Sedative-Hypnotics

Benzodiazepines potentiate the effects of opioids and decrease opioid requirements for loss of consciousness, often in a synergistic fashion.^{[518] [519]} On the contrary, concerning the antinociceptive effect, interaction between these two types of drugs may be less than additive.^{[520] [521]} Midazolam enhances opioid-induced antinociception at the spinal level but inhibits it at the supraspinal level.^[522] Studies have shown that benzodiazepine-opioid interactions for many properties other than analgesia are synergistic (supra-additive).^[523] Both the cardiovascular and the respiratory actions of opioids can be significantly altered by the concomitant administration of benzodiazepines.^[524] Combinations of benzodiazepines and opioids, although occasionally preserving ventricular function, can cause significant and occasionally profound decreases in blood pressure, cardiac index, heart rate, and systemic vascular resistance.^{[124] [525]} Fluid loading may attenuate circulatory depression that occurs when benzodiazepines and opioids are combined.

Either thiopental or propofol can be employed safely in combination with opioids. However, either drug can potentiate or produce hypotension if too large a dose is administered.^[526] Hypotension after barbiturate-opioid combinations is due to venodilatation and decreased cardiac filling. Other mechanisms include myocardial depression and decreased sympathetic nervous system activity. Reducing induction doses of barbiturates administered concomitantly with opioids is recommended. The administration of propofol-opioid combinations provides unconsciousness and blocks responses to noxious stimuli, whereas neither drug alone reliably does both. Propofol-fentanyl and propofol-sufentanil anesthesia for coronary artery bypass surgery may provide acceptable conditions, but mean arterial pressure can decrease to levels that may jeopardize coronary perfusion, especially during the induction of anesthesia.^{[527] [528]} In healthy volunteers, the addition of alfentanil (effect site concentration of 50 or 100 ng/mL) did not affect the changes in the BIS induced by propofol, but blocked BIS increase induced by painful stimuli.^[529] In patients undergoing spine fusion, infusion of fentanyl to blood levels of 1.5 to 4.5 ng/mL reduced the infusion rate of propofol necessary to stabilize mean arterial pressure but delayed spontaneous eye opening and recovery of orientation.^[530] In patients undergoing ambulatory gynecologic laparoscopy, the administration of fentanyl (100 µg IV) at the time of anesthetic induction reduced maintenance propofol requirement, but failed to provide effective postoperative analgesia and increased the need for postoperative use of antiemetics.^[531]

Other anesthetic induction agents such as etomidate and ketamine can be combined in low doses with opioids with little loss of cardiovascular stability. In patients scheduled for coronary artery bypass grafting, etomidate (0.25 mg/kg) plus fentanyl (6 µg/kg) resulted in less hypotension after induction and intubation than propofol (1 mg/kg) plus fentanyl (6 µg/kg).^[532] As described previously, it was reported that opioid-induced hyperalgesia and subsequent acute opioid tolerance can be prevented by ketamine in rats, suggesting the usefulness of a combination of ketamine and opioids for postoperative analgesia. However, it was shown that the combination of ketamine (2.5 or 10 mg IV) and alfentanil (0.25 or 1 mg IV) provided no advantage over a larger dose of either drug alone in relieving pain caused by intradermal capsaicin injection in healthy volunteers.^[533] Furthermore, the combination of ketamine (1 mg/mL) and morphine (1 mg/mL) for PCA did not provide benefit to patients undergoing major abdominal surgery.^[534] In contrast, Lauretti and associates reported that oral ketamine and transdermal nitroglycerine effectively reduced the daily consumption of oral morphine in patients with cancer pain.^[535]

Gabapentin, a structural analog of γ-aminobutyric acid, is a novel anticonvulsant drug, and has analgesic effects on neuropathic pain. One study suggests that both pharmacodynamic and pharmacokinetic interactions between morphine and gabapentin lead to increased analgesic effects.^[536] Gamma-aminobutyric acid-A (GABA_A ) receptors contribute to inhibitory control at the spinal cord level. Intrathecal administration of muscimol or baclofen (the GABA_A and GABA_B receptor agonists, respectively)

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