Clinical Trial of Gabapentin to Decrease Postoperative Delirium and Pain

• ClinicalTrials.gov Identifier: NCT00221338
• Recruitment Status: Completed
• First Posted: September 22, 2005
• Results First Posted: September 10, 2020
• Last Update Posted: September 10, 2020
• Sponsor: University of California, San Francisco
• Information provided by (Responsible Party): University of California, San Francisco

Study Description

Brief Summary:

This will be a double blind, placebo-controlled study of patients ≥65 years of age undergoing surgery of the spine, hips and knees replacement at the University of California, San Francisco (UCSF) Medical Center. Intraoperative anesthetic and postoperative pain management will be standardized. Patients will be randomized to receive either placebo or gabapentin preoperatively, and continued postoperatively until discharge. Intraoperative anesthetic and other postoperative pain management strategies will be standardized. Postoperative delirium will be measured using structured interviews. Cognitive function will be measured using a battery of neurocognitive tests pre- and post-operatively. Using an intention to treat strategy, we, the researchers at UCSF, will compare the incidence of postoperative delirium and cognitive dysfunction, the amount of postoperative pain, and narcotic requirements between the two groups. The primary outcome will be postoperative delirium. Secondary outcomes will be postoperative pain and opioids use, and length of hospital stay, and cognitive dysfunction.

Condition or disease	Intervention/treatment	Phase
Postoperative Delirium; Postoperative Pain; Opioid Use; Hospital Length of Stay	Drug: Gabapentin	Phase 3

Detailed Description:

Postoperative delirium is a common condition, occurring in 10-70% of surgical patients after major surgery. To date, few studies have examined events in the postoperative period as contributing factors to postoperative delirium. We recently completed a study in over 500 geriatric surgical patients to examine whether the mode of postoperative analgesia delivery, medication types, and the severity of postoperative pain may impact the occurrence of postoperative delirium. In this study, 46% of patients developed postoperative delirium on either the first or second postoperative day. By multivariate logistic regression, variables which had independent association with postoperative delirium included age ≥80 years, moderate to severe preoperative resting pain, and increased level of resting pain postoperatively in comparison with preoperative baseline. When the analysis was focused on patients who used Patient Controlled Analgesia (PCA) alone for postoperative pain control, the amount of narcotic used (hydromorphone) was significantly higher in those with postoperative delirium as compared to those without, suggesting that inadequate pain control and/or the central effects of opioids may be associated with postoperative delirium. Since increasing the doses of opioids in the elderly patients will likely lead to unwanted side effects such as respiratory depression, the addition of a non-opioid agent may result in a narcotic-sparing effect, and also reducing pain postoperatively.

Gabapentin is a structural analog of gamma-amino butyric acid, and has been used as an anti-convulsant and anti-nociceptive drug. It is not metabolized in humans (therefore no hepatic enzyme induction), and is eliminated from the body by renal clearance. In animal studies, gabapentin has been demonstrated to be effective in reducing both allodynia and hyperalgesia, and may have selective effect on the nociceptive process involved in central sensitization. Gabapentin has been successfully used in the treatment of neuropathic pain and other painful conditions. Recently, there is substantial evidence to suggest that gabapentin also may be useful in the treatment of postoperative pain. To date, there have been nine randomized clinical trials of gabapentin versus placebo including a total of over 700 patients. Taken together, these studies reported that gabapentin given perioperatively significantly reduced postoperative analgesic requirements, and had minimum side effects. The only reported significant side effects in these trials were mild sedation in two studies. In patients with epilepsy, gabapentin can be introduced at therapeutic doses, and presents no safety or serious side effect issues. Since gabapentin has negligible protein binding, it has no interactions with other medications. It is recommended that metabolic and laboratory monitoring is not necessary, and excellent cognitive profile is evident. At UCSF, gabapentin has been used safely in a relatively large number of patients on an empiric bases in the postoperative period, typically in surgical patients with substantial chronic pain, and more recently, in patients who have undergone spinal surgery as an adjuvant agent to narcotics to relieve postoperative radicular pain (personal communication with Peter Koo, Clinical Pharmacist at UCSF). Typically, patients are started on gabapentin 300 mg po TID on the first day, rapidly escalating to 600 mg TID on the second day, and finally to 900 mg TID the third day until discharge. The UCSF experience suggests that gabapentin is well tolerated with minimal side effects.

Hypothesis

We hypothesize that intensive pain management postoperatively using an adjuvant agent, gabapentin, will lead to a decrease in the amount of postoperative pain experienced, thereby resulting in a decrease in the incidence of postoperative delirium in older patients undergoing noncardiac surgery.

