Phase Ia and Ib Study of Amitriptyline for Ulnar Nerve Block in Humans: Side Effects and Efficacy

Background: The antidepressant amitriptyline is used as an adjuvant in the treatment of chronic pain conditions. Among its many actions, this drug also blocks ion channels, such as Na+ channels. Preliminary animal studies suggested that amitripty-line would be a longer-lasting local anesthetic than bupivacaine, with potentially fewer side effects. Therefore, the authors investigated the adverse effects and effectiveness of this drug when given for ulnar nerve blockade in human volunteers.

Methods: After obtaining written institutional review board approval and informed consent, a typical phase Ia trial was conducted by administration to the ulnar nerve at the level of the wrist in an open-label, dose-escalating fashion. Amitripty-line hydrochloride, 4 ml, at concentrations of 5, 10, and 20 mM (n = 4-9/group) was used for each volunteer. If no major side effects and nerve block were encountered, comparison in a randomized, double-blinded trial of amitriptyline (20 mM) to placebo and bupivacaine (4 mm) (n = 4-9/group), was to follow. A blunt needle was used to grade the pain, and motor blockade was assessed by the Froment test.

Results: There was no significant statistical difference in terms of side effects (pain, swelling, erythema, and sedation) among any groups. The analgesic effects of 20 mM amitriptyline and 4 mm bupivacaine solution were significantly higher than those of the placebo solution.     

Doxepin by topical application and intrathecal route in rats

The tricyclic antidepressant, doxepin, has been reported to be a potent local anesthetic in rat sciatic nerve blockade. We hypothesized that topical doxepin has significantly longer antinociception compared with control and intrathecally compared with bupivacaine. Solutions of 0.3 mL of doxepin at 50, 75, and 100 mM and control (only the vehicle solution) were applied as a patch to the shaved dorsal skin of rats. After a 2-h contact interval, the patch was removed, and the rats were tested by three sets of six pinpricks. Inhibition of withdrawal to pain and cutaneous trunci muscle reflex were graded. In the second investigation, 60 muL of doxepin at 10, 20, and 50 mM was injected through intrathecal catheters implanted in the lumbar region of rats, which were evaluated for motor function, proprioception, and nociception. Topical doxepin at concentrations of 75 mM and 100 mM was significantly more effective than control (P < 0.05). Complete recovery for the 100-mM concentration occurred at 60 h, although two of five rats demonstrated erythema and scarring. Intrathecally, 20 mM of doxepin was not significantly different for motor and proprioceptive function from 23 mM (0.75%) bupivacaine; however, neurotoxicity (defined as persistent neurological deficit) commenced at 50 mM.     

Effect of Subarachnoid Bupivacaine Block on Anesthetic Requirements for Thiopental in Rats

Background: Subarachnoid bupivacaine blockade has been reported to reduce thiopental and midazolam hypnotic requirements in patients. The purpose of this study was to examine if local anesthetically induced lumbar intrathecal blockade would reduce thiopental requirements for blockade of motor responses to noxious and nonnoxious stimuli in rats.

Methods: After intrathecal and external jugular catheter placement, rats were assigned randomly to two groups in a crossover design study, with each rat to receive either 10 micro liter of 0.75% bupivacaine or 10 micro liter of normal saline intrathecally. The doses of intravenously administered thiopental required to ablate the eyelid reflex, to block the withdrawal reflex of a front limb digit, and to block the corneal reflex were compared. In two separate groups of animals, hemodynamic parameters and concentrations of thiopental in the brain were compared between intrathecally administered bupivacaine and saline.

Results: The thiopental dose required to block the described responses was decreased with intrathecally administered bupivacaine versus intrathecally administered saline from (mean +/- SD) 40 +/- 5 to 24 +/- 4 mg/kg (P < 0.001) for the eyelid reflex, from 51 +/- 6 to 29 +/- 6 mg/kg (P < 0.005) for front limb withdrawal, and from 67 +/- 8 to 46 +/- 8 mg/kg (P < 0.01) for the corneal reflex. The concentration of thiopental in the brain at the time of corneal reflex blockade for the group given bupivacaine was significantly lower than in the group given saline (24.1 vs. 35.8 micro gram/g, P = 0.02).     

Can estrogen influence the response to noxious stimuli?

STUDY OBJECTIVES: To evaluate estrogen-induced alternations in noxious stimuli response. DESIGN: Randomized, prospective, double-blind study. SETTINGS: Tertiary-care academic medical center. PATIENTS: 40 ASA physical status I and II women at the beginning and conclusion of an in vitro fertilization stimulation cycle. INTERVENTIONS: Stimuli were applied to the fingers of the dominant hand via a Basile Analgesy-Meter, which applied increasing pressure (g/cm(2)) in a continuous fashion, and ice water immersion. MEASUREMENTS: Serum hormonal concentrations and responses to noxious (pressure and cold thermal) stimuli were studied. MAIN RESULTS: Estrogen and progesterone concentrations changed from 377 +/- 323.42 pg/mL to 2078.05 +/- 1175.92 pg/mL (p < 0.001) and 1.20 +/- 0.56 to 1.03 +/- 0.35 ng/mL (p = NS), respectively. Although no significant difference was noted in the response to pressure (16.92 +/- 4.41 to 17.85 +/- 4.95 g/cm(2)), a significant reduction in the tolerance to ice water immersion (34.18 +/- 28.29 to 24.05 +/- 23.02 s) was observed. CONCLUSIONS: High estrogen concentrations are associated with significantly lower tolerance to cold, but not pressure stimuli.     

The anesthesia machine valve tester: A new device and method for evaluating the competence of unidirectional anesthetic valves

Objective. Current methods of determining anesthesia machine unidirectional valve (UDV) competence are time-consuming, ineffective, or carry the risk of transmitting infections disease to the anesthetist or patient. New methods of testing these valves are needed. The purpose of this study was to determine the prevalence of incompetent UDVs at one institution by employing the Anesthesia Machine Valve Tester (AMVT), a new way to test anesthesia machine UDVs.Methods. We tested each expiratory and inspiratory UDV on all anesthesia machines in functioning operating rooms at the Brigham and Women's Hospital. If a UDV was found to be incompetent, we cleaned and reseated it, and then tested it again with the AMVT.Results. We found a 13% prevalence of UDV malfunction in out machines. Three of the 10 incompetent valves were repaired quickly by us and were made competent by either reseating the valve or by first cleaning and then reseating it.Conclusions. We found that the AMVT was able to detect UDV failure quickly with no risk to the tester or to the patient. We conclude that the AMVT can be used to check the UDV as recommended by the FDA anesthesia machine check-out protocol.