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Anesth Analg 2004;98:1370-1373
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000108964.70485.B2

PAIN MEDICINE

The Analgesic Effects of Gabapentin After Total Abdominal Hysterectomy

Alparslan Turan, MD*, Beyhan Karamanlioglu, MD*, Dilek Memis, MD*, Pinar Usar, MD*, Zafer Pamukçu, MD*, and Mevlüt Türe, MD PhD{dagger}

*Department of Anaesthesiology, and the {dagger}Department of Biostatistics, Trakya University Medical Faculty, Edirne, Turkey

Address correspondence to Alparslan Turan, MD, Trakya University Medical Faculty, Department of Anesthesiology and Reanimation, 22030 Edirne, Turkey. Address email to alparslanturan{at}yahoo.com


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We investigated, in a randomized, placebo-controlled, double-blind study, the efficacy and safety of gabapentin on pain after abdominal hysterectomy and on tramadol consumption in patients. The 50 patients were randomized to receive either oral placebo or gabapentin 1200 mg 1 h before surgery. Anesthesia was induced with propofol and maintained with sevoflurane in 50% N2O/O2 with a fresh gas flow of 2 L/min (50% N2O in O2) and fentanyl (2 µg/kg). All patients received patient-controlled analgesia with tramadol with a 50 mg initial loading dose, 20 mg incremental dose, 10-min lockout interval, and 4-h limit of 300 mg. The incremental dose was increased to 30 mg if analgesia was inadequate after 1 h. Patients were studied at 4, 8, 12, 16, 20, and 24 h for visual analog (VAS) pain scores, heart rate, peripheral oxygen saturation, mean arterial blood pressure, respiratory rate, sedation, and tramadol consumption. The VAS scores in the sitting and supine position at 1, 4, 8, 12, 16, and 20 h were significantly lower in the gabapentin group when compared with the placebo group up to 20 h after surgery. The tramadol consumption at 12, 16, 20, and 24 h and total tramadol consumption were significantly less in the gabapentin group when compared with placebo group. Sedation scores were similar at all the measured times. There were no differences between groups in adverse effects. Preoperative oral gabapentin decreased pain scores and postoperative tramadol consumption in patients after abdominal hysterectomy.

IMPLICATIONS: This randomized, controlled trial examined the effects of preoperative oral gabapentin 1200 mg on postoperative pain and tramadol consumptions. We conclude that preoperative oral gabapentin is effective in reducing postoperative pain scores and tramadol consumption in patients after abdominal hysterectomy.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Postoperative pain affects recovery from surgery and anesthesia. The use of opioids by patient-controlled analgesia (PCA) is popular but limited by side effects and by the fact that certain types of pain respond poorly to opioids (1). Because of the multiplicity of mechanisms involved in postoperative pain, a multimodal analgesia regimen, with a combination of opioid and non-opioid analgesic drugs is often used to enhance analgesic efficacy and reduce opioid requirements and side effects (2).

Gabapentin, a structural analog of {gamma}-aminobutyric acid, is used as an anticonvulsant drug. In addition, it has been effective in neuropathic pain (3), diabetic neuropathy (4), postherpetic neuralgia (5), and reflex sympathetic dystrophy (6). Pretreatment with gabapentin can block the development of hyperalgesia (7). Studies have demonstrated that mechanical hyperalgesia surrounding the wound in postoperative patients and experimentally, heat-induced, secondary hyperalgesia share a common mechanism and that central neuronal sensitization contributes to postoperative pain (8). Gabapentin has a selective effect on the nociceptive process involving central sensitization (7).

Gabapentin and morphine have synergistic analgesic effects in animals and in humans (9–11). In a recent study, a single dose of oral gabapentin reduced postoperative morphine consumption and movement-related pain after radical mastectomy (12).

