Li k e surgeons in many other specialties, neurosurgeons. Postoperative pain management with tramadol after craniotomy: evaluation and cost analysis

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1 See the corresponding editorial in this issue, pp J Neurosurg 112: , 2010 Postoperative pain management with tramadol after craniotomy: evaluation and cost analysis Clinical article Sc o t t Y. Ra h i m i, M.D., Ca r g i l l H. Al l e y n e Jr., M.D., Er i c Ve r n i e r, M.D., Mar k R. Wi t c h e r, Ph.D., a n d Jo h n R. Ve n d e r, M.D. Department of Neurosurgery, Medical College of Georgia, Augusta, Georgia Object. Patients undergoing craniotomies have traditionally received opiates with acetaminophen for the management of their postoperative pain. The use of narcotic pain medications can be costly, decrease rates of early postoperative ambulation, lengthen hospital stays, and alter a patient s neurological examination. The use of alternative pain medications such as tramadol may benefit patients by resolving many of these issues. Methods. The authors conducted a randomized, blinded prospective study to evaluate the efficacy of alternative pain management strategies for patients following craniotomies. Fifty patients were randomly assigned either to a control group who received narcotics and acetaminophen alone or an experimental group who received tramadol in addition to narcotic pain medications (25 patients assigned to each group). Results. The control group was noted to have statistically significant higher visual analog scale pain scores, an increased length of hospital stay, and increased narcotic use compared with the tramadol group. The narcotics and acetaminophen group also had increased hospitalization costs when compared with the tramadol group. Conclusions. The use of scheduled atypical analgesics such as tramadol in addition to narcotics with acetaminophen for the management of postoperative pain after craniotomy may provide better pain control, decrease the side effects associated with narcotic pain medications, encourage earlier postoperative ambulation, and reduce total hospitalization costs. (DOI: / ) Ke y Wo r d s pain management craniotomy opioid tramadol Li k e surgeons in many other specialties, neurosurgeons continually confront postoperative pain man agement issues. Traditionally several classes of analgesics have been used for the treatment of postoperative pain. These include opioids, NSAIDs, cox-2 inhibitors that are a subset of NSAIDs, and a miscellaneous category including acetaminophen and tramadol. Neurosurgical patients requiring craniotomies have historically been treated exclusively with narcotic pain medications and acetaminophen. Although these medications are very effective for pain, they cause many side effects including nausea and vomiting, constipation, respiratory depression, and altered mental status that may interfere with the neurological examination of these patients. As new classes of analgesics become available, some patients could benefit from alternative medication regimens that may avoid the side effects of narcotics. A newer analgesic, tramadol can provide effective pain relief without the side effects of narcotic medications at a lower cost to patients and hospitals. Tramadol in particular is superior Abbreviations used in this paper: cox = cyclooxygenase; LOS = length of stay; NSAID = nonsteroidal antiinflammatory drug; VAS = visual analog scale. to other analgesics in that it does not have the side effects typically associated with opioids, or the inhibitory effects on platelets induced by NSAIDs. Method Institutional review board approval was obtained for our randomized controlled study. No financial interests were associated with this study. The VAS was used by our nursing staff to assess patient pain levels. Patients with VAS scores requiring medication administration were documented. The average LOS for both groups was documented. Exclusion criteria included pregnancy, age younger than 18 years, ventilator dependence for longer than 24 hours, allergies to medications used, and emergency surgery. Patients undergoing emergency surgery were excluded because of the difficulty in obtaining consent from these patients as required by our institutional review board. Patient Selection Patients who underwent elective craniotomy for vascular, tumor, and epilepsy procedures were blindly randomized into 1 of 2 groups. A control group of 25 patients 268 J Neurosurg / Volume 112 / February 2010