Our specific aims were to: 1. Assess whether the administration of gabapentin was associated with decreased occurrence of delirium, 2. Determine the extent to which gabapentin-associated reductions in pain and/or opiate use reduced the occurrence of delirium, and 3. Determine whether the administration of gabapentin was associated with shorter hospital stays. We hypothesized that intensive pain management postoperatively using an adjuvant agent, gabapentin, would lead to a decrease in the amount of opioids received, a decrease in postoperative pain experienced, thereby resulting in a decrease in the incidence of postoperative delirium.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 750 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Clinical Trial of Gabapentin to Decrease Postoperative Delirium and Pain in Surgical Patients
• Study Start Date: January 2006
• Actual Primary Completion Date: January 2014
• Actual Study Completion Date: July 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Gabapentin; Double blind, placebo controlled	Drug: Gabapentin; This is a Double blind, placebo-controlled experimental study in which gabapentin adjusted for renal clearance (or placebo) is given preoperatively and also the first three postoperative days; Other Name: gabapentin versus placebo
Placebo Comparator: Placebo; Double blind	Drug: Gabapentin; This is a Double blind, placebo-controlled experimental study in which gabapentin adjusted for renal clearance (or placebo) is given preoperatively and also the first three postoperative days; Other Name: gabapentin versus placebo

Outcome Measures

Primary Outcome Measures :

1. Incidence of Postoperative Delirium by Study Group [ Time Frame: postoperative days 1, 2 and 3 ]
   Number of subjects who developed postoperative delirium, as measured by the Confusion Assessment Method, a validated tool for assessing delirium based on DSM-III-R, on any of the first three postoperative days.

Secondary Outcome Measures :

1. Median Postoperative Opioid Doses Across Study Follow up Period [ Time Frame: Study follow up period: postoperative days 1, 2 and 3 ]
   Postoperative intravenous opioid doses converted to morphine equivalents. Median derived from total opioid doses on first, second and third postoperative days.
2. Hospital Length of Stay [ Time Frame: Typically within the first week after surgery ]
3. Postoperative Pain Score - Postoperative Day 1 [ Time Frame: Postoperative day 1 ]
   Postoperative pain as measured by Visual Analog Pain scale (0=no pain, 10=worst pain imaginable).
4. Postoperative Pain Score - Postoperative Day 2 [ Time Frame: Postoperative day 2 ]
   Postoperative pain as measured by Visual Analog Pain scale (0=no pain, 10=worst pain imaginable).
5. Postoperative Pain Score - Postoperative Day 3 [ Time Frame: Postoperative day 3 ]
   Postoperative pain as measured by Visual Analog Pain scale (0=no pain, 10=worst pain imaginable).

Eligibility Criteria

• Ages Eligible for Study: 65 Years and older (Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Male or female ≥65 years of age undergoing surgery involving the spine, hip or knee replacement.
• English speaking.
• Anticipated to stay in the hospital for at least 48 hours.

Exclusion Criteria:

• Patients who take gabapentin preoperatively, or have known sensitivity to the drug, or those unable to be randomized to receive gabapentin.
• Subjects who are unable to provide informed consent.
• Patients with a history of narcotic tolerance.
• Patients with planned two stage spinal procedures (anterior-posterior spinal fusion to be done on two separate days).

Contacts and Locations

Locations

United States, California

University of California, San Francisco

San Francisco, California, United States, 94143-0648

Sponsors and Collaborators

University of California, San Francisco

Investigators

• Principal Investigator: Jacqueline M Leung, MD, MPH; University of California, San Francisco, CA, USA

More Information

Publications of Results:

Leung JM, Sands LP, Rico M, Petersen KL, Rowbotham MC, Dahl JB, Ames C, Chou D, Weinstein P. Pilot clinical trial of gabapentin to decrease postoperative delirium in older patients. Neurology. 2006 Oct 10;67(7):1251-3. Epub 2006 Aug 16.

Other Publications:

Leung JM, Sands LP, Chen N, Ames C, Berven S, Bozic K, Burch S, Chou D, Covinsky K, Deviren V, Kinjo S, Kramer JH, Ries M, Tay B, Vail T, Weinstein P, Chang S, Meckler G, Newman S, Tsai T, Voss V, Youngblom E; Perioperative Medicine Research Group. Perioperative Gabapentin Does Not Reduce Postoperative Delirium in Older Surgical Patients: A Randomized Clinical Trial. Anesthesiology. 2017 Oct;127(4):633-644. doi: 10.1097/ALN.0000000000001804.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT00221338
• Other Study ID Numbers: H5636-26795-01
• First Posted: September 22, 2005
• Results First Posted: September 10, 2020
• Last Update Posted: September 10, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: Plan to share undecided

Keywords provided by University of California, San Francisco:

gabapentin; pain; surgery; delirium; cognitive decline

Additional relevant MeSH terms:

Delirium; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Gabapentin; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anticonvulsants; Anti-Anxiety Agents; Tranquilizing Agents; Central Nervous System Depressants; Psychotropic Drugs; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antimanic Agents