Jkms.org

Copyright � The Korean Academy Hemodynamic Effects of Gabapentin in Rats Gabapentin has been known to elicit the antinociceptive effect. However, little has been known about the effect of gabapentin on the cardiovascular system. The author’s Department of Anesthesiology and Pain Medicine aim of this experiment was to examine the hemodynamic effects of gabapentin. Male Chonnam National University, Medical School, Sprague-Dawley rats were used. Intrathecal or intracerebroventricular catheters were implanted and gabapentin was delivered through each catheter or directly into theperitoneal cavity. For hemodynamic measurements, catheters were inserted into the tail artery. Blood pressure and heart rate were measured over 60 min following administration of gabapentin. Intrathecal and intraperitoneal gabapentin did not inducesignificant changes of hemodynamics over the 60 min compared to the baseline value. Intracerebroventricular gabapentin increased systolic and diastolic blood pres- sure, but there is no statistically difference in blood pressure change according to Department of Anesthesiology and Pain Medicine, Chonnam National University, Medical School, 8 Hakdong, Donggu, Gwangju 501-757, Korea Key Words : Gabapentin; Hemodynamics; Injections, Spinal; Injections, Intraventricular; Injections, Tel : +82.62-220-6893, Fax : +82.62-232-6294.
INTRODUCTION
MATERIALS AND METHODS
Gabapentin, a structural analogue to gamma-aminobu- All experiments were reviewed and approved by the Insti- tyric acid (GABA), is orginally developed as an anticonvul- tutional Animal Care Committee, Research Institute of Med- sant (1). It has been shown to reverse allodynia and hyperal- ical Science, Chonnam National University. gesia of many pain models in animal studies. Intrathecal Male Sprague-Dawley rats weighing 300-325 g were used.
gabapentin attenuates tactile-evoked allodynia in the Chung Rats were housed in groups of 4-6 with free access to food model of neuropathy (2) and thermal hyperalgesia in a rat model of painful peripheral neuropathy (3). Partridge et al.
For IT administration of the drug, rats were implanted demonstrates its efficacy on substance-P induced thermal with polyethylene (PE)-10 catheter (10). Briefly, under enflu- hyperalgesia (4). In studies on facilitated pain in rats follow- rane (3-4%)/O2 anesthesia, the head of rats was placed in a ing the formalin test, gabapentin suppress the pain behavior stereotactic head holder. A skin incision was made along the observed during the second phase (5, 6). Furthermore, its dorsum of the skull, and dura mater was exposed by blunt effectiveness for the treatment of neuropathic pain such as dissection. The dura was incised, and a polyethylene (PE-10) postherpetic neuralgia (7) and complex regional pain syn- catheter was advanced caudally to end at lumbar enlargement.
drome (8) has been reported in human studies.
The external catheter was tunneled under the skin and exit- Although some adverse effects have been noted, they were usually slight and disappeared within 2 weeks without inter- The ICV route for drug injection was constructed through ruption of the treatment, and the most serious adverse effect skull (11). Placing the rat in a stereotactic holder under enflu- rane (3-4%)/O2 anesthesia, a burr hole was made at 0.5 mm Owing to these advantages and effectiveness, gabapentin caudally from the coronal suture and 1.0 mm laterally from has been widely used in the management of a variety of neu- the sagittal suture. Through this hole, a stainless steel, thin- ropathic pain, but there are lack of data or information about walled guide cannula was placed into the ventricle to a depth its effect on hemodynamics and no known cardiovascular side of 3 mm from dura mater and affixed to the skull with stain- less steel screws and cranioplastic cement. Therefore, the purpose of this study was to examine the After surgery, rats were kept in individual cages. Animals changes of hemodynamics following administration of intra- showing neurologic dysfunction postoperatively were sacri- thecal (IT), intracerebroventricular (ICV), and intraperitoneal ficed immediately by excessive enflurane inhalation. Only rats that displayed no postsurgical motor or sensory deficitswere assessed. Experiments were performed at least 4-5 days ics were measured at the same time intervals. For IP administration, the drug was injected into the peri- All data are presented as means±SEM. Baseline blood pressure and heart rate were compared by using one-way In order to measure hemodynamic changes, a PE-50 catheter ANOVA. Stastistical analysis of hemodynamic changes was was inserted into the tail artery under enflurane (3-4%)/O2 done using two-way repeated-measures ANOVA. A p value anesthesia and then the rats were restrained in a restraint <0.05 was considered statistically significant.
cylinder. The catheter was flushed with 0.5 mL heparinizedsaline. The arterial line was connected to a pressure trans-ducer of monitor (Datex-Ohmeda AS/3, Finland) for con- tinuous recording of blood pressure and heart rate.