The aim of the present study was to determine the effect of gabapentin on postoperative pain and on PCA tramadol consumption in patients after abdominal hysterectomy.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After obtaining the approval of the Institutional Ethics Committee (Trakya University, Edirne, Turkey) and written informed consent from the patients, 50 patients, ASA physical status I–II, undergoing elective total abdominal hysterectomy with salpingo-oophorectomy were studied. Patients were eligible for participation if they were at least 18 yr old, weighed more than 40 kg, and could operate a PCA device. Exclusion criteria were known allergy to opioids, asthma, contraindications to tramadol or any drug used, renal insufficiency, a history of a peptic ulcer or a history of a bleeding diathesis.

The patients were randomly divided into 2 groups with 25 patients in each. The study design was randomized and double-blind. Patients were randomly allocated according to computer-generated randomization. For premedication, midazolam 0.07 mg/kg and atropine 0.01 mg/kg were administered IM 45 min before the surgical procedure. Patients in the control group received oral placebo capsules, and those in the gabapentin group received 1200 mg gabapentin (Neurontin 400-mg capsule; Pfizer, Goedecke GmbH, Germany) 1 h before surgery. The study drugs were prepared by the pharmacy and an appropriate code number was assigned.

In the operating room, a crystalloid infusion was started through an IV cannula inserted in an antecubital vein, and the mean arterial blood pressure (MAP), heart rate (HR), and peripheral oxygen saturation (SpO2) were monitored (Cato PM 8040; Dräger, Lübeck, Germany). Anesthesia was induced with propofol (2 mg/kg) and atracurium (0.5 mg/kg) and maintained with sevoflurane with a fresh gas flow of 2 L/min (50% N2O in O2) and fentanyl (2 µg/kg). Surgery was performed via a Pfannenstiel incision. The lungs of the patients were mechanically ventilated (Cato; Dräger) and ventilation was adjusted to maintain end-expiratory CO2 between 34–36 mm Hg. At the end of surgery, neuromuscular block was antagonized with neostigmine 1.5 mg and atropine 0.5 mg.

After tracheal extubation, patients were transferred to the postanesthesia care unit (PACU). Assessment of postoperative pain was made on the basis of the visual analog score (VAS), where 0 cm = "no pain" and 10 cm = "worst pain imaginable." Postoperative analgesia was provided with IV-PCA tramadol. The PCA technique and the VAS were explained to the patients during the preoperative visit. Patients were connected to the PCA device (Pain Management Provider; Abbott, North Chicago, IL) on arrival in the PACU. All patients received tramadol PCA (3 mg/mL) with an initial 50 mg loading dose, 20 mg incremental dose, 10-min lockout interval, and 4-h limit of 300 mg. The incremental dose was increased to 30 mg if analgesia was inadequate after 1 h. Sedation was assessed by the Ramsay sedation scale. During the first 1 h in the PACU, then at 4, 8, 12, 16, 20, and 24 h, patients were evaluated for pain scores, HR, SpO2, MAP, respiratory rate, sedation, tramadol use, and total dose of tramadol by an anesthesiology resident not otherwise involved in the study. The occurrence of any side effects, such as nausea and vomiting, constipation, respiratory depression, dizziness, somnolence, peripheral edema, diarrhea, headache, and pruritus was recorded. Assessment of postoperative pain was made both when lying down and on movement by putting the patient in a sitting position. Tramadol was stopped if the patient had a respiratory rate <12 breaths/min, an oxygen saturation measured by pulse oximetry <95%, or a serious adverse event related to opioid administration. On patient request or if nausea and vomiting occurred, ondansetron 4 mg IV was given. All measurements were recorded by the same anesthesia resident that was blinded as to the study drugs administered.

A sample size of 25 patients by group was calculated to detect a significant difference of 15% or more in tramadol consumption with a power of 85% and a significance level of 5%. Descriptive statistics are expressed as mean ± SD unless otherwise stated. All variables were tested for normal distribution by Kolmogorov-Smirnov test. Student’s t-test was used for comparison of the means of continuous variables and normally distributed data. The Mann-Whitney U-test was used otherwise. Two-way analysis of variance or Friedman test was used for variable differences in groups, and Bonferroni or Tukey HSD test was used for multiple comparisons. Categorical data were analyzed using {chi}2 test analysis or Fisher’s exact test, as appropriate. Significance was determined at P < 0.05.


