Clinical trial NCT03334903
Conditions: Knee Osteoarthritis Knee Pain Chronic Opioid Use Opioid Dependence
Keywords: Total Knee Arthroplasty Neurontin Gabapentin Opioid Tapering
Sponsor: Brigham and Women's Hospital
Start date: 2018-05-15; Completion date: 2019-04-24
Enrollment: 77 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the best strategy of administering gabapentin in connection with our current approach to perioperative pain management. We aim to evaluate two different adjunct gabapentin regimens given in the perioperative period, and to identify which manages patient pain more effectively and safely. In this evaluation, we will identify the quantity of patients' opioid consumption, the quality of their pain management, and the frequency and severity of any side effects they might experience.

Patients who are undergoing total knee replacement (TKR) and choose to participate will be randomly assigned to a treatment group using computer-generated randomization. Patients in group 1 (the control group) will receive the standard of care as pertains to gabapentin. This consists of a single 600 mg dose of gabapentin administered to the patient approximately one to two hours before surgery, then a dose of 600 mg each morning during postoperative admission. Patients in Group 2 will receive 600 mg preoperatively, plus an additional postoperative gabapentin regimen: they will take 300 mg of gabapentin every 8 hours for 1 week, then a single nightly dose of 300 mg for another month.

Detailed description:
The purpose of this study is to determine the best strategy of administering gabapentin in connection with our current approach to perioperative pain management. We aim to evaluate two different adjunct gabapentin regimens given in the perioperative period, and to identify which manages patient pain more effectively and safely. In this evaluation, we will identify the quantity of patients' opioid consumption, the quality of their pain management, and the frequency and severity of any side effects they might experience. The target enrollment is 68.

Patients who are undergoing total knee replacement (TKR) at Brigham and Women's Hospital will be informed about the study and asked whether they would like to participate. Upon agreement, a patient will sign his/her consent and will be assigned to a treatment group. Patients in group 1 (the control group) will receive the standard of care as pertains to gabapentin. This consists of a single 600 mg dose of gabapentin administered to the patient approximately one to two hours before surgery, then a dose of 600 mg each morning during postoperative admission. Patients in Group 2 will receive 600 mg preoperatively, plus an additional postoperative gabapentin regimen: they will take 300 mg of gabapentin every 8 hours for 1 week, then a single nightly dose of 300 mg for another month.

Every patient being discharged from the hospital will receive from the nursing staff verbal and written instructions - the latter of which will be either printed or in electronic form - about narcotic medications. The instructions will explain when to use such medications and how to taper off their consumption. Following discharge, patients will take gabapentin as directed by their discharge instructions, and in the process track their opioid consumption on their own in their diaries. They will also document their pain, nausea and satisfaction levels according to the visual analogue scale (VAS). At the first post-operative appointment, patients' levels of opioid use will be verified and compared to the amount recorded in each diary; the actual number of tablets consumed will be compared with the documented amounts and with the prescriptions they received. Patients receiving a new prescription will also receive a matching diary for the total length of opioid treatment, including further directions on how to wean themselves off their medications. Outcome measures will be collected at both post-operative visits, the first occurring 8-10 days after surgery and the second 2-3 months following. Additional data including length of stay, postoperative complications including infection and readmission, Emergency Department visits, and routinely collected postoperative functional outcome measures (PROMs) will be recorded.

The Principal Investigator (PI) will review all drug consumption data and patient-reported outcome measures with the research assistant (RA) on a monthly basis as it is collected. The PI will participate in the collection of outcome data at the first and second postoperative visits. Data which could indicate a potential complication, whether related to the study or not - such as heightened risk of adverse outcomes or non-compliance with the tracking diary - will be addressed by the PI immediately. The PI will determine if the study should be altered in any way or stopped for safety reasons. Reasons for stoppage include a rate of adverse events greater than 10% in either group. Adverse events of primary concern include:

* Excessive sleepiness
* Allergic reactions to the opioid medications or gabapentin

All adverse events are recorded in an adverse event log, which will be kept by the RA throughout the study. The PI will review the data on a monthly basis, as well as whenever the RA alerts the PI to any potential adverse event. These checks will help to ensure validity and patient safety. Unanticipated problems will be reported to the PHRC in accordance with PHRC guidelines.

Arms: arm 1: Standard of care includes one dose of 600 mg gabapentin in the immediate preoperative period (1-2 hours before surgery), then a dose of 600 mg each morning during postoperative admission. arm 2: Single preoperative dose of 600 mg, as described above, plus an additional postoperative regimen. Patients will take 300 mg gabapentin every 8 hours for 1 week after discharge, then a single nightly dose of 300 mg gabapentin for another month.
Interventions: intervention 1: Gabapentin
Intervention descriptions: intervention 1: 600 mg gabapentin before and after surgery. 300 mg gabapentin for approx. 5 weeks after surgery.