2 Pain management with tramadol after craniotomy received narcotic pain medications with acetaminophen alone with a placebo (narcotics group). The experimental group (25 patients) received tramadol twice daily in addition to narcotic pain medications (tramadol group). Dural opening was performed in all patients in both groups. Medications Used Narcotic pain medications included oxycodone/acetaminophen (Percocet) 5/325 mg given 1 2 tablets every 4 hours as needed, and 1 2 mg of intravenous morphine given every 2 hours as needed. The alternate analgesic regimen included 100 mg of tramadol (Ultram) given twice daily. Tramadol was chosen because it uses a different functional pathway than opioid analgesics and because it is on formulary at our institution. We were therefore able to use this medication without any additional cost to our patients or the hospital. The amount of antiemetic medication used was also recorded for both groups. These medications included promethazine (Phenergan) 12.5 mg (1 dose) and ondansetron (Zofran) 4 mg (1 dose). Medication Costs The cost of each medication used was obtained from the Medical College of Georgia inpatient pharmacy department. The prices included 5/325 mg of oxycodone/ acet aminophen, $6; 100 mg of tramadol, $8; 12.5 mg of in tra venous promethazine, $20; 1 mg of intravenous morphine, $12.50; and 4 mg of intravenous ondansetron, $81. The cost for a non intensive care unit room at our institution was calculated to be ~ $900 per night. Ondansetron has recently become generic and its price may vary at different institutions. Results Narcotics Group Data The average age for patients undergoing craniotomies in the narcotics group was 44.1 years. Location of surgery included frontal in 10 patients, parietal in 3, occipital in 4, and temporal in 8. This included 6 epilepsy, 7 vascular, and 12 tumor procedures. The mean surgical time for these patients was 3.2 hours (range hours). This group used an average of 13.3 oxycodone/acetaminophen tablets and 11 mg intravenous morphine per patient. The total amount of antiemetics used by this group included 25 doses of promethazine and 15 doses of ondansetron. This corresponded to a cost per patient of $79.80 for oxycodone/acetaminophen and $ for morphine. The total cost for promethazine and ondansetron was $500 and $1215, respectively. The average VAS score was 4.7. No perioperative complications including postoperative hematomas were noted in the control group (Table 1). Tramadol Group Data The average age for patients underoing craniotomies in the tramadol group was 53.8 years. Location of surgery included frontal in 10 patients, parietal in 4, occipital in 6, and temporal in 5. This included 5 epilepsy, 5 vascular, and 15 tumor procedures. Surgical time for this group J Neurosurg / Volume 112 / February 2010 TABLE 1: Summary of medication use in the narcotics group following craniotomy* Case No. Age (yrs), Sex Craniotomy Site Percocet Morphine Antiemetics VAS Score 1 52, F frontal P , F frontal , M temporal Z , M frontal , F parietal 9 40 Z , F occipital Z , F temporal P-2/Z , F frontal , M frontal 22 0 P-4/Z , M frontal P , F temporal 8 0 P , F temporal , M frontal 4 10 Z , F parietal 0 0 Z , F occipital , F temporal , M temporal 2 12 P , M parietal P , M frontal , F frontal Z , M occipital P , F occipital 7 8 P , M temporal , F temporal , F frontal * P-# = no. of Phenergan doses; Z-# = no. of Zofran doses. was hours, with a mean of 3.6 hours. The tramadol group used an average of 8.5 oxycodone/acetaminophen tablets and 6 mg intravenous morphine per patient. Antiemetics used included 16 doses of promethazine and 20 doses of ondansetron. This corresponded to a cost per patient of $51 for oxycodone/acetaminophen and $75 for morphine. The total cost for promethazine and ondansetron was $320 and $1629, respectively. Each patient used an average of 6.3 tramadol tablets for a cost of $51 per patient. The average VAS score was 3. No perioperative complications including postoperative hematomas were noted in the tramadol group (Table 2). Length of Stay The average LOS for patients in the narcotics group was 4.1 days (range 2 7 days) compared with 3.1 days (range 1 6 days) in the tramadol group (Fig. 1). Statistical Analysis The variable scores were analyzed for group differences using the Student t-test. Data were found to have normal distributions and similar variances. Statistical significance was determined at p The tramadol 269

3 S. Y. Rahimi et al. TABLE 2: Summary of medication use in the tramadol group following craniotomy Case No. Age (yrs), Sex group showed a significantly shorter LOS (p < 0.02) and significantly reduced VAS scores (p < 0.005) than the control group. Similarly, the tramadol group had a significantly reduced use of morphine compared with the control group (p < 0.03). The tramadol group also showed a tendency toward decreased use of Percocet, although this trend did not reach statistical significance (p = 0.057). Both groups showed similar requirements for Phenergan (p = 0.33) and Zofran (p = 0.53) (Table 3). No statistically significant values were seen when comparing specific surgical locations between the 2 groups because of the small sample size for each surgical location. A power analysis was performed to determine the differences for each variable. Power variables include LOS 84.9%, VAS 95.9%, morphine 73.4%, Percocet 60.8%, Phenergan 25.4%, and Zofran 15.6%. Pain Management Craniotomy Site Percocet Morphine Discussion Antiemetics VAS Score 1 24, F frontal , M parietal , F occipital 16 6 P-2/Z , M frontal 6 1 P-2/Z , F occipital 8 14 P-2/Z , F frontal , M temporal , M temporal , M frontal , F parietal 3 8 Z , M frontal P-1/Z , F temporal 2 14 Z , M temporal 8 4 P , M frontal 20 5 Z , F frontal 21 5 P , F frontal , M parietal , M temporal , M parietal , M frontal 3 1 Z , F frontal , F occipital 4 0 Z , M occipital , F occipital 21 8 P-5/Z , F occipital 13 2 P-2/Z Fig. 1. Bar graph showing a comparison of VAS scores, LOS, and morphine use for the tramadol and control groups. Opioids. Narcotic pain medications including codeine, oxycodone, hydrocodone, propoxyphene, and morphine have traditionally been used for successful pain management in patients after craniotomies. 