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

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.

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