October 12, 2002

A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy

Dirks J, Fredensborg BB, Christensen D, Fomsgaard JS, Flyger H, Dahl JB Anesthesiology 2002; 97:560-564.

Gilron I. Anesthesiology. 2002; 97:537-539.

Commentary by Richard Rosenquist, M.D.

The manuscript entitled "A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy" and the accompanying editorial entitled "Is gabapentin a 'broad-spectrum' analgesic?" provide an interesting snapshot of the application of gabapentin in an acute postoperative pain setting. Gabapentin has demonstrated its utility in the treatment of chronic neuropathic pain. However, its use in the acute postoperative pain setting has not been explored. It has been suggested that central neuronal sensitization may amplify postoperative pain, but the relative contribution of various pain mechanisms to postoperative pain has not yet been clearly established. The authors of this manuscript hypothesize that gabapentin's potent anti-hyperalgesic effects may reduce postoperative pain. In particular, the objective of this study was to investigate the effect of a single dose of 1,200 mg oral gabapentin on morphine consumption and overall pain in the immediate postoperative period after unilateral radical mastectomy and axillary dissection.

Study patients included women aged 18-75 years scheduled for unilateral radical mastectomy with axillary dissection. All patients received 0.125 mg sublingual triazolam and 1,200 mg of oral gabapentin or placebo one hour before surgery. General anesthesia was accomplished with propofol and remifentanil. At the end of the surgical procedure, 0.5 mg of alfentanil was administered intravenously to all patients. Postoperative pain treatment consisted of patient-controlled intravenous morphine, 2.5 mg bolus, with a 10-minute lock-out time. Additional morphine 2.5 mg IV was administered by a nurse observer if requested by the patient during the lock-out period.

The primary outcome measure was total morphine consumption from hours 0 to 4 postoperatively. Secondary outcome measures included pain at rest and during mobilization from the supine to the sitting position, and side effects including nausea, somnolence, lightheadedness, dizziness, headache, visual disturbances and vomiting.

A total of 70 patients were included in the study; however, five were subsequently excluded. Four of these were in the gabapentin group and one in the placebo group. There were no significant differences observed between the two groups.

Total morphine consumption was reduced from 29 (21-33) mg to 15 (10-19) mg in the gabapentin group (p>0.0001). Pain at rest was reduced from 33 mm (23-44) to 19 mm (10-43) in the gabapentin group at two hours postoperatively and from 12 (9-30) to 7 (1-18) mm at four hours postoperatively. These reductions were not statistically significant. Pain during movement was reduced from 41 (31-59) mm to 22 (10-38) mm in the gabapentin group at two hours postoperatively and from 31 (12-40) mm to 9 (3-34) mm at four hours postoperatively, a statistically significant reaction. The most common side effect was somnolence, which was typically described as mild to moderate. Lightheadedness and dizziness were also common and were also described as mild to moderate. Other adverse effects were rare.

A single dose of 1,200 mg of oral gabapentin administered preoperatively resulted in a 50% reduction in postoperative morphine consumption and a significant reduction in movement-related pain two hours and four hours after radical mastectomy. Pain at rest was also reduced, but this reduction was not statistically significant. There were no significant differences in side effects between gabapentin and placebo in this study. This is the first clinical study to demonstrate an analgesic or anti-hyperalgesic effect of gabapentin on somatic postoperative pain. These results should be validated in other surgical procedures with multiple dosing and prolonged follow-up.

Editorial comments
This manuscript was accompanied by an editorial entitled "Is gabapentin a 'broad spectrum' analgesic?" The editorial reiterated that injury-induced neuroplasticity following surgical tissue injury can result in spinal sensitization, i.e., metabolic activation and hyperexcitability of spinal nociceptive neurons, expansion of sensory receptive fields and alterations in the processing of innocuous stimuli. These neuroplastic changes underlie the development of "pathologic" pain, characterized by hyperalgesia and allodynia. The editorial focused on the fact that gabapentin selectively reduces pain transmission in a "sensitized" nervous system, but not in a normal nervous system. It highlighted the possibility that gabapentin selectively reduces movement-evoked pain over spontaneous pain and that the ability to reduce movement-evoked pain is of particular clinical interest in that movement-evoked pain has been linked to postoperative physiologic impairment. This is especially appealing in the face of the fact that numerous postoperative studies have demonstrated that opioids are extremely limited in their ability to provide control of movement-evoked pain. The editorial closes by suggesting that the favorable therapeutic profile outlined in the Dirks study of gabapentin may make it a welcome addition to the anesthesiologist's pharmacopoeia of "coanalgesics" such as nonsteroidal antiinflammatory drugs and local anesthetics.

Postoperative pain has previously been divided into pain at rest and movement related pain, although little has been written about the relative contributions of either to the entire postoperative pain experience. The ability to control spinal sensitization or the expansion of receptive fields that result in neuropathic pain-type complaints following surgical procedures may improve postoperative pain control and reduce the need for opiate pain medications. Further studies to clarify the role of this individual medication as well as this class of medications will be required in order to determine its role in the perioperative period. In addition, specific surgical procedures for which this is most effective will also have to be determined. This concept will provide further fertile ground for future research projects that may markedly improve our ability to control postoperative pain while minimizing unwanted side effects.

ABSTRACT

TITLE:
A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy

AUTHORS:
Dirks J, Fredensborg BB, Christensen D, Fomsgaard JS, Flyger H, Dahl JB

SOURCE:
Anesthesiology. 2002; 97:560-564.

ABSTRACT:
BACKGROUND: The anticonvulsant gabapentin has proven effective for neuropathic pain in three large placebo-controlled clinical trials. Experimental and clinical studies have demonstrated antihyperalgesic effects in models involving central neuronal sensitization. It has been suggested that central neuronal sensitization may play an important role in postoperative pain. The aim of the study was to investigate the effect of gabapentin on morphine consumption and postoperative pain in patients undergoing radical mastectomy.
METHODS: In a randomized, double-blind, placebo-controlled study, 70 patients received a single dose of oral gabapentin (1,200 mg) or placebo 1 h before surgery. Patients received patient-controlled analgesia with morphine at doses of 2.5 mg with a lock-out time of 10 min for 4 h postoperatively. Pain was assessed on a visual analog scale at rest and during movement, and side effects were assessed on a four-point verbal scale 2 and 4 h postoperatively.
RESULTS: Thirty-one patients in the gabapentin group and 34 patients in the placebo group completed the study. Gabapentin reduced total morphine consumption from a median of 29 (interquartile range, 21-33) to 15 (10-19) mg (P< 0.0001). Pain during movement was reduced from 41 (31-59) to 22 (10-38) mm at 2 h postoperatively (P < 0.0001) and from 31 (12-40) to 9 (3-34) mm at 4 h postoperatively (P = 0.018). No significant differences between groups were observed with regard to pain at rest or side effects.
CONCLUSION: A single dose of 1,200 mg oral gabapentin resulted in a substantial reduction in postoperative morphine consumption and movement-related pain after radical mastectomy, without significant side effects. These promising results should be validated in other acute pain models involving central neuronal sensitization.