7,19,22,23 Narcotic pain medications exert their effect by stimulating the mu (analgesia), sigma, and kappa subtype opioid receptors that are widespread in the central and peripheral nervous system. The use of narcotics can have several side effects associated with activation of these receptors, which in turn may delay recovery and ambulation, and lead to extended hospital stays. Opioid analgesics with acetaminophen or morphine are typically used on an as-needed basis because of their adverse side effects, in particular their association with respiratory depression. Because of this side effect profile, it may be unsafe to use narcotics as part of a regularly scheduled regimen. Nonsteroidal Antiinflammatory Drugs. These drugs provide analgesia by a different mechanism than opioids. 6 These medications inhibit the cyclooxygenase enzyme which has 2 distinct isomers: cox-1 and cox-2. 4 Although NSAIDs are effective in providing analgesia (cox-2 isomer), they can also lead to platelet dysfunction and increased bleeding times (cox-1 isomer) which can be devastating in neurosurgery patients. The administration of NSAIDs after craniotomy has therefore been described as a major risk factor leading to perioperative bleeding. 18 Antiinflammatory Drugs: Cox-2 Inhibitors. The successful use of cox-2 inhibitors for management of postoperative pain has been well described in the orthopedic literature concerning patients who have undergone hip and knee arthroplasty, lumbar discectomies, and spinal fusions. 1,5,8,14,21 Success with cox-2 inhibitors has also been documented among patients who have undergone gynecological and oral surgery procedures. 9,15,24 The cox-2 inhibitors are antiinflammatory analgesics that, because of their selective inhibition of the cox-2 enzyme, do not entail an increased risk of bleeding. 11,12 The use of cox-2 inhibitor has been shown to decrease postoperative pain in patients after craniotomy without an increased risk of postoperative hemorrhage. 20 Because of recent concern regarding the increased risk of cardiovascular disease due to thrombotic events, however, the use of cox-2 inhibitors for pain management has been limited by many institutions. Other Analgesics. Acetaminophen is an analgesic 270 J Neurosurg / Volume 112 / February 2010

4 Pain management with tramadol after craniotomy TABLE 3: Statistical analysis for tramadol and control groups* Variable Control Tramadol p Value LOS 4.08 ± ± VAS score 4.7 ± ± morphine 11.0 ± ± Phenergan 1.04 ± ± Zofran 0.6 ± ± Percocet ± ± * There were 25 patients in each group. Data are given as means ± SDs. that is effective for mild-to-moderate pain although it has no antiinflammatory action. 17 Additionally, acetaminophen is already present in many oral analgesics which are used for postoperative pain such as Percocet, Vicodin, and Darvocet. Tramadol is a relatively new analgesic that is underused for the management of postoperative pain in neurosurgical patients. Tramadol has been used very effectively for postoperative pain management in patients after orthopedic, cardiothoracic, and obstetric procedures for several years. 2,3,10,16 Tramadol exerts its analgesic effects by inhibiting the reuptake of serotonin and norepinephrine, although the exact mechanism of its analgesic effect is not completely understood. Tramadol has no effect on platelet or coagulation function, making it a safe medication to use for neurosurgical patients after craniotomy. Tramadol also has a weak interaction with opioid receptors which can lead to some similar side effects as opioids including nausea, vomiting, dry mouth, and dizziness. 