Interaction of Intrathecally Infused Morphine and Lidocaine in Rats (Part I): Synergistic Antinociceptive Effects

Background Synergistic antinociception of opioids and local anesthetics has been established in bolus injections but not in long‐term use. The somatic and visceral antinociceptive effects of intrathecally infused morphine or lidocaine were characterized, and the nature of the interaction of those agents in rats was evaluated. Methods Intrathecal catheters were implanted in rats. Morphine (0.3 to 10 [micro sign]g [middle dot] kg‐1 [middle dot] h‐1), lidocaine (30‐1,000 [micro sign]g [middle dot] kg‐1 [middle dot] h‐1), a combination of those, or saline was infused intrathecally at a constant rate of 1 [micro sign]l/h for 6 days. The tail flick and colorectal distension tests were used to measure the somatic and visceral antinociceptive effects, respectively. Nociceptive tests and motor function tests were repeated on days 1, 2, 3, 4, and 6. Isobolographic analysis was performed on the results of the tail flick test to determine the magnitude of the interaction. Results Intrathecally infused morphine produced dose‐dependent antinociceptive effects in both the tail flick and the colorectal distension tests. Morphine showed a lower peak percentage maximum possible effect (%MPE) in the colorectal distension test than in the tail flick test. Intrathecal lidocaine also produced dose‐dependent antinociceptive effects. Lidocaine infusion at 1,000 [micro sign]g [middle dot] kg‐1 [middle dot] h‐1 caused motor impairment. Coinfusion of morphine 0.3 [micro sign]g [middle dot] kg‐1 [middle dot] h‐1 and lidocaine 200 [micro sign]g [middle dot] kg‐1 [middle dot] h‐1, which had no effects by themselves, significantly increased the percentage maximum possible effects (P < 0.01). Coinfused lidocaine potentiated the duration and the magnitude of morphine antinociception. Isobolographic analysis of the tail flick test on day 1 showed a synergistic interaction between morphine and lidocaine. Conclusions Morphine and lidocaine intrathecally coadministered synergistically potentiated the antinociceptive effects of each other. That coinfusion dramatically potentiated visceral antinociception, whereas the infusion of morphine alone showed little visceral antinociception.

[1]  Yoji Saito,et al.  Antinociceptive effects of epidural and intravenous ketamine to somatic and visceral stimuli in rats , 1996, Canadian journal of anaesthesia = Journal canadien d'anesthesie.

[2]  D. Scott,et al.  Postoperative Analgesia Using Epidural Infusions of Fentanyl with Bupivacaine: A Prospective Analysis of 1,014 Patients , 1995, Anesthesiology.

[3]  G. Gebhart,et al.  Spinal mu and delta, but not kappa, opioid-receptor agonists attenuate responses to noxious colorectal distension in the rat , 1995, Pain.

[4]  L. Kitahata,et al.  Visceral antinociceptive effects of spinal clonidine combined with morphine, [D-Pen2, D-Pen5] enkephalin, or U50,488H. , 1995, Anesthesiology.

[5]  L. Kitahata,et al.  Contrasting Actions of Intrathecal U50, 488H, Morphine, or [D-Pen sup 2, D-Pen sup 5] Enkephalin or Intravenous U50, 488H on the Visceromotor Response to Colorectal Distension in the Rat , 1995, Anesthesiology.

[6]  F. Cerveró,et al.  Visceral pain: mechanisms of peripheral and central sensitization. , 1995, Annals of medicine.

[7]  L. Arendt-Nielsen,et al.  Quantitative sensory examination of epidural anaesthesia and analgesia in man: Effects of pre- and post-traumatic morphine on hyperalgesia , 1994, Pain.

[8]  F. Burgess,et al.  Thoracic epidural analgesia with bupivacaine and fentanyl for postoperative thoracotomy pain. , 1994, Journal of cardiothoracic and vascular anesthesia.

[9]  Y. Kosaka,et al.  Comparison of continuous epidural infusion of morphine/bupivacaine with fentanyl/ bupivacaine for postoperative pain relief , 1994, Acta anaesthesiologica Scandinavica.

[10]  P. Stewart,et al.  Activation of spinal delta-1 or delta-2 opioid receptors reduces carrageenan-induced hyperalgesia in the rat. , 1994, The Journal of pharmacology and experimental therapeutics.

[11]  M. Kaneko,et al.  Synergistic Antinociceptive Interaction after Epidural Coadministration of Morphine and Lidocaine in Rats , 1994, Anesthesiology.

[12]  J. Levine,et al.  Antinociception produced by receptor selective opioids. Modulation of supraspinal antinociceptive effects by spinal opioids , 1993, Brain Research.

[13]  J. Bourgain,et al.  Postoperative Pulmonary Complications Epidural Analgesia Using Bupivacaine and Opioids Versus Parenteral Opioids , 1993, Anesthesiology.

