Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
The Acute Pain Service (APS) at Sunnybrook has been using Gabapentin 200 mg three times a day
 (TID) resulting in anecdotal benefits in terms of analgesia and opioid sparing effects.
 Higher doses of Gabapentin were associated with an increased incidence of sedation. The
 purpose of the study is to investigate if Gabapentin 200 mg given three times a day for 72
 hours (9doses) results in a reduction in the total amount of opioid required after radical
 prostatectomy surgery as compared to placebo, and if analgesia is improved. This study will
 also examine the possible anxiety sparing effects and any health related quality of life
 (HRQL) changes, which may be a result of our perioperative use of gabapentin.
Gabapentin Gabapentin is an anti-epileptic agent originally developed to treat spasticity
 (1), and eventually was found to be effective against chronic neuropathic pain (1,2).
 Gabapentin is available as an oral preparation and is primarily absorbed in the small
 intestine (1). Gabapentin is not metabolized in humans and is eliminated unchanged via the
 kidneys. It has no known drug-drug interactions, but it is reported that antacids can reduce
 the bioavailability of Gabapentin by about 20%, and Cimetidine can decrease the clearance of
 Gabapentin from the body by about 12% (1,2). Side effects of Gabapentin tend to be mild with
 somnolence (20%), dizziness (18%), ataxia (13%), and fatigue (11%) being the most common (1).
 The exact mechanism of Gabapentin in pain management is unknown, but it has demonstrated
 inhibition of mechanical hyperalgesia, and mechanical/thermal allodynia in those with
 neuropathic pain (1).

 Over the past 5 years, there have been 20 studies examining the effect of Gabapentin on
 postoperative pain (1 & 3-22). All but one of these studies (16) has found that Gabapentin
 demonstrated a significant reduction in the amount of postoperative opioid required (16-67%)
 and a simultaneous reduction in pain scores. There was no difference in side effect profile
 between the Gabapentin and the control groups in 11 studies(3-5,7,8,10,14-16,18,20), while
 one(18) found a higher incidence of nausea and urinary retention in the control groups, and
 two studies(11,13) found a higher incidence of nausea/vomiting in the Gabapentin group. The
 most common side effect of increased sedation was found in only 4 studies when doses greater
 than 900 mg per day were given (9,11-13). The daily dose of postoperative Gabapentin in the
 current protocol is 200 mg TID (600 mg/day) which we currently use in our clinical population
 with minimal side effect issues.

 There have been 8 studies looking at the administration of Gabapentin in the postoperative
 period (4,6-8,11,20,22,23). Fassoulaki and colleagues (6) examined pain scores and opioid
 consumption in postoperative breast cancer patients. Seventy-five patients undergoing surgery
 for breast cancer were randomized to receive Mexiletine 600 mg/day, Gabapentin 1200 mg/day or
 placebo for 10 days. Opioid consumption was reduced by 50% in the Gabapentin and Mexiletine
 groups vs. the placebo group on days 2-10. Only the Gabapentin group had decreased pain after
 movement from the 2nd to the 5th postoperative day. There were no adverse effects reported in
 the Gabapentin group. Dierking and his colleagues randomized 80 patients to receive either
 1200 mg of Gabapentin or placebo 1 hr preoperatively, then either Gabapentin 600 mg or
 placebo at hours 8, 16, and 24 postoperatively following abdominal hysterectomies(4). Opioid
 consumption was reduced by 32% in this study and there was no significant difference between
 side effects in either group. Another study looking at postoperative outcomes and Gabapentin
 was published by Gilron and his colleagues who randomized 110 patients to 4 study groups: (A)
 placebo (B) Gabapentin 600 mg TID (C) Rofecoxib 50 mg/day (D) Gabapentin 600 mg TID &
 Rofecoxib 50 mg/day starting 1hr preoperatively and continuing for 72 hours postoperatively
 (9). This study was unique because it went further than simply looking at pain scores and
 morphine consumption data. Gilron and his colleagues demonstrated that the Gabapentin and the
 Gabapentin and Rofecoxib groups also significantly decreased movement associated pain evoked
 by sitting and coughing post abdominal hysterectomy. Adverse events were similar in all
 groups except sedation, which was more frequent with Gabapentin. Consistent with previous
 literature, the multimodal Gabapentin/Rofecoxib combination demonstrated opioid sparing,
 lower pain scores, but most importantly, decreased movement associated pain, which may be a
 significant factor in faster rehabilitation. In our study we have chosen to use Gabapentin
 200 mg TID (bioequivalence of 600 mg/day) based on our extensive clinical experience with our
 patient population. This appears to be the dose at which most patients do not exhibit the
 Gabapentin related side effects described earlier. Only four studies have prescribed
 Gabapentin beyond 72 hours postoperatively (6-8,11). This is an area in which further
 research is needed to determine whether prolonged postoperative administration and its
 benefits translate into earlier hospital discharge, decreased chronic pain rates and
 increased functional recovery even beyond the acute post surgical time period. By following
 patients to 4 weeks post surgery, this study will aim to answer some of the questions
 regarding the perioperative use of gabapentin and its possible role ameliorating functional
 recovery beyond the acute hospitalization period.