   Results
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 Abstract
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 Methods
 Results
Discussion
 References
 
From September 1, 2002 to June 1, 2003, 50 consecutive patients who fulfilled the inclusion criterions were included in the study. All the patients allocated were able to complete the study; data from 50 patients were therefore analyzed.

The groups were comparable with respect to age, body weight, height, ASA physical status, and duration of surgery (Table 1). MAP, HR, SpO2, and respiratory rate were not different between the groups at all the measured times (Table 2).


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  		Table 1. Demographic Characteristics, Perioperative, and Postoperative Data
 

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  		Table 2. Postoperative Heart Rate, Mean Arterial Blood Pressure, and Respiratory Rate
 
The VAS scores in both the sitting and supine positions were significantly lower in the gabapentin group compared with the placebo group (Table 3). Sedation scores were similar at all the measured times in the gabapentin and placebo groups.


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  		Table 3. Postoperative Pain Scores in Gabapentin and Placebo Groups
 
Tramadol consumption at 12, 16, 20, and 24 h and total tramadol consumption were significantly less in the gabapentin group compared with the placebo group (Table 4).


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  		Table 4. Tramadol Consumption in the Gabapentin and Placebo Groups
 
The most common side effects during the study were nausea and vomiting (Table 5), but there was no difference in the incidence of side effects between the groups. Number of patients and doses in patients receiving antiemetics during the first 24 h after surgery were similar between groups (Table 6).


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  		Table 5. Incidence of Side Effects
 

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  		Table 6. Number of Patients Receiving Antiemetics and Doses in Patients Receiving Antiemetics During the First 24 Hours After Surgery
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The results of our preoperative oral single-dose study investigating the acute postoperative analgesic effects of gabapentin in patients after total abdominal hysterectomy show that gabapentin decreased postoperative pain scores at rest and on movement, that gabapentin decreased postoperative tramadol consumption, and that gabapentin was not associated with more side effects when compared with placebo.

The main aim in combining different analgesic drugs is to obtain synergistic or additive analgesia, allowing a smaller dose of each drug with an improved safety profile. This can be achieved by combining analgesics acting at different locations (e.g., centrally and peripherally acting analgesics). Tramadol is widely used in PCA for moderate-to-severe postoperative pain. Its efficacy is a result of two complementary mechanisms of action: stimulation of µ opioid receptors and inhibition of norepinephrine and 5-hydroxytryptamine reuptake in pain pathways (13).

In animal models of nociception, gabapentin reduces hypersensitivity associated with nerve injury, inflammation, and pain after surgery (14–16). Mechanical hyperalgesia surrounding the wound in postoperative patients, and experimental, heat-induced secondary hyperalgesia share a common mechanism—central neuronal sensitization—that may contribute to some aspects of postoperative pain. Antihyperalgesic drugs such as gabapentin may have a role in postoperative pain, and the combination with other antinociceptive drugs may produce synergistic analgesia effects (8). Gabapentin enhanced the analgesic effect of morphine in healthy volunteers (10) and the combination produced better analgesia in comparison with morphine alone in patients suffering neuropathic cancer pain (11).

Gabapentin significantly decreased morphine consumption and pain in patients after mastectomy (12), although the patients were evaluated for only 4 h after surgery. In our study we found a reduction in pain scores at rest or after movement throughout the 24 h period, although tramadol consumption was only reduced after first 12 h. Fassoulaki et al. (17), in contrast, were unable to demonstrate a decrease in analgesic consumption and VAS scores at rest and after movement during the first 24 h postoperatively. Differences between results can be attributed to difference in types of surgery and in use of different types of analgesics.

Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used analgesics for minor surgery and are useful adjunctive analgesics in patients undergoing major surgery, decreasing pain and opioid requirements. They are well established, effective, and inexpensive. However, their use in some groups of patients may be limited by adverse renal, gastrointestinal, and hemostatic effects. Gabapentin is less well established and likely to be quite expensive. For it to have a useful place, it may ultimately need to be shown that it provides better opioid-sparing and/or improved pain relief compared with the NSAIDs and is associated with fewer adverse events.