Rats were divided into three groups of IT (n=20), ICV The baseline systolic blood pressure, diastolic blood pres- (n=22), and IP (n=20) according to the route of drug adminis- sure, and heart rate were 127.8±1.5 mmHg, 92.6±9.4 tration. Each group was divided into four subgroups accord- mmHg, and 416.4±2.9 beats/min, respectively. The base- line blood pressure and heart rate in the several treatment The doses of gabapentin for IT and ICV were 10, 30, 100, groups did not differ. No changes of hemodynamics com- and 300 g, respectively, and those for IP were 10, 30, 100, pared with baseline value were seen over the 60 min-period and 300 mg/kg, respectively. Gabapentin was dissolved in following administration of IT and IP gabapentin (Fig. 1, 3).
physiologic saline. A gear-driven microinjector was used to However, systolic and diastolic blood pressure were gradu- deliver the drug in IT and ICV groups, and the drug was ally increased compared with baseline blood pressure after given in 10 L of saline. IT administration was followed by administration of gabapentin in all ICV subgroups (Fig. 2).
an additional 10 L of saline to flush the catheter. In the IP And the change of heart rate was not statistically significant.
group, the drug was injected into the peritoneal cavity with Although the blood pressure was significantly increased after a volume of 3 mL/kg through the slit of the restraint cylin- ICV injection, the extent of change was not different among der. Blood pressure and heart rate were measured at 5, 10, 15, 20, 30, 40, 50, and 60 min after IT and ICV adminis-tration. After 30 min following IP injection, hemodynam- Fig. 1. Time effect curve of intrathecal gabapentin for systolic blood pressure (SBP) and diastolic blood pressure (DBP) and heart rate (HR). Gabapenin was administered at time 0. Each line represents the mean±SEM of 5-7 rats.
Fig. 2. Time effect curve of intracerebroventricular gabapentin for systolic blood pressure (SBP) and diastolic blood pressure (DBP) andheart rate (HR). Gabapenin was administered at time 0. Each line represents the mean±SEM of 5-7 rats. *Statistically significant com-pared with baseline value.
DISCUSSION
response of rat paw formalin test, thermal injury model, ratmodel of peripheral neuropathy and surgically induced neu- Gabapentin, administered via IT, IP, but ICV routes, did not affect the blood pressure or heart rate in the present study.
Although there are many proposals for the mechanism of These findings indicate that gabapentin may be given safely action of gabapentin, it has not been fully elucidated. Non- via IT and IP routes without the change of hemodynamics.
strychnine site of NMDA receptor and the 2 subunit of Numerous animal and human studies have shown that voltage-sensitive calcium channels have been suggested as gabapentin is effective in a wide variety of pain syndromes.
the binding site of gabapentin (4, 5, 13). Clinically, the most In human studies, it consistently provided relief of pain asso- common side effects of gabapentin are dizziness, somnolence, ciated with various conditions including postherpetic neu- headache, and diarrhea (12). Side effects increase linearly with ralgia (7), diabetic peripheral neuropathy (12), and complex the increase of the daily dose, but the relative safety is sup- regional pain syndrome (8). Its efficacy on allodynia and ported in many studies including a case report of overdose hyperalgesia was also demonstrated in numerous animal of 48.9 g with lack of serious toxicity (14, 15). In addition, studies (2-6). In these studies, gabapentin reduced the pain there has been no documentation of side effects on cardio- Fig. 3. Time effect curve of intraperitoneal gabapentin for sys- tolic blood pressure (SBP) and diastolic blood pressure (DBP) and heart rate (HR). Gabapenin was administered at time -30 min. Each line represents the mean±SEM of 5-7 rats.