 The Sunnybrook Health Sciences Acute Pain Service (APS) does not know if 200 mg of Gabapentin
 is effective at reducing morphine consumption, and improving analgesia. Much higher doses
 (i.e. greater than 1800 mg/day) published in the literature were initially used at
 Sunnybrook, but many patients (anecdotally) became too sedated. We are currently using the
 dose suggested in our protocol 200 mg TID without any major problems. Therefore our goal is
 to assess if Gabapentin 200 mg does in fact have opioid reducing and analgesic benefits in
 the radical prostate population. Our pilot data from 15 patients indicates these benefits
 might exist. Furthermore, examining the role of gabapentin in regards to perioperative
 anxiety and following patients beyond the acute post surgical time period and following any
 changes related to their functional recovery and quality of life will help to close some of
 the gaps in the literature regarding the perioperative usefulness of gabapentin.

 Gabapentin and Anxiety

 The preoperative effectiveness of Gabapentin in decreasing anxiety scores and improving early
 functional recovery after anterior cruciate ligament knee surgery (n=40) has recently been
 demonstrated(10). Premedication with Gabapentin 1200 mg improved preoperative anxiolysis,
 postoperative analgesia, and early knee mobilization. By including a physical measure (active
 and passive knee flexion), Menigaux and colleagues also demonstrated that adequate
 postoperative analgesia enhances mobilization of the knee joint, thus potentially improving
 functional recovery. This French study examined patient's preoperative anxiety levels by
 administering an anxiety Visual Analogue Score prior to induction of anesthesia in the
 operating room. Since this method of anxiety testing has not been validated, we will use four
 reliable and well-validated anxiety tools in our present study. These measures are all one
 page questionnaires that are of little burden to patients. The anxiety measures are: The
 Spielberger State-Trait Anxiety Inventory, The Pain Catastrophising Scale, The Pain Anxiety
 Symptoms Scale and a 7 Item Modified Hospital Anxiety & Depression Scale.

 The State-Trait Anxiety Inventory (STAI) consists of two self-report scales, one measuring
 state anxiety and the other measuring trait anxiety (24). Each scale consists of 20
 statements about how the respondent may feel, and they are asked to rate how strongly they
 agree ("very much so") or disagree ("not at all") with the item. The S-Anxiety scale
 evaluates how respondents feel "right now, at this moment", whereas the T-Anxiety scale
 evaluates how they feel "generally". This scale has been used extensively in research and
 clinical practice, and has been shown to be valid and reliable (24).

 Catastrophising or catastrophic thinking refers to "an exaggerated negative 'mental set'
 brought to bear during actual or anticipated pain experience" (25). The PCS is a 13 item
 self-report inventory that measures catastrophic thinking in relation to pain (26).
 Respondents are asked to reflect on past painful experiences and to indicate the degree to
 which they experience each of 13 thoughts or feelings when experiencing pain. Each item is
 rated on a 5-point rating scale with the end points 0 = not at all and 4 = all the time. The
 PCS yields a total score and three subscale scores assessing rumination (i.e., excessive
 focus on pain sensations), magnification (i.e., exaggerating the threat value of pain
 sensations) and helplessness (i.e., perceiving oneself as unable to cope with pain symptoms).
 The PCS has been shown to have high internal consistency {coefficient alphas: total PCS =
 .87, rumination = .87, magnification = .66, and helplessness = .78 (26). The PCS has been
 shown to predict pain intensity in patients with acute postoperative pain (27) and pain
 related disability in chronic neuropathic pain patients even after controlling for pain
 severity (28).

