Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine

University of Louisville, Louisville, Kentucky, United States
Anesthesiology (Impact Factor: 5.88). 07/2005; 103(1):147-55. DOI: 10.1097/00000542-200507000-00022
Source: PubMed


Remifentanil-induced secondary hyperalgesia has been documented experimentally in both animals and healthy human volunteers, but never clinically. This study tested the hypotheses that increased pain sensitivity assessed by periincisional allodynia and hyperalgesia can occur after relatively large-dose intraoperative remifentanil and that small-dose ketamine prevents this hyperalgesia.
Seventy-five patients undergoing major abdominal surgery were randomly assigned to receive (1) intraoperative remifentanil at 0.05 microg x kg(-1) x min(-1) (small-dose remifentanil); (2) intraoperative remifentanil at 0.40 microg x kg(-1) x min(-1) (large-dose remifentanil); or (3) intraoperative remifentanil at 0.40 microg x kg(-1) x min(-1) and 0.5 mg/kg ketamine just after the induction, followed by an intraoperative infusion of 5 microg x kg(-1) x min(-1) until skin closure and then 2 microg x kg(-1) x min(-1) for 48 h (large-dose remifentanil-ketamine). Pain scores and morphine consumption were recorded for 48 postoperative hours. Quantitative sensory tests, peak expiratory flow measures, and cognitive tests were performed at 24 and 48 h.
Hyperalgesia to von Frey hair stimulation adjacent to the surgical wound and morphine requirements were larger (P < 0.05) and allodynia to von Frey hair stimulation was greater (P < 0.01) in the large-dose remifentanil group compared with the other two groups, which were comparable. There were no significant differences in pain, pressure pain detection threshold with an algometer, peak flow, cognitive tests, or side effects.
A relatively large dose of intraoperative remifentanil triggers postoperative secondary hyperalgesia. Remifentanil-induced hyperalgesia was prevented by small-dose ketamine, implicating an N-methyl-d-aspartate pain-facilitator process.

