Safety and efficacy of intranasal ketamine for acute postoperative pain
Introduction
Ketamine is a noncompetitive, nonopioid, N-methyl-d-aspartate (NMDA) receptor antagonist. Its pharmacologic action is characterised by anaesthetic, analgesic, and amnesic properties [1], [2]. Marketed in the United States as ketamine hydrochloride injection (Ketalar®, King Pharmaceuticals, Inc., Bristol, TN), ketamine is indicated for use as an anaesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation. Ketamine has demonstrated a wide margin of safety since its introduction into clinical practice more than 30 years ago.
A substantial clinical literature documents ketamine's use at subanaesthetic doses as a safe and effective analgesic agent in acute [3] and chronic pain including cancer pain [4]. Several publications have described the intranasal administration of ketamine [5], [6], [7]. Low doses of ketamine (administered intranasally or otherwise) have been used as an anaesthetic premedication and to treat neuropathic pain, phantom limb pain, postoperative pain, and acute traumatic pain [8]. Moreover, low (analgesic rather than anaesthetic) doses of ketamine have long been used in post-burn patients to control pain during dressing changes [9]. In addition to its reported analgesic effectiveness, ketamine has little impact upon cardiovascular and respiratory function in physiologically compromised populations.
An intranasal (IN) formulation of ketamine hydrochloride has been developed by Javelin Pharmaceuticals. The physiology of the nasal mucosa makes it an ideal environment for rapid, non-invasive delivery of systemic drugs [10]. The large surface area, uniform temperature, high permeability, and extensive vascularity of the nasal mucosa facilitate rapid absorption of drugs into the bloodstream [11]. A number of drugs, including vasopressin, opiates, antihistamines, and corticosteroids, are effectively administered intranasally (e.g., budesonide, triamcinolone, butorphanol, sumatriptan, mometasone, beclomethasone). IN ketamine administration can provide analgesic blood levels of ketamine and is being investigated for the treatment of various types of pain, including breakthrough pain in patients with cancer and acute pain such as postoperative or trauma pain.
Pain following molar extraction is a well-recognised model of acute postoperative pain that has been widely applied in analgesic drug trials [12], [13]. The present dose-ranging, pilot, single-dose study evaluated the safety and analgesic efficacy of three doses of IN ketamine (10 mg, 30 mg, or 50 mg) in patients with postoperative pain after molar extraction.
Section snippets
Patient population
Healthy patients aged 16 years or older and weighing ≥50 kg were eligible if they required two or more third molar extractions, one of which was at least partially embedded in the mandibular bone. Female patients had to be postmenopausal, physically incapable of childbearing (e.g., post-hysterectomy), or practicing an acceptable method of birth control. Female patients of childbearing potential had to have a negative pregnancy test. All patients had to demonstrate the ability to properly use the
Patients and patient demographics
A total of 40 patients were enrolled with 10 patients in each of the four treatment groups. All patients received their assigned dose, with a single exception. As described in greater detail in the Results section, one patient in the IN ketamine 50 mg group did not administer the fifth spray of medication due to an elevated heart rate (per protocol, dosing was stopped), and therefore received only four sprays (40 mg) of IN ketamine. This patient completed all study assessments, and this patient's
Discussion
Intranasal delivery of ketamine represents a simple, needle-free, easily accessible, patient-friendly route of administration in contrast to painful intramuscular injections and/or cumbersome intravenous delivery [16]. In the present randomised, double-blind study, the safety and efficacy of an intranasal formulation of ketamine were evaluated and compared to placebo.
Despite the small sample size, the primary endpoint of TOTPAR3 was statistically superior to placebo for the highest dose of IN
Conflict of interest
This study was sponsored by Javelin Pharmaceuticals, Inc., Cambridge, MA (formerly Innovative Drug Delivery Systems, Inc.).
Acknowledgement
The authors wish to thank COL Robert H. Vandre, Director, Combat Casualty Care Research, US Army Medical Research & Materiel Command, for his support and encouragement of our development of intranasal ketamine for acute pain.
Grant support: This study was funded by a contract from the United States Department of Defense, DAMD 17-00-1-1712.
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