Gabapentin is well tolerated. It has few side effects and minor interactions with other drugs when used for the treatment of chronic pain (7,18). We did not observe any significant side effects associated with a single oral dose of gabapentin.

In conclusion, a single oral dose of gabapentin given preoperatively enhanced the analgesic effect of tramadol, decreasing tramadol consumption. Further studies, however, are required in different pain models to investigate the efficacy of this drug alone or in combination with other analgesics.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Dickenson A. Neurophysiology of opioid poorly responsive pain. Cancer Surv 1994; 21: 5–16.[Web of Science][Medline]
  2. Fishman S, Borsook D. Opioids in pain management. In: Benzon H, Raja S, Molloy RE, Strichartz G, eds. Essentials of pain medicine and regional anesthesia. New York: Churchill Livingstone, 1999: 51–4.
  3. Rosner H, Rubin L, Kestenbaum A. Gabapentin adjunctive therapy in neuropathic pain states. Clin J Pain 1996; 12: 56–8.[Web of Science][Medline]
  4. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998; 280: 1831–6.[Abstract/Free Full Text]
  5. Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998; 280: 1837–42.[Abstract/Free Full Text]
  6. Mellick GA, Mellick LB. Reflex sympathetic dystrophy treated with gabapentin. Arch Phys Med Rehabil 1997; 78: 98–105.[Web of Science][Medline]
  7. Mao J, Chen LL. Gabapentin in pain management. Anesth Analg 2000; 91: 680–7.[Free Full Text]
  8. Dirks J, Moiniche S, Hilsted KL, Dahl JB. Mechanisms of postoperative pain: clinical indications for a contribution of central neuronal sensitization. Anesthesiology 2002; 97: 1591–6.[Web of Science][Medline]
  9. Shimoyama M, Shimoyama N, Inturrisi CE, Elliott KJ. Gabapentin enhances the antinociceptive effects of spinal morphine in the rat tail-flick test. Pain 1997; 72: 375–82.[Web of Science][Medline]
  10. Eckhardt K, Ammon S, Hofman U, et al. Gabapentin enhances the analgesic effect of morphine in healthy volunteers. Anesth Analg 2000; 91: 185–91.[Abstract/Free Full Text]
  11. Caraceni A, Zecca E, Martini C, De Conno F. Gabapentin as an adjuvant to opioid analgesia for neuropathic cancer pain. J Pain Symptom Manage 1999; 17: 441–5.[Web of Science][Medline]
  12. Dirks J, Fredensborg BB, Christensen D, et al. A randomized study of the effects of single dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy. Anesthesiology 2002; 97: 560–4.[Web of Science][Medline]
  13. Schnitzer T. The new analgesic combination tramadol/acetaminophen. Eur J Anaesth 2003; 20 (Suppl 28): 13–8.
  14. Cheong JK, Pan HL, Eisenach JC. Antiallodynic effect of intrathecal gabapentin and its interaction with clonidine in a rat model of postoperative pain. Anesthesiology 2000; 92: 1126–31.[Web of Science][Medline]
  15. Field MJ, Holloman EF, McCleary S, et al. Evaluation of gabapentin and S-(+)-3-isobutylgaba in a rat model of postoperative pain. J Pharmacol Exp Ther 1997; 282: 1242–6.[Abstract/Free Full Text]
  16. Dirks J, Petersen KL, Rowbotham MC, Dahl JB. Gabapentin suppresses cutaneous hyperalgesia following heat/capsaicin sensitization. Anesthesiology 2002; 97: 102–6.[Web of Science][Medline]
  17. Fassoulaki A, Patris K, Sarantopoulos C, Hogan Q. The analgesic effect of gabapentin and mexiletine after breast surgery for cancer. Anesth Analg 2002; 95: 985–91.[Abstract/Free Full Text]
  18. McLean MJ, Morrell MJ, Willmore LJ, et al. Safety and tolerability of gabapentin as adjunctive therapy in a large, multicenter study. Epilepsia 1999; 40: 965–72.[Web of Science][Medline]
Accepted for publication November 6, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press