Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
Condition: Prostate Cancer
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.

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Intervention name(s): Gabapentin; Placebo Sugar Pill
Intervention type(s): Drug; Drug
Intervention description(s): 200mg 3x/day for 3 days (9 doses total)
Other intervention name(s): Neurontin
Intervention MeSH terms: Gabapentin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: gabapentin; opioid consumption; analgesic; anxiety; quality of life