Download full-text


Available from: Daniel Sessler, Oct 05, 2015
1 Follower
354 Reads
    • "Punctuate hyperalgesia and extent of hyperalgesia were measured prior to surgery on days 1, 2 and 4 and at 3 months using the von Frey filament technique as previously described.[12] The threshold for punctuate hyperalgesia was measured with calibrated von Frey filaments. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background and Aims: Intravenous (I.V.) lidocaine has analgesic, antihyperalgesic and anti-inflammatory properties and is known to accelerate the return of bowel function after surgery. We evaluated the effects of I.V. lidocaine on pain management and acute rehabilitation protocol after laparoscopic nephrectomy. Materials and Methods: A total of 47 patients scheduled to undergo laparoscopic nephrectomy were included in a two-phase observational study where I.V. lidocaine (1.5 mg/kg/h) was introduced, in the second phase, during surgery and for 24 h post-operatively. All patients underwent the same post-operative rehabilitation program. Post-operative pain scores, opioid consumption and extent of hyperalgesia were measured. Time to first flatus and 6 min walking test (6MWT) were recorded. Results: Patient demographics were similar in the two phases (n = 22 in each group). Lidocaine significantly reduced morphine consumption (median [25-75% interquartile range]; 8.5 mg[4567891011121314151617] vs. 25 mg[1920212223242526272829303132]; P < 0.0001), post-operative pain scores (P < 0.05) and hyperalgesia extent on post-operative day 1-day 2-day 4 (mean ± standard deviation (SD); 1.5 ± 0.9 vs. 4.3 ± 1.2 cm (P < 0.001), 0.6 ± 0.5 vs. 2.8 ± 1.2 cm (P < 0.001) and 0.13 ± 0.3 vs. 1.2 ± 1 cm (P < 0.001), respectively). Time to first flatus (mean ± SD; 29 ± 7 h vs. 48 ± 15 h; P < 0.001) and 6MWT at day 4 (189 ± 50 m vs. 151 ± 53 m; P < 0.001) were significantly enhanced in patients with i.v. lidocaine. Conclusion: Intravenous (I.V.) lidocaine could reduce post-operative morphine consumption and improve post-operative pain management and post-operative recovery after laparoscopic nephrectomy. I.V. lidocaine could contribute to better post-operative rehabilitation.
    Journal of Anaesthesiology Clinical Pharmacology 07/2014; 30(3):366-72. DOI:10.4103/0970-9185.137269
  • Source
    • "Without direct measures to assess hyperalgesia such as QST, the results are not easy to distinguish from acute tolerance (Vinik and Kissin, 1998). Clinical studies examining remifentanil-induced hyperalgesia by QST showed that, at a relatively high dose, remifentanil decreased the pain threshold (Gustorff et al., 2002; Joly et al., 2005; Schmidt et al., 2007; Song et al., 2011; Yalcin et al., 2012). These studies used remifentanil infusions at clinically standard rates, and all of them showed clear hyperalgesia either shortly after discontinuing infusion or 1 and 2 days postoperatively. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction The use of opioids has been increasing in operating room and intensive care unit to provide perioperative analgesia as well as stable hemodynamics. However, many authors have suggested that the use of opioids is associated with the expression of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH) in experimental studies and clinical observations in dose and/or time dependent exposure even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management during anesthesia as well as in the intensive care units because of its rapid onset and offset. Objectives Search of the available literature to assess remifentanil AOT and OIH based on available published data. Methods We reviewed articles analyzing remifentanil AOT and OIH, and focused our literature search on evidence based information. Experimental and clinical studies were identified using electronic searches of Medline (PubMed, Ovid, Springer, and Elsevier, ClinicalKey). Results Our results showed that the development of remifentanil AOT and OIH is a clinically significant phenomenon requiring further research. Discussions and Conclusions AOT - defined as an increase in the required opioid dose to maintain adequate analgesia, and OIH - defined as decreased pain threshold, should be suspected with any unexplained pain report unassociated with the disease progression. The clinical significance of these findings was evaluated taking into account multiple methodological issues including the dose and duration of opioids administration, the different infusion mode, the co-administrated anesthetic drug’s effect, method assessing pain sensitivity, and the repetitive and potentially tissue damaging nature of the stimuli used to determine the threshold during opioid infusion. Future studies need to investigate the contribution of remifentanil induced hyperalgesia to chronic pain and the role of pharmacological modulation to reverse this process.
    Frontiers in Pharmacology 05/2014; 5(article 108):108. DOI:10.3389/fphar.2014.00108 · 3.80 Impact Factor
  • Source
    • "Adding ketamine has significant effect on VAS scores and drug dose (P = 0.001) due to analgesia property of this drug and possibly due to the effects of drug on cholinergic and mono aminergic mechanisms.[19] On the other hand ketamine can prevent acute tolerance to drugs that could contribute to the decrease in the morphine consumption.[2021] In fact, nociceptive stimulation can cause activation of NMDA receptors, worsening the post-operative pain and by adding ketamine, this effect may be aborted.[21] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Intravenous patient-controlled analgesia (PCA) with morphine is commonly used for post-operative pain after major surgery. Ketamine has analgesic property at lower doses, and in combination with opioids it could have synergistic effect. The aim of this study is to determine effects of the addition of ketamine to morphine for PCA after orthopedic surgery. In this double-blind randomized clinical trial, 60 patients were randomly allocated to receive PCA consisting: Group 1 (morphine 0.2 mg/ml), Group 2 (morphine 0.2 mg/ml + ketamine 1 mg/ml), and Group 3 (morphine 0.1 mg/ml + ketamine 2 mg/ml). In this, anesthesiologists managed study, patients had orthopedic surgery. Assessments were made at 24 h and 48 h post-operatively. Visual analog scale (VAS) was used for recording pain score. PCA morphine use was recorded at 24 h and 48 h. VAS scores over 48 h were analyzed with analysis of variance for repeated measures. Significance level was taken as 0.05. There is no significant difference between demographic information of the three groups (P > 0.05). Control of pain in Group 2 and Group 3 was better than in Group 1 (only morphine) (P = 0.001) but there was no significant difference between Group 2 and Group 3 (P > 0.05). Rate of narcotic consumption in groups 2 and 3 was significantly lower than Group 1 (P < 0.05). After orthopedic surgery, the addition of ketamine to morphine for intravenous PCA was superior to Intravenous PCA opioid alone. The combination induces a significant reduction in pain score and cumulative morphine consumption.
    Perspectives in clinical research 04/2014; 5(2):85-7. DOI:10.4103/2229-3485.128028
Show more