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ANALGESIA

The Median Effective Dose of Preemptive Gabapentin on Postoperative Morphine Consumption After Posterior Lumbar Spinal Fusion

Alain C. Van Elstraete, MD^*, Myriam Tirault, MD^*, Thierry Lebrun, MD^*, Ignace Sandefo, MD^*, Jean-Christophe Bernard, MD^*, Bruno Polin, MD^*, Patrick Vally, MD, and Jean-Xavier Mazoit, MD, PhD

From the Departments of *Anesthesiology, Neurosurgery, Centre Médico-Chirurgical Saint Paul, Fort-de-France, Martinique, France; Univ Paris-Sud, Laboratoire d’Anesthésie, Faculté de Médecine, F-94276 Le Kremlin-Bicêtre, France; and AP-HP, Departement d’Anesthesie-Réanimation, Hôpital de Bicêtre, F-94275 Le Kremlin-Bicêtre, France.

Address correspondence to Dr. Van Elstraete, Department of Anesthesiology, Centre Médico-Chirurgical Saint Paul, Clairières, 97200 Fort-de-France, Martinique, France. Address e-mail to alainvanel{at}hotmail.com.

Abstract

BACKGROUND: A single dose of preemptive gabapentin reduces postoperative pain and postoperative analgesic consumption. However, the optimal dose of preemptive gabapentin remains to be evaluated.

METHODS: In this prospective study, we defined the median effective analgesic dose using an up-and-down sequential allocation technique of preemptive gabapentin in 67 patients undergoing elective posterior lumbar spinal fusion. The efficacy of the study drug was assessed by morphine consumption during the first 24 h postoperatively.

RESULTS: The median effective analgesic dose (median value and 95% confidence interval) of gabapentin was 21.7 mg/kg (19.9–23.5 mg/kg).

CONCLUSION: Given the large dose of gabapentin needed, further powered studies are warranted to assess side effects.

Central neuronal sensitization contributes to postoperative hypersensitivity to pain.1 As such, postoperative pain may be considered as a transient type of "neuropathic" pain and, consequently there is a rationale for the exploitation of antihyperalgesic drugs for postoperative analgesia.2

Gabapentin, a 3-alkylated analog of -aminobutyric acid, has been shown to be effective for the management of neuropathic pain,3 and may therefore have a role in the prevention of postoperative pain.

Several clinical studies have evaluated the use of a single dose of preemptive gabapentin, and have demonstrated convincing reductions in postoperative pain and in postoperative analgesic consumption.4–11 The doses of gabapentin given were chosen based on the limits of a single dose in the treatment of chronic neuropathic pain as the recommended dose is 300–1200 mg thrice daily.12 However, the absorption kinetics of gabapentin are dose-dependent, and the bioavailability of the drug decreases with increasing dose.13 The optimal dose of preemptive gabapentin therefore remains to be evaluated.

The objective of this prospective study was to define the median effective analgesic dose (ED₅₀, analgesic efficacy in 50% of patients) of preemptive gabapentin using an up-and-down sequential allocation technique in patients undergoing posterior lumbar spinal fusion.14

METHODS

Patient Selection
After IRB approval, 67 consenting ASA class I-II-III patients aged 18–60 yr, scheduled to undergo elective posterior lumbar spinal fusion performed by the same surgeon under general anesthesia were enrolled in the study. Patients were eligible for participation if they weighed more than 60 kg and less than 80 kg. Exclusion criteria included previous treatment with gabapentin, a chronic pain syndrome, substance abuse, daily intake or intake 48 h preoperatively of any analgesic, epilepsy, a psychiatric disorder, renal insufficiency, pregnancy, contraindications to gabapentin, and inability to use a patient-controlled analgesia (PCA) device.

Anesthetic Protocol
The evening before surgery, patients were instructed on the use of a numeric pain scale (0 = no pain to 10 = the worst imaginable pain), and in the use of a PCA device. All patients received general anesthesia with propofol, sufentanil, atracurium, and sevoflurane. Neither local nor regional anesthesia was performed. No sedative premedication other than gabapentin was administered.

Analgesic Protocol
On the day of surgery, patients received oral gabapentin 2.5 h before induction of anesthesia. The dose of gabapentin was prepared by a physician not involved in data collection. The ED₅₀ was established using an up-and-down sequential allocation technique, the dose of preemptive oral gabapentin received by a particular patient being determined by the response of the previous patient.14 The first patient received 4 mg/kg of gabapentin based on estimates from a previous study.6 The dose adjustment interval was 1 mg/kg. Personnel involved in patient management and data collection were blinded to the dose used.

After arrival in the postanesthesia care unit (PACU), pain intensity was assessed using a numeric pain scale, and morphine titration was started according to the usual rules of our PACU until patients were alert enough to use a PCA pump, which was set to deliver bolus doses of morphine 1 mg/mL with an incremental dose of 1.5 mg, a lockout interval of 7 min, a 4-h limit of 40 mg, and no background infusion. No analgesic drug other than morphine was administered. The end point was assessment of total morphine consumption during the first 24 h postoperatively.

