S Houghton M Mao J Altered quantitative sensory testing outcome in subjects with opioid therapy.Pain. 2009; 143: 65-70Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar 6Hina N Fletcher D Poindessous-Jazat F Martinez V Hyperalgesia induced by low-dose opioid treatment before orthopaedic surgery: An observational case-control study.Eur J Anaesthesiol. 2015; 32: 255-261Crossref PubMed Scopus (83) Google Scholar The additional impact of preoperative opioid might aggravate the severity of opioid-induced hyperalgesia. In an interesting study on the intraoperative use of ketamine in surgical patients treated preoperatively by opioid, RW Loftus and colleagues7Loftus RW Yeager MP Clark JA et al.Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery.Anesthesiology. 2010; 113: 639-646Crossref PubMed Scopus (313) Google Scholar observe that the benefit of intraoperative prevention of opioid-induced hyperalgesia was sustained, with a morphine sparing effect for six weeks after surgery. Finally, the immediate postoperative period may not be the optimal period to detect the benefit of opioid-induced hyperalgesia prevention. One study by Salengros and colleagues8Salengros JC Huybrechts I Ducart A et al.Different Anesthetic Techniques Associated with Different Incidences of Chronic Post-thoracotomy Pain: Low-Dose Remifentanil Plus Presurgical Epidural Analgesia is Preferable to High-Dose Remifentanil with Postsurgical Epidural Analgesia.J Cardiothorac Vasc Anesth. 2010; 24: 608-613Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar has suggested that high dose of remifentanil may also be predictive of higher incidence of persistent post-surgical pain after thoracotomy.8Salengros JC Huybrechts I Ducart A et al.Different Anesthetic Techniques Associated with Different Incidences of Chronic Post-thoracotomy Pain: Low-Dose Remifentanil Plus Presurgical Epidural Analgesia is Preferable to High-Dose Remifentanil with Postsurgical Epidural Analgesia.J Cardiothorac Vasc Anesth. 2010; 24: 608-613Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar In this study the high dose of remifentanil (effect site concentration of 5.6 ng ml−1) was compared with a low dose of remifentanil (effect site concentration of 2 ng ml−1). The high dose of remifentanil was responsible for 70% incidence of persistent post-surgical pain, compared with a 16.7% incidence in the low dose remifentanil group. Although the methodology of this study was exposed to some bias as epidural analgesia had a different timing in the two groups, the perspective to connect opioid-induced hyperalgesia and the development of persistent post-surgical pain is quite interesting. Interestingly persistent post-surgical pain has been previously shown to be correlated to the area of peri-incisionnal punctuate mechanical allodynia, in a series of clinical studies in colorectal surgery.9Eisenach JC Preventing chronic pain after surgery: who, how, and when?.Reg Anesth Pain Med. 2006; 31: 1-3PubMed Google Scholar In the recent meta-analysis on opioid-induced hyperalgesia, we were able to show an important increase of peri-incisionnal hyperalgesia at 24 h after high remifentanil dose SMD (0.88 [0.4,1.37]).2Fletcher D Martinez V Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis.Br J Anaesth. 2014; 112: 991-1004Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar Globally these clinical studies suggest that prevention of hyperalgesia either related to opioid or to surgical inflammation induced hyperalgesia may be interesting, to limit slightly immediate postoperative pain and perhaps also the incidence of persistent post-surgical pain. However, this hypothesis will need additional clinical data to be confirmed before it can be included in professional guidelines. The study by M Comelon and colleagues1Comelon M Raeder J Stuhaug A et al.Gradual withdrawal of remifentanil infusion may prevent opioid-induced hyperalgesia.Br J Anaesth. 2016; 116: 524-530Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar supports that gradual withdrawal from remifentanil, as opposed to abrupt withdrawal, may prevent remifentanil-induced hyperalgesia. This study is the first one in humans to confirm previous data obtained with one in vitro study.10Drdla R Gassner M Gingl E Sandkuhler J Induction of synaptic long-term potentiation after opioid withdrawal.Science. 2009; 325: 207-210Crossref PubMed Scopus (162) Google Scholar In this in vitro study on spinal dorsal horns from rats, abrupt withdrawal of remifentanil induced induction of synaptic long-term potentiation, which was prevented by tapered withdrawal.10Drdla R Gassner M Gingl E Sandkuhler J Induction of synaptic long-term potentiation after opioid withdrawal.Science. 