One of the most efficient alternatives for alleviating pain is epidural administration of analgesic drugs. When compared with results for the IM or IV routes of administration, epidural injection of analgesics, such as morphine, may result in a longer duration of analgesia with the use of lower dosages because drugs are administered in close proximity to the receptors that modulate the nociceptive pathway in the spinal cord.1 The goal when combining analgesic drugs administered into the epidural space is to achieve a synergistic analgesic effect via inhibition of nociception through various pathways.1,2
Neostigmine is a cholinomimetic agent used in anesthesia for antagonizing the action of nondepolarizing neuromuscular blocking agents. This drug is devoid of neurotoxic effects when administered intrathecally to dogs and rats.3 In humans, there has been renewed interest in this drug because epidural administration of neostigmine in conjunction with other drugs (eg, lidocaine, bupivacaine, and morphine) substantially improves control of postoperative pain.4–6
Activation of muscarinic receptors located in the spinal cord is the mechanism probably responsible for analgesia induced by cholinomimetic agents such as neostigmine.7 More specifically, the mechanism for analgesia induced by cholinomimetic drugs primarily involves the activation of muscarinic type 1 receptors, although activation of nicotinic receptors may also be involved.8,9
Although intrathecal (subarachnoid) administration of neostigmine results in dose-dependent analgesia, the administration of neostigmine via this route has been virtually abandoned in humans because of a high incidence of vomiting and severe nausea.10–13 As an alternative to the intrathecal route, epidural administration of neostigmine can yield analgesia with a decreased incidence of adverse effects such as nausea and vomiting in humans undergoing orthopedic and obstetric procedures.4–6
Analysis of data from humans suggests that neostigmine may have potential clinical application as an analgesic adjuvant to other drugs administered epidurally.4–6 The study reported here was conducted to evaluate the postoperative analgesic effects of epidural administration of neostigmine alone or in combination with morphine in bitches that underwent ovariohysterectomy.
End-tidal concentration of isoflurane
Mean arterial pressure
Numeric descriptive scale
End-tidal partial pressure of carbon dioxide
Visual analogue scale
Acepran 0.2%, Univet, São Paulo, Brazil.
BD Insyte, Becton-Dickinson, São Paulo, Brazil.
Propovan 1%, Cristália, Itapira, Brazil.
Isoforine, Cristália, Itapira, Brazil.
Conquest 3000, HB Hospitalar, São Paulo, Brazil.
A/S 3 monitor, Datex-Ëngstrom, Helsinki, Finland.
TruWave PX260, Edwards Lifesciences, Irvine, Calif.
YSI 406 temperature probe, Yellow Springs Instruments, Yellow Springs, Ohio.
Warmtouch, Mallinkrodt Medical, Pleasanton, Calif.
Prostigmine, Roche, São Paulo, Brazil.
Dimorf, 10 mg, Cristália, Itapira, Brazil.
SAS for Windows, version 8.02, SAS Institute Inc, Cary, NC.
Walker SM, Goudas LC, Cousins MJ, et al. Combination spinal analgesic chemotherapy: a systematic review. Anesth Analg 2002;95:674–715.
Yaksh TL, Grafe MR, Malkmus S, et al. Studies on the safety of chronically administered intrathecal neostigmine methylsulfate in rats and dogs. Anesthesiology 1995;82:412–427.
Lauretti GR, de Oliveira R, Reis MP, et al. Study of three different doses of epidural neostigmine coadministered with lidocaine for postoperative analgesia. Anesthesiology 1999;90:1534–1538.
Nakayama M, Ichinose H, Nakabayashi K, et al. Analgesic effect of epidural neostigmine after abdominal hysterectomy. J Clin Anesth 2001;13:86–89.
Omais M, Lauretti GR, Paccola CA. Epidural morphine and neostigmine for postoperative analgesia after orthopedic surgery. Anesth Analg 2002;95:1698–1701.
