Prospective Randomized Trial of Patient-Controlled Analgesia

2 Dec



Morphine is commonly used as an analgesic for the control of postoperative pain and is the “gold stan­dard” against which all other analgesics are compared. Morphine acts mainly as an agonist at specific receptor sites in the central nervous system. Evidence suggests that both hyperanalgesic effects after tissue injury and opioid tolerance involve activation of the Л-methyl- D-aspartate (NMDA) receptor and subsequent biochem­ical processes that result in central sensitization. Morphine also causes many undesirable side effects, including nausea and vomiting through direct stimulation of the chemoreceptor trigger zone.

Ketamine, an NMDA receptor antagonist, has both analgesic and anesthetic effects. The mechanisms by which it enhances analgesic effects probably occur within the dorsal horn of the spinal cord. The dorsal horn neuron has both p-opioid and NMDA-receptors. Ketamine blocks the NMDA receptors, reducing central sensitization, while also producing opioid-sparing effects. At normal anesthetic doses, ketamine produces undesirable psychotomimetic effects (dizziness, hallucinations, and dreams), but lower doses are postulated to generate fewer side effects. The addition of low-dose ketamine to morphine for patient-controlled analgesia (PCA) is not a novel idea and has been studied by other researchers. In 1996, Javery and others suggested that low-dose ketamine added to morphine might yield a morphine-sparing effect without psychotomimetic effects. Their research sparked interest in using an old drug in a new way; however, that study was limited to patients undergoing microdiskectomy, a rare surgical procedure. Those authors used PCA to deliver the opioid agents, a method that has gained prominence in the surgical field. This technique allows patients to self-administer preset amounts of drugs by a syringe pump that interfaces electronically with a timing device. Using this technique, the patients can balance pain control with sedation.
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Abdominal hysterectomy is commonly performed at the authors’ institution. Because of postoperative pain, patients who have undergone this procedure usually require large doses of opioids, and the drugs are commonly administered by PCA.
The data for the study reported here were collected in 2001. To check whether other similar studies had been done in the interim, we updated our literature search for the period 2002 to 2007 and found 2 studies involving the combination of ketamine and morphine. In 2004, Subramaniam and others concluded that low-dose ketamine was a safe and useful adjuvant to standard opioid analgesia. In the same year, Schulte and others reported that the combination of low-dose ketamine and morphine led to synergistic analgesic effects. Although both groups of researchers reported positive outcomes and a synergistic effect when ketamine was added to morphine, we felt that publishing the findings of our own study would still be relevant, as these results provide valuable information for a specific group of patients (women undergoing hysterectomy).

The purpose of this prospective double-blind, randomized study was to examine whether the combi­nation of low-dose ketamine and morphine (in a 1:1 ratio) delivered by PCA would be associated with superior analgesic efficacy (i.e., less pain) than morphine alone, also delivered by PCA. In addition, the outcomes of nausea and vomiting, sedation, dizziness, hallucinations, nightmares, dreams, and lower drug usage were compared between the 2 treatment groups.
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