2009; 325: 207-210Crossref PubMed Scopus (162) Google Scholar Exactly how gradual withdrawal of remifentanil infusion can prevent opioid-induced hyperalgesia is not clear. Induction of opioid withdrawal long-term potentiation as described by Drdla and colleagues10 requires postsynaptic activation of heterotrimeric guanine nucleotide-binding proteins and N-methyl-D-aspartate receptors and an increase of postsynaptic calcium concentrations. The neurobiology of opioid-induced hyperalgesia is complex and involves more than one system, with probable differences between acute and chronic settings at both pre- and post-synaptic levels, affecting N-methyl-D-aspartate receptor activity, G-proteins, and intracellular systems.11Colvin LA Fallon MT Opioid-induced hyperalgesia: a clinical challenge.Br J Anaesth. 2010; 104: 125-127Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Therefore, withdrawal long-term potentiation apparently shares pharmacology and signal transduction pathways with opioid-induced hyperalgesia. How can we prevent opioid-induced hyperalgesia in surgical patients? The cumulative dose of remifentanil seems the determinant factor both in experimental and clinical research.2Fletcher D Martinez V Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis.Br J Anaesth. 2014; 112: 991-1004Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar 12Cabanero D Campillo A Celerier E Romero A Puig MM Pronociceptive effects of remifentanil in a mouse model of postsurgical pain: effect of a second surgery.Anesthesiology. 2009; 111: 1334-1345Crossref PubMed Scopus (95) Google Scholar In a recent review we described the clear association between high dose remifentanil and clinical signs of hyperalgesia.2Fletcher D Martinez V Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis.Br J Anaesth. 2014; 112: 991-1004Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar However, we were unable to define a cut-off value responsible for this remifentanil-induced hyperalgesia. Beyond opioid dose reduction, different approaches have been tested including perioperative ketamine,13Joly V Richebe P Guignard B et al.Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine.Anesthesiology. 2005; 103: 147-155Crossref PubMed Scopus (495) Google Scholar 14Angst MS Koppert W Pahl I Clark DJ Schmelz M Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal.Pain. 2003; 106: 49-57Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar clonidine,15Koppert W Sittl R Scheuber K Alsheimer M Schmelz M Schuttler J Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans.Anesthesiology. 2003; 99: 152-159Crossref PubMed Scopus (243) Google Scholar propofol,2Fletcher D Martinez V Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis.Br J Anaesth. 2014; 112: 991-1004Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar 16Shin SW Cho AR Lee HJ et al.Maintenance anaesthetics during remifentanil-based anaesthesia might affect postoperative pain control after breast cancer surgery.Br J Anaesth. 2010; 105: 661-667Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar non-steroidal anti-inflammatory drug,17Lenz H Raeder J Draegni T Heyerdahl F Schmelz M Stubhaug A Effects of COX inhibition on experimental pain and hyperalgesia during and after remifentanil infusion in humans.Pain. 2011; 152: 1289-1297Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar propranolol18Chu LF Cun T Ngai LK et al.Modulation of remifentanil-induced postinfusion hyperalgesia by the beta-blocker propranolol in humans.Pain. 2012; 153: 974-981Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar or nitrous oxide.19Echevarria G Elgueta F Fierro C et al.Nitrous oxide (N(2)O) reduces postoperative opioid-induced hyperalgesia after remifentanil-propofol anaesthesia in humans.Br J Anaesth. 2011; 107: 959-965Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar All these approaches can be responsible of additional side-effects. The effect of gradual withdrawal from remifentanil infusion remains to be studied in a clinical setting but if confirmed, gradual remifentanil withdrawal is easy to implement and an inexpensive way to prevent postoperative remifentanil-induced hyperalgesia, without side-effects from adjuvants proposed to prevent remifentanil-induced hyperalgesia. In conclusion this study in volunteers supports the use of gradual withdrawal as a simple technique to limit the development of remifentanil-induced hyperalgesia. This can be easily transferred in clinical practice and further clinical studies may help in the future to determine the value of this prevention. None declared.