 The Pain Anxiety Symptoms Scale (PASS) is a 40-item assessment tool that measures fear and
 anxiety responses to pain, and the short form of the PASS is a condensed version of the full
 PASS with only 20 items (29). The PASS-20 is a reliable and valid scale with adequate
 psychometric properties.

 Finally, The Hospital Anxiety and Depression Scale (HADS, 30) is a widely used scale for
 measuring the symptoms of anxiety and depression among medical inpatients, outpatients and in
 the general population (31). The HADS is a 14-item questionnaire that measures symptoms of
 anxiety (7 items) and depression (7 items). For each item, the patient is asked to select
 from among 4 possible choices (scored from 0 to 3) the one that best describes how they have
 been feeling over the past week. The HADS yields an anxiety (HADS-A) and a depression
 (HADS-D) subscale score. We have chosen to administer only the (HADS-D) component because we
 feel that the other anxiety measure provide enough information in regards to anxiety. In
 general, the psychometric properties of the HADS are excellent. It has been administered in
 more than 700 studies to more than 35,000 individuals. Internal consistency for the anxiety
 and depression subscales show Chronbach alphas of between 0.80-0.93 for the anxiety subscale
 and between 0.81 and 0.90 for the depression subscale (31,32). Concurrent validity of the
 HADS is very good as measured by correlation coefficients of between 0.62 and 0.73 for the
 HADS-D with various well-validated depression scales (e.g., Beck Depression Inventory, SCL-90
 Depression subscale (31,32). The HADS has been demonstrated to be sensitive to changes due to
 disease progression and in response to therapeutic interventions (32). The 7 item modified
 HADS will take less than 2 minutes to fill out (33).

 The burden to patients will be minimal because all of the above measures can be completed in
 15-20 minutes. Patients will be asked to complete these items at baseline (prior to surgery),
 on the day of hospital discharge (likely POD 3) and at the 3 month follow up post surgery.

 Health Related Quality of Life

 Outcomes pertaining to health related quality of life (HRQOL) are gaining importance when
 assessing the impact that interventions have on various disease states (34). Many tools are
 available, however it has been recommended that both a general and disease specific HRQOL
 tool be used to help ensure any changes in HRQOL status are captured (34,35). Regardless of
 the instrument(s) chosen they should be valid & reliable, as well as sensitive and responsive
 to change (35, 36). Other key considerations include utilizing a tool that captures the key
 dimensions of HRQOL, specifically physical, psychological, & social/role functioning (35,
 37). A critical component to assessing HRQOL is that, given the subjective nature of quality
 of life, the data should be assessed by the patient, not the health care provider (37).

 In order to meet all of these criteria, this study will utilize the SF-36 Health Outcomes
 questionnaire (SF-36), the UCLA Prostate Cancer Index, (UCLA-PCI) and the Brief Pain
 Inventory (BPI).

 The SF-36 is a widely used general HRQOL tool, with extensive validity and reliability and
 responsiveness across many populations (38, 39). The SF-36 is a 36 question survey used to
 describe overall health status. It has 8 subscales (physical functioning, role limitations,
 bodily pain, general health perception, vitality, social function, role limitation as a
 result of emotional problems, and general mental health). It takes 5-10 minutes to complete
 and can be used with persons 14 and older.

 The UCLA Prostate Cancer Index (UCLA-PCI) is also a valid and reliable tool, measuring health
 related outcomes specific to the prostate cancer population (40). It takes about 10 minutes
 to complete. In a recent review of HRQL in prostate cancer studies, the SF-36 and UCLA-PCA
 were the most frequently used general and disease specific tools used (41)

 In order to make the measurement of pain more robust, a valid and reliable tool should be
 used. The Numeric Rating Scale (NRS) & Brief Pain Inventory will be used. The Brief Pain
 Inventory (BPI) is a widely used tool that has been validated in a wide variety of clinical
 and research populations, including the cancer population (42) and post operative population
 (43). It takes about 5 minutes to complete. The BPI measures pain intensity and pain
 interference on work, activity, mood, enjoyment sleep, walking, and relationships. It is
 important to assess baseline pain when undertaking a trial to assess pain or analgesia
 related outcomes.

 Recently published articles have examined the effect of post operative pain on HRQOL after
 discharge, and have found that pain contributes to lower scores on HRQOL indices (44-46), at
 one week and one month post discharge.

 1. Rose MA, Kam PC. Gabapentin: pharmacology and its use in pain management. Anaesthesia
 2002;57:451-62.

 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.