13 Tramadol can therefore be safely given to patients on a regularly timed schedule. Data Analysis Our analysis of medication costs and LOS at our institution revealed that the use of tramadol could potentially decrease the final cost associated with a craniotomy procedure. The cost of total medications used was $32 less per patient for the tramadol group compared with control group patients who received opioids with acetaminophen. Even with the addition of tramadol to the analgesic regimen, patients received less analgesic medication at a lower total cost. The mean LOS for patients in the tramadol and control groups was 3.1 and 4.1 days, respectively. We conjecture that this decreased hospital stay can be attributed to the fact that patients in the tramadol group tolerated oral intake earlier, ambulated sooner, and had fewer opioid side effects compared with the patients who took narcotics alone. This could lead to major savings, as the cost of one non intensive care unit bed at our institution is ~ $900 per night. A decrease in LOS would in turn lead to greater bed availability for other patients, allowing hospitals to serve more people. Patients who received tramadol in addition to opioid analgesics with acetaminophen experienced less postoperative pain than those who did not receive tramadol. This is evident by an average VAS score of 3 in the tramadol J Neurosurg / Volume 112 / February 2010 group compared with 4.7 in the narcotics group. No significant difference was noted in the amount of antiemetics used in the tramadol versus the narcotics group. This may be due to the irritative effects of blood products on the central nervous system after craniotomies or the weak agonist action of tramadol on opioid receptors. Overall we observed several advantages when tramadol was used as an adjunct to narcotic pain medications. Conclusions Most neurosurgery patients continue to receive only narcotic analgesics with acetaminophen postoperatively. The addition of tramadol to a narcotic regimen appears to achieve better pain control in patients after craniotomy, while allowing for the administration of smaller doses of narcotics with acetaminophen for pain control. The use of atypical approaches such as scheduled nonopioids in addition to narcotics for management of postoperative pain after neurosurgery can decrease the side effects associated with narcotic medications, encourage earlier ambulation, decrease LOS, and ultimately reduce the overall cost of hospitalization. Further research into the preoperative administration of these medications and their use after other neurosurgical procedures such as spine surgery may reveal more advantages to their use in the treatment of postoperative pain. Discaimer The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. References 1. 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5 S. Y. Rahimi et al. 10. Kocabas S, Karaman S, Uysallar E, Firat V: The use of tramadol and morphine for pain relief after abdominal hysterectomy. Clin Exp Obstet Gynecol 32:45 48, Leese PT, Hubbard RC, Karim A, Isakson PC, Yu SS, Geis GS: Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: a randomized, controlled trial. J Clin Pharmacol 40: , Leese PT, Recker DP, Kent JD: The COX-2 selective inhibitor, valdecoxib, does not impair platelet function in the elderly: results of a randomized controlled trial. J Clin Pharmacol 43: , Leppert W, Luczak J: The role of tramadol in cancer pain treatment a review. Support Care Cancer 13:5 17, Malan TP Jr, Marsh G, Hakki SI, Grossman E, Traylor L, Hubbard RC: Parecoxib sodium, a parenteral cyclooxygenase 2 selective inhibitor, improves morphine analgesia and is opioid-sparing following total hip arthroplasty. Anesthesiology 98: , Mehlisch DR, Desjardins PJ, Daniels S, Hubbard RC: Single doses of parecoxib sodium intravenously are as effective as ketorolac in reducing pain after oral surgery. J Oral Maxillofac Surg 61: , Mimis D, Turan A, Karamanlioglu B, Tukenmez B, Pamukcu Z: The effect of tramadol or clonidine added to intraperitoneal bupivacaine on postoperative pain in total abdominal hysterectomy. J Opioid Manag 1:77 82, Mycek MJ, Harvey RA, Champe PC (eds): Nonsteroidal antiinflammatory drugs, in Lippincott s Illustrated Reviews: Pharmacology, ed 2. Philadelphia: Lippincott Williams & Wilkins, 2000, pp Palmer JD, Sparrow OC, Iannotti F: Postoperative hematoma: a 5-year survey and identification of avoidable risk. Neurosurgery 35: , Quiney N, Cooper R, Stoneham M, Walters F: Pain after craniotomy. A time for reappraisal? Br J Neurosurg 10: , Rahimi SY, Vender JR, Macomson SD, French A, Smith JR, Alleyne CH Jr: Postoperative pain management following craniotomy: evaluation and cost analysis. Neurosurgery 59: , Reuben SS, Connelly NR: Postoperative analgesic effects of celecoxib or refecoxib after spinal fusion surgery. Anesth Analg 91: , Roberts G: A review of the efficacy and safety of opioid analgesics post-craniotomy. Nurs Crit Care 9: , Stoneham MD, Cooper R, Quiney NF, Walters FJ: Pain following craniotomy: a preliminary study comparing PCA morphine with intramuscular codeine phosphate. Aneaesthesia 51: , Tang J, Li S, White PF, Wender RH, Quon R, Sloninski A, et al: Effect of parecoxib, a novel intravenous cyclooxygenase type-2 inhibitor on the postoperative opioid requirement and quality of pain control. Anesthesiology 96: , 2002 Manuscript submitted November 25, Accepted September 29, Please include this information when citing this paper: published online July 24, 2009; DOI: / Address correspondence to: Scott Y. Rahimi, M.D., BI-3088; th Street, Department of Neurosurgery, Medical College of Georgia, Augusta, Georgia scottrahimi@yahoo.com. 272 J Neurosurg / Volume 112 / February 2010