Protocol documents:
Prot_SAP_000.pdf: 
Gabapentin Regimens and Their Effects on Opioid Consumption 
 
A randomized controlled trial 
 
Version Date: 3/20/2018 
 
 
Background and Significance  
 
Gabapentin is a first-line therapy for treating neuropathic pain in adults, and is also well known 
as a treatment for epileptic seizures.  Its exact mechanism of effect remains uncertain [1], but 
gabapentin has been found to reduce acute pain on its own [2–3], to limit cravings and symptoms 
of withdrawal in people addicted to substances [4–6], and to decrease nausea [7–8]. 
Perhaps gabapentin’s greatest benefit is to decrease opioid use in patients as they recover from 
surgery.  Patients who take gabapentin in conjunction with opioids after surgery, or even in the 
two-hour window beforehand [9–18], take fewer opioid medications and experience little to no 
side-effects during the recovery process [19–24]. 
We wanted to determine the best strategy of administering gabapentin in connection with our 
current approach to perioperative pain management.  We wanted to balance gabapentin’s 
obvious usefulness with its own side effects; gabapentin can cause drowsiness and unsteady 
bearing [11, 15–18] and poses its own small risk of addiction and abuse [24].  We therefore 
propose a two-armed trial to evaluate different adjunct gabapentin regimens given in the 
perioperative period, and to identify which manages patient pain most effectively and safely.  In 
this evaluation, we will identify the quantity of patients’ opioid consumption, the quality of their 
pain management, and the frequency and severity of any side effects they might experience. 
 
Specific Aims 
 
With this project, we intend to determine whether administering a regimen of gabapentin after 
surgery can reduce opioid consumption more effectively than the standard of care, which is a 
single preoperative dose of 600 mg, followed by a dose of 600 mg each morning during 
postoperative admission.  The experimental regimen would add one week of standing gabapentin 
followed by a month of nightly doses.  Furthermore, we would like to know more about 
gabapentin’s potential to cause drowsiness in patients and whether it has any effect on their 
ability to sleep after surgery.  Finally, we want to know how long patients remain on gabapentin 
after surgery. 
 
 
Subject Selection 
 
Inclusion Criteria: 
- 
At least 18 years of age 
- 
Receiving surgery for total knee replacement (TKR)  
- 
Opioid naïve 


- 
Agrees to use tracking diary to monitor opioid consumption 
 
Exclusion Criteria:  
- 
Over 75 years of age on the date of surgery 
- 
If female, pregnant 
- 
Has received investigational articles < 30 days prior to enrollment or is currently 
receiving investigational products or devices 
- 
Chronic pain syndrome 
- 
Taking chronic narcotics and/or taking more than 10 mg of codeine per day, any amount 
of Hydrocodone, over 200 mg of tramadol per day, or any other narcotics prescribed for 
moderate or severe pain 
- 
Involved in pain clinics for chronic pain, or pain that is not related to the surgical site 
- 
On long-term gabapentin regimen 
- 
Taking Lyrica or Gralise 
- 
Known history of depression or has been treated for depression with medication 
- 
Has entertained suicidal thoughts and behaviors 
 
 
Subject Enrollment 
 
Patients who schedule total knee replacement (TKR) with Dr. Wolfgang Fitz at Brigham and 
Women’s Faulkner Hospital and meet all eligibility criteria will be informed about the study 
during their preoperative appointment.  Specific topics discussed will included an introduction to 
the patient-maintained diary to document narcotic medications, and the PI’s use of gabapentin 
for his surgical patients.  All patients will be offered the chance to discuss with both the RA and 
the Principal Investigator (PI) and ask questions.  
  
Each qualifying patient will be sent a letter describing the study and asking the patient to 
consider participating.  After a reasonable elapse of time, the RA will call the patient by phone 
and ask whether the patient agrees to participate.  The patient’s response to this request will be 
recorded in research records.  During this phone call, the RA will confirm that the patient meets 
the inclusion criteria and does not meet any exclusion criterion.  If, later in the study, a patient 
meets any one of the exclusion criteria, he or she will be removed from the study.   
 
Patients’ informed consent will be obtained by the research assistant(s) when they come to the 
hospital for pre-op testing.  If this is somehow impossible, written informed consent may be 
obtained in preoperative holding before surgery.  Upon giving consent, the patient will be 
randomly assigned to a treatment group using computer-generated randomization. 
 
The study will have two treatment arms: 
 
Patients in Group 1 will receive the standard of care as pertains to gabapentin.  This consists of a 
single 600 mg dose of gabapentin administered to the patient approximately one to two hours 
before surgery, then a dose of 600 mg each morning during postoperative admission.   
 


Patients in Group 2 will receive the above standard of care, plus an additional home regimen: 
they will take 300 mg of gabapentin every 8 hours for 1 week, then a single nightly dose of 300 
mg for another month. 
 
Patients in both groups will record the amount of pain medications they consume and answer 
enclosed VAS scales every day in a tracking diary. 
 
