Anaesthesiology Intensive Therapy, 2011,XLIII,1; 12-15

Effect of pre-emptive pregabalin on pain intensity and morphine requirement after hysterectomy

*Krzysztof Przesmycki1, Ewa Wiater-Kozioł1, Jan Kotarski2, Mirosław Czuczwar1, Robert Jaskowiak1, Marta Ząbek1, Agnieszka Kołacz1, Magdalena Fijałkowska1, Marzena Kotus1


12nd Department of Anaesthesiology and Intensive Therapy, Medical University of Lublin


21st Department of Gynaecological Surgery, Medical University of Lublin

  • Table 1. Demographic characteristics of patients
  • Table 2. Mean doses of fentanyl administered during surgery
  • Table 3. Severity of postoperative pain after the loading dose of morphine
  • Table 4. Mean doses of morphine used after surgery
  • Table 5. Intensity of rest pain during the first postoperative day
  • Table 6. Intensity of exertion pain during the first postoperative day

Background. Pregabalin, an antiepileptic and chronic pain medication, has been used by various authors for preoperative analgesia. We have assessed the effect of pre-emptive administration of the drug to patients scheduled for elective abdominal hysterectomy. 

Methods. Seventy-four ASA I and II patients were included in this prospective, double blind study. They were randomised to receive 75, 150, or 300 mg of pregabalin, or 7.5 mg of midazolam as a placebo, one hour before anaesthesia and surgery. Anaesthesia was induced with propofol and maintained with sevoflurane or desflurane. Fentanyl was used for analgesia and rocuronium for muscle relaxation. Immediately after surgery, patients received morphine intravenously in 2 mg increments until the NRS score was below 3. This was then followed by PCA.

Results. Morphine consumption and pain scores were only significantly lower in the 300 mg pregabalin group, when compared to the placebo and other treatment groups; there were no differences between placebos and lower doses of pregabalin.

Conclusion. We conclude that pre-emptive administration of 300 mg pregabalin reduces postoperative pain and morphine consumption. Further studies on higher doses would appear to be justified.

Gabapentin and pregabalin, the antiepileptic drugs, approved by the Food and Drug Administration (FDA) for the management of neuropathic pain, are capable of inhibiting chronic neuropathic pain [1]. Our experimental studies on novel antiepileptic drugs demonstrated their efficacy in the experimental animal model of neuropathy (the formalin test) when administered pre-emptively before formalin [2, 3, 4, 5].

The available literature contains few randomized clinical trials evaluating the efficacy of pregabalin premedication. According to Paech and co-workers [6], a single dose of 100 mg of pregabalin used preoperatively did not affect markedly the severity of pain after minor gynaecological procedures. Agarwal and colleagues [7] have shown that a single dose of 150 mg of pregabalin given in premedication effectively reduced the severity of pain and fentanyl consumption in the postoperative period after laparoscopic cholecystectomy.

Hysterectomy is associated with a relatively high risk of chronic postoperative pain, developing in 4.7-31.9% of cases [8]. Additionally, such procedures are frequently performed and thus are a good model to study postoperative pain [9].

The aim of the study was to assess the efficacy of pregabalin premedication in relieving postoperative pain in patients undergoing gynaecological surgical procedures.  

METHODS

The prospective, randomized (computer-generated), double blind study was carried out.

The study included ASA I and II patients scheduled for abdominal hysterectomy who were assumed to require patient-controlled analgesia (PCA) over the period of 24 h to relieve postoperative pain of medium or severe intensity. All patients gave informed consent.

One hour before anaesthesia, patients were premedicated with oral pregabalin (Lyrica, Pfizer, GB): 75 mg – group A, 150 mg – group B and 300 mg – group C; group D (controls) received midazolam 7.5 mg as active placebo.

After wheeling into the operating room and installing the intravenous line, fentanyl 2 mg kg-1 was administered and preoxygenation used for 5 min. Anaesthesia was induced with propofol 2-3 mg kg-1 and rocuronium 0.6 mg kg-1 and maintained with sevoflurane or desflurane administered in the mixture of oxygen (50%) and air. The concentrations of anaesthetics were adjusted to maintain the bispectral index of 40-50. During maintenance of anaesthesia, patients received fentanyl 50-100 µg and rocuronium 0.15 mg kg-1 if needed. After the completion of surgery, neuromuscular block was routinely reversed.

Immediately after anaesthesia completion, patients received intravenously the initial loading dose of morphine in single injections, 2 mg each, over the period of 10 min to reduce the intensity of pain <3 according to the numeric rating scale (NRS). If failed, an additional dose of 5 mg was administered.

Pain management was continued using PCA with the pump containing 1 mg morphine in 1 mL of 0.9% NaCl (single dose 1 mg, maximum dose 12 mg h-1, lockout time 5 min) over 24 h.

If the patients experienced uncontrolled, extremely severe pain, “crisis management” was introduced neglecting the limitations of the PCA pump and administering additionally 2 maximum morphine doses, 5 mg each, over 24 h. If pain persisted, paracetamol 1-2 g was used.  

The severity of pain was assessed according to NRS (0-10), at rest and on exertion after the test of lower limb lifting. The morphine consumption in the initial saturating dose and during PCA over 24 h was recorded. The following parameters were monitored throughout the study period: SAP/DAP, HR and f at regular time intervals (at 2, 4, 8, 24 postoperative h). Ondansetron 4 mg was used once nausea and vomiting persisted. If unsatisfactory, metoclopramide was additionally administered.