A previous open study at our institution (unpublished results), which included 30 patients scheduled to undergo the same surgical procedure performed by the same surgeon, as in this study, showed that exclusive morphine consumption for the first 24 h postoperatively was 62.5 ± 16.5 mg (mean ± sd). The morphine-sparing value was defined as a 30% reduction in morphine consumption, i.e., 44-mg/24 h. The cumulative morphine consumption included IV morphine administered by the nurse in the PACU.

Two outcomes were considered:

• Effective: decrease in morphine consumption of at least 30% (a result defined as effective, directed a decrement of 1 mg/kg of gabapentin for the next patient).
  
• Ineffective: decrease in morphine consumption <30% (a result defined as ineffective, directed an increment of 1 mg/kg of gabapentin for the next patient).
  

Morphine consumption and adverse effects were recorded at 1, 2, 4, 8, 12, and 24 h after the end of anesthesia. Adverse effects included drowsiness, dizziness, fatigue, nystagmus, headache, blurred vision, postoperative nausea and vomiting.

Statistical Analysis
The ED₅₀ leading to a 30% reduction of morphine consumption for the first 24 h postoperatively, and the 95% confidence interval (95% CI) of ED₅₀ were calculated using Dixon’s up-and-down sequential allocation technique.14 The up-and-down method estimates the threshold for an all-or-none response, usually defined as a point above which 50% of the subjects respond to the stimulus and below which 50% of the subjects do not respond. Briefly, a first dose is given to the first patient, and the next doses are given according to the following rule: if the subject responds positively, the dose is decreased one step for the next subject and, conversely, if the subject does not respond, the dose is increased one step. Dixon’s up-and-down method calculates the mean ± se of the ED₅₀. It is therefore based on the assumption of normality, which precludes asymmetry around the median value to avoid bias. Also, it is necessary to reject sequences with three to six identical results. If these two conditions hold (leading to frequent pairs with opposite results), the minimum number of patients suggested by Dixon is six.14 In practice, at least 12 patients are required and most experiments studied at least 18 subjects. In the present case, sampling was begun including the third pair of opposite results. Data are expressed as the mean ± sd.

RESULTS

ED₅₀ (95%CI) of gabapentin was 21.7 mg/kg (19.9–23.5 mg/kg) (Fig. 1). Five patients were excluded from the study because of incomplete data sheets (two patients), administration of medication not prescribed in the study protocol (two patients), and inadequate skill to operate a PCA device (one patient). All these exclusions were performed before the inclusion of the next patient.

View larger version (9K): [in this window] [in a new window]   Figure 1. Sequence of dosing in the 62 patients. The premedication was considered as effective if the patient’s total morphine consumption during the 24 h postoperatively was <44 mg (i.e., a 30% reduction when compared to a control group). Open squares represent failures and closed circles successes. The horizontal lines are the median ED50 (thick line) and its 95% confidence interval (dashed lines).

Demographic and surgical data are shown in Table 1.

Adverse effects included drowsiness [n = 4 (6%)], dizziness [n = 4 (6%)], headache [n = 1 (1.5%)], blurred vision [n = 2 (3%)], and postoperative nausea and vomiting [n = 3 (4.5%)]. No adverse effect required intervention.

DISCUSSION

Our study is the first to define the median effective analgesic ED₅₀ of preemptive oral gabapentin in postoperative patients. We used the Dixon up-and-down technique that allows determination of ED₅₀ with fewer patients than conventional techniques.14 This is the reason why this technique is used to calculate the minimum effective dose of analgesics in postoperative patients.15

Interestingly, in the study of Pandey et al.,6 an average single dose of 5 mg/kg of preemptive gabapentin in patients undergoing single-level lumbar discectomy induced a 35% decrease in fentanyl consumption during the 24 h postoperatively. The discrepancy with our results might be explained by a different level of postoperative pain induced by the surgical procedures. Indeed, Bjune et al.16 have shown that the pain-relieving effect of analgesics becomes evident only in patients experiencing severe, but not mild or moderate, pain. Postoperative pain in our model, i.e., spinal fusion surgery, is much more severe than that after single level discectomy. This prompted us to hypothesize that our model was likely to be more reliable for the study. Similarly, Turan et al.7 found a 38% decrease in morphine consumption during the first 24 h after spinal surgery in patients who were given preemptive oral gabapentin 1200 mg. The mean body weight of these patients was close to 75 kg, and the dose of gabapentin was therefore close to 16 mg/kg. However, only 20% of patients included in their study underwent spinal fusion, whereas 80% underwent single discectomy. Again, the discrepancy with our results might be due to the different surgical procedures performed in our studies.