[14]  T. Yaksh,et al.  Interaction of intrathecal morphine with bupivacaine and lidocaine in the rat. , 1992, Anesthesiology.

[15]  L. Boxer,et al.  ALFENTANIL AND PROPOFOL FOR BONE MARROW PROCEDURES: A DOSE-RESPONSE STUDY , 1992 .

[16]  J. Harbers,et al.  Thoracic Epidural Bupivacaine Plus Sufentanil: High Concentration/Low Volume Versus Low Concentration/High Volume , 1992, Regional Anesthesia & Pain Medicine.

[17]  E. Kharasch,et al.  Chronic epidural bupivacaine-opioid infusion in intractable cancer pain , 1992, Pain.

[18]  Ronald J. Tallarida,et al.  Statistical analysis of drug combinations for synergism , 1992, Pain.

[19]  N. Badner,et al.  Bupivacaine 0.1% does not improve postoperative epidural fentanyl analgesia after abdominal or thoracic surgery , 1992, Canadian journal of anaesthesia = Journal canadien d'anesthesie.

[20]  H. Kehlet,et al.  Differential analgesic effects of low-dose epidural morphine and morphine-bupivacaine at rest and during mobilization after major abdominal surgery. , 1992, Anesthesia and analgesia.

[21]  N. Janjan,et al.  Epidural opiates and local anesthetics for the management of cancer pain , 1991, Pain.

[22]  F. Cerveró.  Mechanisms of acute visceral pain. , 1991, British medical bulletin.

[23]  J. Fujimoto,et al.  Isobolographic analysis of analgesic interactions between intrathecally and intracerebroventricularly administered fentanyl, morphine and D-Ala2-D-Leu5-enkephalin in morphine-tolerant and nontolerant mice. , 1991, The Journal of pharmacology and experimental therapeutics.

[24]  N. Badner,et al.  Low‐Dose Bupivacaine Does Not Improve Postoperative Epidural Fentanyl Analgesia in Orthopedic Patients , 1991, Anesthesia and analgesia.

[25]  J. Koeller.  Understanding cancer pain. , 1990, American journal of hospital pharmacy.

[26]  T. Ness,et al.  Visceral pain: a review of experimental studies , 1990, Pain.

[27]  J. Eisenach,et al.  Labor analgesia with epidural bupivacaine plus fentanyl: enhancement with epinephrine and inhibition with 2-chloroprocaine. , 1990, Anesthesiology.

[28]  M. Douglas,et al.  Influence of bupivacaine as an adjuvant to epidural morphine for analgesia after cesarean section. , 1988 .

[29]  T. Ness,et al.  Characterization of neurons responsive to noxious colorectal distension in the T13-L2 spinal cord of the rat. , 1988, Journal of neurophysiology.

[30]  D. Scott,et al.  Postoperative analgesia by continuous extradural infusion of bupivacaine and diamorphine. , 1988, British journal of anaesthesia.

[31]  T. Ness,et al.  Colorectal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudaffective reflexes in the rat , 1988, Brain Research.

[32]  A. Ivankovich,et al.  Continuous thoracic epidural analgesia for postoperative pain relief following thoracotomy: a randomized prospective study. , 1987, Anesthesiology.

[33]  D. Chestnut,et al.  Continuous Infusion Epidural Analgesia during Labor: A Randomized, Double-blind Comparison of 0.0625% Bupivacaine / 0.0002% Fentanyl Versus 0.125% Bupivacaine , 1987 .

[34]  T. Ness,et al.  Characterization of neuronal responses to noxious visceral and somatic stimuli in the medial lumbosacral spinal cord of the rat. , 1987, Journal of neurophysiology.

[35]  F. Cerveró,et al.  Distribution of somatic and visceral primary afferent fibres within the thoracic spinal cord of the cat , 1984, The Journal of comparative neurology.

[36]  R. Tallarida,et al.  Manual of Pharmacologic Calculations: With Computer Programs , 1984 .

[37]  G. Gebhart,et al.  Antinociceptive synergy between intrathecal morphine and lidocaine during visceral and somatic nociception in the rat. , 1992, Anesthesiology.

[38]  R. Hickey,et al.  Comparison of the Clinical Efficacy of Three Techniques of Axillary Brachial Plexus Block , 1992, Regional Anesthesia & Pain Medicine.

[39]  A Cowan,et al.  Statistical analysis of drug-drug and site-site interactions with isobolograms. , 1989, Life sciences.

[40]  T. Yaksh,et al.  In vivo studies on spinal opiate receptor systems mediating antinociception. II. Pharmacological profiles suggesting a differential association of mu, delta and kappa receptors with visceral chemical and cutaneous thermal stimuli in the rat. , 1984, The Journal of pharmacology and experimental therapeutics.