RESULTS

The study involved 80 patients. In one of them the drug-related adverse side effects developed, another one was not included after administration of the initial dose of morphine as the severity of pain was not decreased <3 (NRS=9). Two patients were excluded due to allergy to morphine (urticaria after the loading dose). Another 2 women were disqualified due to extended surgery. Finally, 74 patients were included in the study.

Demographic parameters of patients in individual groups did not differ significantly. The demographic data and the number of patients in particular groups are compiled in Table 1.

The mean doses of fentanyl during surgery were comparable (Table 2).
The administration of first loading doses of morphine after surgery markedly reduced the pain (NRS<3) (Table 3).

The demand for PCA morphine over 24 h was significantly lower after pregabalin premedication in group C yet not in group A, B and D (Table 4).

The intensity of rest postoperative pain was significantly lower at hour 2, 4 and 24 in group C compared to group D (Table 5). However, no significant decrease in exertion pain intensity was observed at hour 2, 4, 8 and 24 after surgery (Table 6).

DISCUSSION

In recent years, numerous studies on the pathomechanism of acute and chronic pain in surgical patients have been conducted. Their findings demonstrate that surgical stimuli are likely to induce sensitization of CNS nociceptive neurons, including the posterior spinal horns, which enhances the postoperative pain sensations [10, 11, 12]. An additional important problem is that central sensitization during and after surgery may lead to persistent and chronic neuropathic pain [13], which is likely to develop in 10-50% of surgical patients (according to various estimates) and persist for over 3-6 months. This factor is relevant and in many cases associated with substantially deteriorated quality of life [14].

The meta-analysis involving 16 randomized clinical studies, 1151 patients in total, showed that the administration of gabapentin in premedication reduced the pain intensity, demands for opioids and incidences of side effects (vomiting, urticaria) in the postoperative period [15]. Similar conclusions were presented in other publications [16]. The available clinical studies neglected the effects of gabapentin on the incidence and intensity of neuropathic pain in the remote postoperative period. Moreover, the optimal dose of gabapentin was not determined.

Our study demonstrated that the model of analgesia used provided low-intensity postoperative pain in anaesthetized patients. Among the doses tested, i.e. 75, 150 and 300 mg, only the last one administered in oral premedication substantially reduced PCA morphine demands over 24 hours after surgery. Further studies, with the dose of 600 mg, are needed to assess thoroughly the effects of this agent on the intensity of postoperative pain.

CONCLUSION

Oral premedication with pregabalin 300 mg significantly reduces the intensity of postoperative rest pain and morphine consumption in the postoperative period.

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REFERENCES

1.     Wallace JM: Update on pharmacotherapy guidelines for treatment of neuropathic pain. Curr Pain Headache Rep 2007; 11: 208-214.

2.     Czuczwar M, Kiś J, Łuszczki J, Turski WA, Przesmycki K: Evaluation of interaction between gabapentin and baclofen in the formalin test in mice. Pol J Pharmacol 2003; 55: 803-806.

3.     Czuczwar M, Kiś J, Potasiński A, Turski WA, Przesmycki K: Isobolographic analysis of interaction between vigabatrin and baclofen in the formalin test in mice. Pol J Pharmacol 2001a; 53: 527-30.

4.     Czuczwar M, Kiś J, Świąder M, Turski WA, Przesmycki K: Evaluation of interaction between valproate and baclofen in the formalin test in mice. Pol J Pharmacol 2001b; 53: 51-54.

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6.     Paech MJ, Goy R, Chua S, Scott K, Christmas T, Doherty DA: A random, placebo-controlled trial of preoperative oral pregabalin for postoperative pain relief after minor gynecological surgery. Anesth Analg 2007; 105: 1449-1453.

7.     Agarwal A, Gautam S, Gupta D, Agarwal S, Singh P. K, Singh U: Evaluation of a single preoperative dose of pregabalin for attenuation of postoperative pain after laparoscopic cholecystectomy. Br J Anaesth 2008; 101: 700-704.

8.     Brandsborg B, Nikolajsen L, Kehlet H, Jensen TS: Chronic pain after hysterectomy. Acta Anaesthesiol Scand 2008; 52: 327-331.

9.     Farquhar CM, Steiner CA: Hysterectomy rate in the United States 1990-1997. Obstet Gynecol 2002; 99: 229-234.

10.     Woolf CJ, Salter MW: Neuronal plasticity: increasing the gain in pain. Science 2000; 288: 1765-1769.

11.     Woolf CJ, Max MB: Mechanism-based pain diagnosis: issues for analgesic drug development. Anesthesiology 2001; 95: 241-249.

12.     Scholz J, Woolf CJ: Can we conquer pain? Nat Neurosci 2002; 5: 1062-1067.

13.    Dahl JB, Møiniche S: Pre-emptive analgesia. Br Med Bull 2004 13; 71: 13-27.   

14.     Kehlet H, Jensen TS, Woolf CJ: Persistent postsurgical pain: risk factors and prevention. Lancet. 2006; 13/367: 1618-1625.  

15.     Ho KY, Gan TJ, Habib AS: Gabapentin and postoperative pain-a systematic review of randomized controlled trials. Pain 2006; 15: 91-101.

16.     Tiippana EM, Hamunen K, Kontinen VK, Kalso E: Do surgical patients benefit from perioperative gabapentine/pregabalin? A systemic review of efficacy and safety. Anesth Analg 2007; 104: 1545-1556. 

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address:

*Krzysztof Przesmycki
II Klinika Anestezjologii i Intensywnej Terapii
Uniwersytet Medyczny w Lublinie
Al. Racławickie 1, 20-059 Lublin
tel.: 81 528 84 00

received: 02.08.2010
accepted: 10.11.2010