tionship are uncertain and further studies for the side effects Although the current study was undertaken on animals, of ICV gabapentin including cardiovascular effects are re- it showed that neither systemic nor intrathecal gabapentin quired. The above mentioned findings jointly suggest that affected the hemodynamics. These results are consistent with gabapentin does not affect cardiovascular responses when it the previous findings (5, 6). Furthermore, intraduodenal is used via IT or IP but ICV route. Thus, if another prepara- gabapentin (100 mg/kg) produced no significant effects on tion of IT or IP route is developed in the future, albeit only the mean arterial blood pressure and heart rate (16), although oral agents are clinically available now, it can be prescribed animals in that study were pretreated with guanethidine and safely without cardiovascular side effects. But the result of anesthetized owing to the invasiveness of the study. And 100 increased blood pressure caused by ICV gabapentin suggests mg/kg gabapentin did not change the mean blood pressure that it should be used cautiously, especially in patients with within 60 min after intravenous administration in another In conclusion, ICV gabapentin increased systolic and In our study, IT or IP administration of gabapentin did diastolic blood pressure, but IT and ICV gabapentin did not affect blood pressure and heart rate. However, systolic and diastolic blood pressure were increased after ICV admin-istration. Considering the minimal hemodynamic effect ofIT gabapentin, increased blood pressure in ICV gabapentin REFERENCES
was an unexpected result. Furthermore, dose-dependency wasnot observed in the ICV group. This different result might 1. Taylor CP, Gee NS, Su TZ, Kocsis JD, Welty DF, Brown JP, Doo- be related with very low volume of test drug, which could ley DJ, Boden P, Singh L. A summary of mechanistic hypotheses of not have reached the brain when administered intrathecally.
gabapentin pharmacology. Epilepsy Res 1998; 29: 233-49. The unknown change of pharmacokinetics of ICV gabapen- 2. Hwang JH, Yaksh TL. Effect of subarachnoid gabapentin on tactile- tin could be thought of as one for the result, and the CNS side evoked allodynia in a surgically induced neuropathic pain model in effects of gabapentin such as nausea, vomiting and headache the rat. Reg Anesth Pain M 1997; 22: 249-56. might be attributed to the result. However, the reasons of 3. Xiao W-H, Bennet GJ. Gabapentin has an anti-nociceptive effect these changes of blood pressure without dose-response rela- mediated via a spinal site of action in a rat model of painful periph- eral neuropathy. Analgesia 1997; 2: 267-73. 4. Partridge BJ, Chaplan SR, Sakamoto E, Yaksh TL. Characteriza- 12. Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, tion of the effects of gabapentin and 3-isobutyl-gamma-aminobu- Hes M, LaMoreaux L, Garofalo E. Gabapentin for the symptomatic tyric acid on substance P-induced thermal hyperalgesia. Anesthesi- treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998; 280: 1831-6. 5. Yoon MH, Yaksh TL. The effect of intrathecal gabapentin on pain 13. Bryans JS, Davies N, Gee NS, Dissanayake VU, Ratcliffe GS, Hor- behavior and hemodynamics on the formalin test in the rat. Anesth well DC, Kneen CO, Morrell AI, Oles RJ, O’ Neill JA. Identification of novel lig- 6. Yoon MH, Yaksh TL. Evaluation of interaction between gabapentin ands for the gabapentin binding site on the alpha2delta subunit of a and ibuprofen on the formalin test in rats. Anesthesiology 1999; 91: calcium channel and their evaluation as anticonvulsant agents. J 7. Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller 14. Fischer JH, Barr AN, Rogers SL, Fischer PA, Trudeau VL. Lack of L. Gabapentin for the treatment of postherpetic neuralgia: a ran- serious toxicity following gabapentin overdose. Neurology 1994; domized controlled trial. JAMA 1998; 280: 1837-42. 8. Mellick GA, Mellicy LB, Mellick LB. Gabapentin in the manage- 15. Verma A, St Clair EW, Radtke RA. A case of sustained massive ment of reflex sympathetic dystrophy. J Pain Symptom Manage 1995; gabapentin overdose without serious side effects. Ther Drug Monit 9. McLean MJ, Morrell MJ, Willmore LJ, Privitera MD, Faught RE, 16. Parsons AA, Bingham S, Raval P, Read S, Thompson M, Upton N.
Holmes GL, Magnus-Miller L, Bernstein P, Rose-Legatt A. Safety Tonabersat (SB-220453), a novel benzopyran with anticonvulsant and tolerability of gabapentin as adjunctive therapy in a large, mul- properties, attenuates trigeminal nerve-induced neurovascular reflex- ticenter study. Epilepsia 1999; 40: 965-72. es. Br J Pharmacol 2001; 132: 1549-57. 10. Yaksh TL, Rudy TA. Chronic catheterization of the spinal subarach- 17. Gillin S, Sorkin LS. Gabapentin reverses the allodynia produced by noid space. Physiol Behav 1976; 17: 1031-6. the administration of anti-GD2 ganglioside, an immunotherapeutic 11. Lee YW, Chaplan SR, Yaksh TL. Systemic and supraspinal, but not drug. Anesth Analg 1998; 86: 111-6. spinal, opiates suppress allodynia in a rat neuropathic pain model.

Source: http://jkms.org/Synapse/Data/PDFData/0063JKMS/jkms-18-478.pdf