Evaluating the Role of Pregabalin in Reducing Opioid Requirement in Spinal Fusion Surgeries of Two or More Vertebrae

Phase 3

Terminated

Conditions: Spinal Fusion

Interventions: Other: placebo
Drug: Pregabalin

Registration Number: NCT03031340

Lead Sponsor: Montefiore Medical Center

Brief Summary: To see if the administration of 3 dosses of pregabalin (1 dose preoperative, 2 doses postoperative) will reduce the postoperative opiate requirements of patients undergoing spinal fusion surgeries of two or more vertebrae.

Detailed Description: Introduction

Postoperative pain is often thought to be inadequately treated in half of all surgical procedures . Postoperative pain management in patients undergoing spine surgery is often difficult and challenging. The challenges of opioid tolerance and paucity of efficient opioid sparing agents makes pain management even more complex. Preoperative strategies that can minimize postoperative pain include proper surgical technique, which would avoid or lessen nerve injury, and the use of preemptive analgesia. Studies have shown that the intensity of acute postoperative pain correlates with the risk of developing persistent pain. Post operative pain results from the direct activation of nociceptors, inflammation, and in some cases direct nerve injury to the nerves.

The data on preemptive analgesia are inconclusive . The concept, however, has sparked interest in mechanism-based analgesia and highlighted the process of central sensitization as a target for analgesic intervention .

The use of opioids is limited by their side effect profile and by the poor response of certain types of pain . The multiplicity of mechanisms involved in pain suggests that combination of opioid and non-opioid analgesic drugs will enhance analgesia. The concomitant reduction in opioid requirements, anticipated with the use of multimodal therapy, can also be expected to reduce side effects.

Pregabalin is a lipophilic gamma-amino-butyric acid (GABA) analog with anticonvulsant, anxiolytic and sleep-modulating properties. The effectiveness of pregabalin has been demonstrated in several pain models including neuropathic pain , , incisional injury and inflammation . Several previous studies conducted found that the use of gabapentin, the predecessor of pregabalin, reduced post operative pain and opioid requirements and decreased the number of opioid related adverse events , . Pregabalin is the pharmacologically active S enantiomer of 3-aminomethyl-5-methyl hexanoic acid; it has a similar pharmacological profile to gabapentin . Like gabapentin, pregabalin also binds to the α-2-δ subunit of voltage gated calcium channels, reducing the release of excitatory neurotransmitters: glutamate, norepinephrine, serotonin, dopamine and substance-P. It blocks the development of hyperalgesia and inhibits central sensitization , . Pregabalin has greater absorption, bioavailability, anticonvulsant, anti-hyperalgesic and anxiolytic properties than gabapentin , .

Rationale for selecting spine surgeries. Low back pain is a major medical problem and a significant source of disability for people under 45 years of age . Spine surgeries are considered to be among the most complex, and long-lasting. The postoperative period is particularly challenging for efficient pain management. Postoperative pain may be due to nociceptive pain as well as hyperalgesia secondary to surgical trauma. Central sensitization is a key mechanism in the development and maintenance of chronic pain, particularly for neuropathic pain and pain after spine surgery .

Rationale for using pregabalin

Animal studies in surgical pain models and clinical studies of inflammatory pain in volunteers demonstrated that both of these interventions can cause allodynia and hyperalgesia- these are both susceptible to pregabalin and its analogues , .

The sensitization of dorsal horn neurons has been demonstrated in acute pain models and may be responsible for the development of chronic pain after surgery , , . The ability of pregabalin to reduce the hyperexcitability of dorsal neurons induced by tissue damage confirms its role in preemptive analgesia . Its anxiolytic effect and ability to prevent opioid tolerance could also be beneficial . Alternately, antihyperalgesia drugs like pregabalin may block pathological pain, while leaving the physiological pain (with its protective function) intact. This class of agents function through opiate independent pathways and do not affect gut motility .

Pharmacodynamics and Pharmacokinetics:

Pregabalin is an FDA-approved drug available in 50-300 mg/day (the FDA-recommended maximum is 300mg/day). It is rapidly absorbed following oral administration with peak plasma concentration occurring between 0.7-1.3hrs. The mean oral bioavailability is 90% after 1-300mg of single oral dose. The elimination half-life is 5.5-6.5 hrs independent of dose and repeated administration. Plasma clearance is essentially equivalent to renal clearance. The elimination rate is nearly proportional to creatinine clearance and dose reduction is recommended in patients with low creatinine clearance. Ninety percent of the dose is excreted in the urine .

Adverse events of pregabalin Pregabalin is generally well tolerated and associated with mild to moderate adverse events which are dose dependent. The most frequently reported (22-29%) are dizziness and somnolence. Other less common adverse events reported are dry mouth, peripheral edema, blurred vision and inability to concentrate .

Hypothesis:

Our hypothesis is that pre-operative administration of pregabalin can reduce the central neural sensitization, efficiently reverse inflammatory hyperalgesia and can cause opioid sparing effect. These actions of pregabalin will reduce the amount of opioids need by the patient intraoperatively and in the immediate postoperative period. The reduction of opioids will lessen opioid related adverse events and will augment the perioperative satisfaction level.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 3

Inclusion Criteria

Age : > 18 years old
Fusion of > two vertebrae
Capacity to provide consent
ASA I-IV
Ability to swallow capsules

Exclusion Criteria

Plan of care includes intubated ICU admission post-op
Allergy to gabapentin or pregabalin
Two week prior use of pregabalin
Significant renal dysfunction (creatinine level >2)
Severe cardiovascular disease
History of frequent headaches or dizziness
Significant hepatic dysfunction (LFT's > 4 times the normal ranges)
Active usage of alcohol or illicit substances three days prior to surgery
History of seizure disorders
Taking medication for anxiety, antiseizure, and psychiatric diagnoses
Re-operation patients

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	placebo	-
Pregabalin	Pregabalin	-

Primary Outcome Measures

Name	Time	Method
Postoperative Opioid Requirement	48 hours	The primary objective of this study is to evaluate the role of three doses of pregabalin on intra and postoperative (48hrs) opioid requirements in patients undergoing fusion of two or more vertebrae.

Secondary Outcome Measures

Name	Time	Method
Pain Using the Visual Analog Scale (VAS) Pain Score	2 hours, 24 hours, 48 hours	evaluate pain using the visual analog scale (VAS) pain score at two hrs post-op, the morning following surgery 24 hours and 48 hours post-op
Post Operative Cognitive Function	48 hours	48 hours post operative headache, dizziness, sedation and blurred vision
Pre-operative Anxiety	24 hours prior to surgery	Measure the level of pre-operative anxiety using the visual analog scale (VAS)
Anesthesia Satisfaction	24 hours post surgery	To measure the level of overall anesthesia satisfaction among the two groups at discharge.
Incidence of 48 Hours Post Operative Nausea and Vomiting	48 hours	Find the incidence of 48 hours post operative nausea and vomiting in the target population