 3. Al-Mujadi H, AR, Katzarov MG et al. Preemptive gabapentin reduces postoperative pain and
 opioid demand following thyroid surgery. Can J Anaesth 2006;53:268-73.

 4. Dierking G, Duedahl TH, Rasmussen ML et al. Effects of gabapentin on postoperative
 morphine consumption and pain after abdominal hysterectomy: a randomized, double-blind
 trial. Acta Anaesthesiol Scand 2004;48:322-7.

 5. 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.

 6. 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, table of
 contents.

 7. Fassoulaki A, Stamatakis E, Petropoulos G et al. Gabapentin attenuates late but not
 acute pain after abdominal hysterectomy. Eur J Anaesthesiol 2006;23:136-41.

 8. Fassoulaki A, Triga A, Melemeni A, Sarantopoulos C. Multimodal analgesia with gabapentin
 and local anesthetics prevents acute and chronic pain after breast surgery for cancer.
 Anesth Analg 2005;101:1427-32.

 9. Gilron I, Orr E, Tu D et al. A placebo-controlled randomized clinical trial of
 perioperative administration of gabapentin, rofecoxib and their combination for
 spontaneous and movement-evoked pain after abdominal hysterectomy. Pain
 2005;113:191-200.

 10. Menigaux C, Adam F, Guignard B et al. Preoperative gabapentin decreases anxiety and
 improves early functional recovery from knee surgery. Anesth Analg 2005;100:1394-9,
 table of contents.

 11. Mikkelsen S, Hilsted KL, Andersen PJ et al. The effect of gabapentin on post-operative
 pain following tonsillectomy in adults. Acta Anaesthesiol Scand 2006;50:809-15.

 12. Pandey CK, Navkar DV, Giri PJ et al. Evaluation of the optimal preemptive dose of
 gabapentin for postoperative pain relief after lumbar diskectomy: a randomized,
 double-blind, placebo-controlled study. J Neurosurg Anesthesiol 2005;17:65-8.

 13. Pandey CK, Priye S, Singh S et al. Preemptive use of gabapentin significantly decreases
 postoperative pain and rescue analgesic requirements in laparoscopic cholecystectomy.
 Can J Anaesth 2004;51:358-63.

 14. Pandey CK, Sahay S, Gupta D et al. Preemptive gabapentin decreases postoperative pain
 after lumbar discoidectomy. Can J Anaesth 2004;51:986-9.

 15. Pandey CK, Singhal V, Kumar M et al. Gabapentin provides effective postoperative
 analgesia whether administered pre-emptively or post-incision. Can J Anaesth
 2005;52:827-31.

 16. Radhakrishnan M, Bithal PK, Chaturvedi A. Effect of preemptive gabapentin on
 postoperative pain relief and morphine consumption following lumbar laminectomy and
 discectomy: a randomized, double-blinded, placebo-controlled study. J Neurosurg
 Anesthesiol 2005;17:125-8.

 17. Rorarius MG, Mennander S, Suominen P et al. Gabapentin for the prevention of
 postoperative pain after vaginal hysterectomy. Pain 2004;110:175-81.

 18. Turan A, Karamanlioglu B, Memis D et al. Analgesic effects of gabapentin after spinal
 surgery. Anesthesiology 2004;100:935-8.

 19. Turan A, Karamanlioglu B, Memis D et al. The analgesic effects of gabapentin after total
 abdominal hysterectomy. Anesth Analg 2004;98:1370-3, table of contents.

 20. Turan A, Kaya G, Karamanlioglu B et al. Effect of oral gabapentin on postoperative
 epidural analgesia. Br J Anaesth 2006;96:242-6.

 21. Turan A, Memis D, Karamanlioglu B et al. The analgesic effects of gabapentin in
 monitored anesthesia care for ear-nose-throat surgery. Anesth Analg 2004;99:375-8, table
 of contents.

 22. Turan A, White PF, Karamanlioglu B et al. Gabapentin: an alternative to the
 cyclooxygenase-2 inhibitors for perioperative pain management. Anesth Analg
 2006;102:175-81.

 23. Gilron I. Review article: the role of anticonvulsant drugs in postoperative pain
 management: a bench-to-bedside perspective. Can J Anaesth 2006;53:562-71.

 24. Spielberger CD, Gorsuch RL, Lushene R et al. State-Trait Anxiety Inventory for Adults:
 Manual. Palo Alto: Mind Garden, 1983.

