Pfizer Canada and the SMH ORA could not come into an agreement on responsibility to be the Importer of Record for the trial.

Objective: To compare the incidence of chronic pain at 3 months among adults undergoing craniotomy between those received two different doses of pregabalin and those receiving placebo.

Hypothesis: Perioperative pregabalin will reduce the incidence of chronic post-operative pain, and will reduce the opioid consumption, opioid-related side effects, and hospital length of stay compared with placebo in patients undergoing elective craniotomy.

Methods: 316 adults (18-65y), ASA I-III, undergoing elective craniotomy will be randomized to receive: 100mg or 150mg pregabalin or placebo once pre-operatively and 50mg or 75mg or placebo twice daily for 14 post-operative days. NRS pain scores, opioid consumption and side effects will be assessed up to 48h, and long-term pain at days 7, 14, 30, and 90. The primary analysis will involve the comparison between the 2 treatment groups together vs. placebo. A stepwise method will be used to evaluate the pairwise comparisons.

Outcomes: The primary outcome will be the incidence of chronic post-craniotomy pain at 3 mos. Important secondary outcomes are: neuropathic component of pain at 3 mos., total opioid consumption in the first 24h, and incidence and severity of opioid-related side effects at days 1, 2 and 7.

Inclusion Criteria:

• Adults, 18 to 65 years (limited to 65 years to lower the risk of over-sedation for elderly patients)
• Undergoing elective craniotomy (supratentorial or infratentorial) under general anaesthesia for: biopsy or resection of a tumour, clipping of an unruptured aneurysm, or excision of an arteriovenous malformation
• ASA physical status I-III

Exclusion Criteria:

• predicted need for prolonged post-operative ventilation (> 12 hours)
• chronic pain secondary to previous craniotomy
• known adverse reaction to drugs used (gabapentin, pregabalin, hydromorphone, and/or acetaminophen)
• prior use of pregabalin or gabapentin (within 2 weeks before surgery)
• current history of moderate to severe headaches (NRS ≥ 4) related to intracranial pathology (tumour pain) since it may be difficult to discriminate between ongoing tumour pain and surgery-related post-operative pain
• current history of migraines
• pre-existing chronic pain requiring chronic opioid use (30mg morphine equivalent within 4 weeks of surgery)
• currently taking any drug that could interact with pregabalin
• current history of alcohol or recreational drug abuse
• known or suspected addiction to narcotic substances or chronic narcotic use in the last 2 weeks
• history of malignant hyperthermia (contraindicates the anaesthesia protocol of this study)
• history of angioedema
• Body Mass Index ≤ 18.4 or ≥ 35
• history of untreated obstructive sleep apnea
• any condition that would contraindicate the use of patient-controlled analgesia (PCA)
• lacks fluency in English
• pre-existing renal impairment (for pregabalin elimination)
• pregnancy