The large dose of preemptive gabapentin needed for spinal fusion surgery, when compared with that needed for other painful surgeries, might be explained by a long-term peripheral nerve root compression leading to a severe central sensitization. Surprisingly, given the large dose of gabapentin and morphine used in the study, the occurrence of side effects was low. However, because of the small number of patients studied, any definite conclusion cannot be drawn. Powered studies would be valuable in this field to assess the occurrence of side effects. Preemptive gabapentin was given 2.5 h before surgery because the maximal plasma level in humans is not reached before 2–3 h after oral administration.17 Since many lumbar spine surgery patients are obese, a major concern of this study is the potential applicability of the results in these patients. However, tissue distribution of gabapentin is not identical among all tissues, and the level in adipose tissue has been shown to be the lowest.18 On the other hand, the absorption kinetics of gabapentin are dose-dependent, possibly due to a saturable transport system, and the bioavailability of the drug decreases with increasing dose.13 Increasing the dose of preemptive gabapentin in these obese patients should be therefore performed with caution.

In conclusion, it should be emphasized that ED₅₀ obtained in our study is of value only in the specific clinical circumstances in which it was determined (i.e., patients after painful surgery). Extrapolation of these data to other clinical situations should be made with caution. The effective dose in a larger proportion of patients such as the median effective dose in 95% of the patients needs to be estimated, and further powered studies are warranted to assess the occurrence of adverse effects.

Footnotes

Accepted for publication September 11, 2007.

Reprints will not be available from the author.

REFERENCES

1. 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]
2. Dahl JB, Mathiesen O, Moiniche S. "Protective premedication": an option with gabapentin and related drugs? A review of gabapentin and pregabalin in the treatment of post-operative pain. Acta Anaesthesiol Scand 2004;48:1130–6[Web of Science][Medline]
3. Tremont-Lukas IWW, Megeff G, Backunja MM. Anticonvulsants for neuropathic pain syndromes: mechanisms of action and place in therapy. Drugs 2000;60:1029–52[Web of Science][Medline]
4. Dirks J, Fredensborg BB, Christensen D, Fomsgaard JS, Flyger H, Dahl JB. 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]
5. Pandey CK, Priye S, Singh S, Singh U, Singh RB, Singh PK. Preemptive use of gabapentin significantly decreases postoperative pain and rescue analgesic requirements in laparoscopic cholecystectomy. Can J Anaesth 2004;51:358–63[Web of Science][Medline]
6. Pandey CK, Sahay S, Gupta D, Ambesh SP, Singh RB, Raza M, Singh U, Singh PK. Preemptive gabapentin decreases postoperative pain after lumbar discoidectomy. Can J Anaesth 2004;51:986–9[Web of Science][Medline]
7. Turan A, Karamanlioglu B, Memeis D, Hamancioglu MK, Tukenmez B, Pamukçu Z, Kurt I. Analgesic effects of gabapentin after spinal surgery. Anesthesiology 2004;100:935–8[Web of Science][Medline]
8. Turan A, Karamanlioglu B, Memeis D, Usar P, Pamukçu Z, Túre M. The analgesic effects of gabapentin after total abdominal hysterectomy. Anesth Analg 2004;98:1370–3[Abstract/Free Full Text]
9. Turan A, Memeis D, Karamanlioglu B, Yagiz R, Pamukçu Z, Yavuz E. The analgesic effects of gabapentin in monitored anesthesia care for ear-nose-throat surgery. Anesth Analg 2004;99:375–8[Abstract/Free Full Text]
10. Rorarius MGF, Mennender S, Suominen P, Rintala S, Puura A, Pirhonen R, Salmelin R, Haanpââ M, Kujansuu E, Yli-Hankala A. Gabapentin for the prevention of postoperative pain after vaginal hysterectomy. Pain 2004;110:175–181[Web of Science][Medline]
11. Menigaux C, Adam F, Guignard B, Sessler DI, Chauvin M. Preoperative gabapentin decreases anxiety and improves early functional recovery from knee surgery. Anesth Analg 2005; 100:1394–9[Abstract/Free Full Text]
12. Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M, LaMoreaux L, Garofalo E. 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]
13. Goa KL, Sorbin EM. Gabapentin. A review of its pharmacological properties and clinical potential in epilepsy. Drug 1993; 46:409–27[Web of Science][Medline]
14. Dixon WJ. Staircase bioassay: the up-and-down method. Neurosci Biobehav Rev 1991;15:47–50[Web of Science][Medline]
15. Delage N, Maaliki H, Beloeil H, Benhamou D, Mazoit JX. Median effective dose (ED₅₀) of nefopam and ketoprofen in postoperative patients. A study of interaction using sequential analysis and isobolographic analysis. Anesthesiology 2005; 102:1211–6[Web of Science][Medline]
16. Bjune K, Stubhaug A, Dodgson MS, Breivik H. Additive analgesic effect of codeine and paracetamol can be detected in strong, but not moderate, pain after Caesarean section. Baseline pain-intensity in a postoperative analgesic trial. Acta Anaesthesiol Scand 1996;40:399–407[Web of Science][Medline]
17. Beydoun A, Uthman BM, Sackellares JC. Gabapentin: pharmacokinetics, efficacy, and safety. Clin Neuropharmacol 1995; 18:469–81[Web of Science][Medline]
18. Vollmer KO, von Hodenberg A, Kölle EU. Pharmakokinetics and metabolism of gabapentin in rat, dog and man. Drug Res 1986;36:830–9[Medline]

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