 25. Sullivan MJ, Thorn B, Haythornthwaite JA et al. Theoretical perspectives on the relation
 between catastrophizing and pain. Clin J Pain 2001;17:52-64.

 26. Sullivan MJ, Bishop SR, Pivik J. The Pain Catastrophizing Scale: Development and
 Validation. Psychological Assessment 1995;7:524-32.

 27. Pavlin DJ, Sullivan MJ, Freund PR, Roesen K. Catastrophizing: a risk factor for
 postsurgical pain. Clin J Pain 2005;21:83-90.

 28. Sullivan MJ, Lynch ME, Clark AJ. Dimensions of catastrophic thinking associated with
 pain experience and disability in patients with neuropathic pain conditions. Pain
 2005;113:310-5.

 29. McCracken LM, Dhingra L. A short version of the Pain Anxiety Symptoms Scale (PASS-20):
 Preliminary development and validity. Pain Research and Management 2002;7:45-50.

 30. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand
 1983;67:361-70.

 31. Bjelland I, Dahl AA, Haug TT, Neckelmann D. The validity of the Hospital Anxiety and
 Depression Scale. An updated literature review. J Psychosom Res 2002;52:69-77.

 32. Herrmann C. International experiences with the Hospital Anxiety and Depression Scale--a
 review of validation data and clinical results. J Psychosom Res 1997;42:17-41.

 33. Snaith RP. The Hospital Anxiety And Depression Scale. Health Qual Life Outcomes
 2003;1:29.

 34. Gotay CC. Assessing cancer-related quality of life across a spectrum of applications. J
 Natl Cancer Inst Monogr 2004:126-33.

 35. Fletcher A. Quality-of-life measurements in the evaluation of treatment: proposed
 guidelines. Br J Clin Pharmacol 1995;39:217-22.

 36. Herr HW. Quality of life in prostate cancer patients. CA Cancer J Clin 1997;47:207-17.

 37. Fossa SD. Good quality of life in prostate cancer patients: how can it be obtained?
 Scand J Urol Nephrol Suppl 1999;203:51-2.

 38. Hopman WM, Towheed T, Anastassiades T et al. Canadian normative data for the SF-36
 health survey. Canadian Multicentre Osteoporosis Study Research Group. Cmaj
 2000;163:265-71.

 39. Lofland JH. Measuring Patients' Health-Related Quality of LIfe: Practical Considerations
 for Implementing an Outcomes Management Program. P & T 2002;27:209-11.

 40. Litwin MS, Hays RD, Fink A et al. The UCLA Prostate Cancer Index: development,
 reliability, and validity of a health-related quality of life measure. Med Care
 1998;36:1002-12.

 41. McNaughton-Collins M, Walker-Corkery E, Barry MJ. Health-related quality of life,
 satisfaction, and economic outcome measures in studies of prostate cancer screening and
 treatment, 1990-2000. J Natl Cancer Inst Monogr 2004:78-101.

 42. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad
 Med Singapore 1994;23:129-38.

 43. Tittle MB, McMillan SC, Hagan S. Validating the brief pain inventory for use with
 surgical patients with cancer. Oncol Nurs Forum 2003;30:325-30.

 44. Strassels SA, mcNicol E, Wagner AK et al. Persistent Postoperative Pain, Health-Related
 Quality of LIfe, and Functioning 1 Month After Hospital Discharge. Acute Pain
 2004;6:95-104.

 45. Wu CL, Naqibuddin M, Rowlingson AJ et al. The effect of pain on health-related quality
 of life in the immediate postoperative period. Anesth Analg 2003;97:1078-85, table of
 contents.

 46. VanDenKerkhof EG, Hopman WM, Towheed T et al. Pain, health-related quality of life and
 health care utilization after inpatient surgery: a pilot study. Pain Res Manag
 2006;11:41-7.
Inclusion Criteria:

 -  Undergoing radical prostatectomy

 -  Able to read and write english (assistance is allowed)

 -  Normal creatinine blood serum level

 -  No known allergies to study medications

 Exclusion Criteria:

 -  Patients not providing informed consent

 -  Patients less than 18 years of age or greater than 75 years of age

 -  Known allergy to any of the medications being used

 -  History of drug or alcohol abuse

 -  Preoperative pain

 -  Patients unable or unwilling to use PCA

 -  Patients with impaired renal function (Creatinine >106)