Yaksh TL, Dirksen R, Harty GJ. Antinociceptive effects of intrathecally injected cholinomimetic drugs in the rat and cat. Eur J Pharmacol 1985;117:81–88.
Chiari A, Tobin JR, Pan HL, et al. Sex differences in cholinergic analgesia I: a supplemental nicotinic mechanism in normal females. Anesthesiology 1999;91:1447–1454.
Hood DD, Eisenach JC, Tuttle R. Phase I safety assessment of intrathecal neostigmine methylsulfate in humans. Anesthesiology 1995;82:331–343.
Lauretti GR, Reis MP. Postoperative analgesia and antiemetic efficacy after subarachnoid neostigmine in orthopedic surgery. Reg Anesth 1997;22:337–342.
Lauretti GR, Mattos AL, Reis MP, et al. Intrathecal neostigmine for postoperative analgesia after orthopedic surgery. J Clin Anesth 1997;9:473–477.
Klamt JG, Garcia LV, Prado WA. Analgesic and adverse effects of a low dose of intrathecally administered hyperbaric neostigmine alone or combined with morphine in patients submitted to spinal anaesthesia: pilot studies. Anaesthesia 1999;54:27–31.
Holton LL, Scott EM, Nolan AM, et al. Relationship between physiological factors and clinical pain in dogs scored using a numerical rating scale. J Small Anim Pract 1998;39:469–474.
Fowler D, Isakow K, Caulkett N, et al. An evaluation of the analgesic effects of meloxicam in addition to epidural morphine/ mepivacaine in dogs undergoing cranial cruciate ligament repair. Can Vet J 2003;44:643–648.
Lauretti GR, Lima IC. The effects of intrathecal neostigmine on somatic and visceral pain: improvement by association with a peripheral anticholinergic. Anesth Analg 1996;82:617–620.
Modified criteria14 for the NDS for assessment of pain in dogs after ovariohysterectomy.
|Heart rate||≤ 10% above value recorded before surgery||0|
|> 10% to 30% above value recorded before surgery||1|
|> 30% to 50% above value recorded before surgery||2|
|> 50% above value recorded before surgery||3|
|Respiratory pattern||Thoracoabdominal movement||0|
|Moderate abdominal movement||1|
|Marked abdominal movement||2|
|Rectal temperature||Within reference range||0|
|Greater than reference range||1|
|Salivation||Typical amounts of saliva||0|
|Excessive amounts of saliva||1|
|Mild changes (eyelids partially closed; ears fattened or abnormal carriage)||1|
|Moderate changes (eyes sunken or glazed; unthrifty)||2|
|Severe changes (eyes pale; large pupils; grimace or other abnormal facial expressions; protective posture; hunched-back position; abnormal limb position; grunting before expiration; teeth grinding)||3|
|Comfort||Calm, awake, and interested in surroundings||0|
|Awake but not interested in surroundings||1|
|Extremely agitated or thrashing||2|
|Behavior without interaction||Typical behavior, interested in surroundings||0|
|Minor changes, less interested in surroundings than usual||1|
|Moderately abnormal (less mobile and less alert than usual; unaware of surroundings; extremely restless)||2|
|Markedly abnormal (extremely restless; vocalization; self-mutilation; groaning; facing the back of the cage)||3|
|Behavior in response to manipulation of surgical incision||No aversive behavior||0|
|Minimal aversive behavior, pulls away when surgical site is touched, and turns head to look at surgical incision||1|
|Vocalizes and turns head to look at surgical incision Violent reactions to stimuli; vocalizing; growling when approached; snapping; extremely restless; will not move when coaxed||3|
|Vocalization that can be interrupted by calmly speaking to dog and petting||1|
|Intermittent vocalization or whimpering; no response to calmly speaking to dog and petting||2|
|Continuous vocalization that is abnormal for the specific dog||3|
|Movement||Typical amount of movement||0|
|Frequent position changes or reluctance to move||1|