 
Study Procedures 
 
Every patient being discharged from the hospital will receive from the nursing staff verbal and 
written instructions — the latter of which will be either printed or in electronic form — about 
narcotic medications.  The instructions will explain when to use opioid medications and how to 
taper off their consumption.  Following discharge, patients will take gabapentin as directed by 
their discharge instructions, and in the process track their opioid consumption on their own in 
their diaries.  They will also document their pain, nausea and satisfaction levels according to the 
visual analogue scale (VAS).   
 
At the first post-operative appointment, approximately 9–10 days following surgery, patients’ 
levels of opioid use will be verified and compared to the amount recorded in each diary; the 
actual number of tablets consumed will be compared with the documented amounts and with the 
prescriptions they received.  Patients receiving a new prescription will also receive a matching 
diary for the total length of opioid treatment, including further directions on how to wean 
themselves off their opioid medications.  
 
Our primary outcome measures will be the amount of patients’ opioid consumption, calculated in 
total doses of morphine equivalent, and the total number of days the patients took opioids.  Our 
secondary outcome measures will be VAS scores for surgical site pain (both at rest and during 
physical activity), nausea, sleep quality, and satisfaction with pain management — all of which 
are reported on a daily basis within the tracking diary.  Tertiary outcome measures will be the 
number of patients who are taking gabapentin beyond the length of time prescribed by the study, 
measured at the second postoperative visit 2–3 months after surgery.  
 
Additional data including length of stay, postoperative complications including infection and 
readmission, ED visits and routinely collected postoperative functional outcome measures 
(PROMS) will be recorded.  
 
 
Biostatistical Analysis 
 
We will be comparing the two arms of the trial to see whether there exists a statistically 
significant difference between them.  Variables in which we are interested include total opioid 
consumption, the amount of days spent using opioids, and the amount of days spent taking 
gabapentin.  We will also record the other outcome measures detailed in the previous section.  
When comparing the branches, all analyses will be run at a type I error rate of 5%. 
 


The study will end once we have enrolled the requisite number of patients in the study and taken 
the diary-based data from them.  According to previous literature on the opioid-sparing effects of 
gabapentin, experimental groups tend to consume anywhere between 20% and 50% fewer opioid 
medications than control groups, with the average approximately 35%, and standard deviation 
approximately half the mean [9, 22, 23, 25].  Powering the study to detect this approximate 
difference, the total number of patients will be 68, with 34 in each arm. 
 
 
Risks and Discomforts 
 
Members of both interventions are at the standard risk for TKR patients for long-lasting opioid 
dependence following surgery, which can be about 8%.  Patients who attempt taper off their 
medications too quickly are at risk of experiencing acute post-operative pain.  Patients in the 
intervention group, who will be administered gabapentin for a greater length of time, may be at 
greater risk for gabapentin dependence than members of the control group. 
 
 
Potential Benefits 
 
While we do not guarantee benefits to participation, it is possible that the members of our 
intervention group may taper off their narcotic medications more quickly and more successfully 
than those who receive our standard of care, thus lessening their risk of long-term dependence on 
the medications.  This could result in increased health and satisfaction.  
 
We hope that finding an optimal gabapentin regimen can help patients reduce their narcotic 
consumption after total knee replacements, which will reduce their risk of becoming dependent 
on narcotics for pain management.  Results of the study thus may help improve medication 
regimens for future patients. 
 
 
Monitoring and Quality Assurance  
 
The principal investigator will take responsibility for regular reviews of the study’s progress and 
any concerns regarding subject safety.  Study progress including data completion and entry will 
be discussed at protocol meetings to be held as needed during the duration of the protocol 
activity.  The principal investigator will report adverse events or other unanticipated problems to 
PHRC as described in the PHRC policy on Adverse Event Reporting and Unanticipated 
Problems Involving Risks to Subjects or Others. 
 
Adverse events will be reported immediately to the PI and to the IRB in accordance with the IRB 
adverse event reporting guidelines. 
 
The principal investigator is responsible for adherence to all IRB rules and guidelines.  The 
research coordinator will be responsible for the accuracy and completeness of all forms, entries, 
and informed consent.  As an added quality assurance measure, study staff will hold monthly 
meetings to ensure that adherence to protocol is maintained by all of the study staff as well as to 


monitor the status and quality of the study.  Subject data will be kept on a protocol-specific, 
password-protected, Partners Healthcare System-maintained computer that is kept in a locked 
office.  PHS computers maintain the latest anti-virus software and firewall protections. 
 
Patients will be identified only by an identification code, and not by their name, SSN, or hospital 
medical record number.  Research staff will maintain a separate confidential enrollment log 
which matches identifying codes with the patients’ names and addresses available only to IRB-
approved study staff.  
 
All study forms, reports, and other records that are part of the study data collection materials will 
be identified by coded number to maintain patient confidentiality.  All paper records will be kept 
in locked file cabinets.  All electronic records of study data will be identified by coded number. 


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