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Dr Wise Young

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    Dr Wise Young

    Dr Young

    Can you please give me your thoughts on interthecal clonidine. I have a bacolfen pump and my doctor is going to add clonidine for pain that I'm having in my perinial area and lower back.

    There is ample evidence in both human clinical trials and animals studies that intrathecal clonidine or systemic clonidine both have synergistic effects with various drugs in neuropathic pain. Since one of clonidine's main side-effects is hypotension (low blood pressure), intrathecal administration of the drug is a reasonable approach of giving sufficient doses of the drug with minimal side effects directly to the spinal cord. It may not always help but I think that it may be worth a try. I list some recent references on the subject:

    • Bennett G, Deer T, Du Pen S, Rauck R, Yaksh T and Hassenbusch SJ (2000). Future directions in the management of pain by intraspinal drug delivery. J Pain Symptom Manage. 20 (2): S44-50. Summary: Management of pain by intraspinal delivery of drugs enables physicians to target specific sites of action. While this novel approach is gaining increasing use, well-designed studies are needed. A major limitation is the lack of published information on existing drugs used for intrathecal delivery. (The strengths and weaknesses of this information are reviewed in the accompanying literature review article.) Promising agents such as bupivacaine, hydromorphone, and morphine/clonidine combinations warrant further research in large prospective (ideally randomized and double-blind) clinical safety and efficacy studies. These studies may provide data for pain management guidelines, such as those included in the preceding paper. Research must also address issues of formulation, chemical stability/compatibility, pharmacokinetics, and toxicology during clinical development and drug approval. Finally, more basic studies and early phase trials of other potential agents for intrathecal pain management (e.g., gabapentin) are needed. <> Department of Neurology, MCP Hahnemann University, Philadelphia, PA, USA.

    • Danshaw CB (2000). An anesthetic approach to amputation and pain syndromes. Phys Med Rehabil Clin N Am. 11 (3): 553-7. Summary: Primary anesthetic intervention is a very effective modality in the prevention of phantom limb pain. The first phase is reduction of the preamputation pain by epidural or intrathecal infusion with local anesthetic and opioid. The catheter can be used for the operative phase, along with an intraneural catheter placement, if necessary. The epidural/intrathecal infusion can continue for 2 to 3 days and eventually be converted to a pharmacologic regimen. This can include opioids for surgical pain, along with a tricyclic antidepressant and an alpha-2 adrenergic agonist. If phantom sensation or phantom limb pain develops, gabapentin (Neurontin) is an effective agent for neuropathic pain. Surgical ablative therapy consists of cordotomy, rhizotomy, dorsal root entry zone lesion, or thalamotomy. Other modalities include dorsal column stimulation to facilitate inhibitory descending pathways. An intrathecal delivery system can be placed to infuse clonidine, local anesthetic, and opioid. For pain management, implantable intrathecal delivery systems may become an important tool for the future management of postamputation pain syndrome. <> Department of Anesthesiology and Pain Management, HealthSouth Cityview Hospital, Fort Worth, Texas, USA.

    • Dolezal T (2001). [In Process Citation]. Cesk Fysiol. 50 (2): 81-7. Summary: The dorsal horn of the spinal cord contains many transmitters and receptors involving in pain transmission and modulation. Monoamines and gamma-aminobutyric acid (GABA) play a key role in the modulation at level of dorsal horn (DH) of the spinal cord, the site of primary processing of afferent nociceptive information. Agents that enhance the action of GABA at the GABAA receptors can produce antinociception. For example intrathecal administration of benzodiazepines increases pain threshold in various models of pain. There is also substantial evidence for robust antinociceptive properties of spinal administration of clonidine and other alpha 2-agonists. <> Ustav farmakologie 3. LF UK, Praha.

    • Giroux N, Reader TA and Rossignol S (2001). Comparison of the effect of intrathecal administration of clonidine and yohimbine on the locomotion of intact and spinal cats. J Neurophysiol. 85 (6): 2516-36. Summary: Several studies have shown that noradrenergic mechanisms are important for locomotion. For instance, L-dihydroxyphenylalanine (L-DOPA) can initiate "fictive" locomotion in immobilized acutely spinalized cats and alpha(2)-noradrenergic agonists, such as 2,6,-dichloro-N-2- imidazolidinylid-enebenzenamine (clonidine), can induce treadmill locomotion soon after spinalization. However, the activation of noradrenergic receptors may be not essential for the basic locomotor rhythmicity because chronic spinal cats can walk with the hindlimbs on a treadmill in the absence of noradrenergic stimulation because the descending pathways are completely severed. This suggests that locomotion, in intact and spinal conditions, is probably expressed and controlled through different neurotransmitter mechanisms. To test this hypothesis, we compared the effect of the alpha(2) agonist, clonidine, and the antagonist (16 alpha, 17 alpha)-17-hydroxy yohimbine-16- carboxylic acid methyl ester hydrochloride (yohimbine), injected intrathecally at L(3)--L(4) before and after spinalization in the same cats chronically implanted with electrodes to record electromyograms (EMGs). In intact cats, clonidine (50-150 microg/100 microl) modulated the locomotor pattern slightly causing a decrease in duration of the step cycle accompanied with some variation of EMG burst amplitude and duration. In the spinal state, clonidine could trigger robust and sustained hind limb locomotion in the first week after the spinalization at a time when the cats were paraplegic. Later, after the spontaneous recovery of a stable locomotor pattern, clonidine prolonged the cycle duration, increased the amplitude and duration of flexor and extensor bursts, and augmented the foot drag at the onset of swing. In intact cats, yohimbine at high doses (800--1600 microg/100 microl) caused major walking difficulties characterized by asymmetric stepping, stumbling with poor lateral stability, and, at smaller doses (400 microg/100 microl), only had slight effects such as abduction of one of the hindlimbs and the turning of the hindquarters to one side. After spinalization, yohimbine had no effect even at the largest doses. These results indicate that, in the intact state, noradrenergic mechanisms probably play an important role in the control of locomotion since blocking the receptors results in a marked disruption of walking. In the spinal state, although the receptors are still present and functional since they can be activated by clonidine, they are seemingly not critical for the spontaneous expression of spinal locomotion since their blockade by yohimbine does not impair spinal locomotion. It is postulated therefore that the expression of spinal locomotion must depend on the activation of other types of receptors, probably related to excitatory amino acids. <> Centre de Recherche en Sciences Neurologiques, Departement de Physiologie, Faculte de Medecine, Universite de Montreal, Montreal, Quebec H3C 3J7, Canada.

    • Hama AT, Lloyd GK and Menzaghi F (2001). The antinociceptive effect of intrathecal administration of epibatidine with clonidine or neostigmine in the formalin test in rats. Pain. 91 (1-2): 131-8. Summary: The analgesic effect of intrathecal injection of epibatidine, clonidine and neostigmine, compounds that elevate ACh, was examined in the formalin test, a model of post-injury central sensitization in the rat. The compounds were injected alone and in combination. Intrathecal injection of epibatidine alone did not alter pain behaviors, compared to vehicle-treated rats. Intrathecal injection of clonidine dose- dependently reduced tonic pain behaviors (ED(50)+/-95% confidence limits=6.7+/-4.8 microg). The combination of clonidine and epibatidine (C:E), in the ratio of 26:1, dose-dependently reduced tonic pain behaviors; and the ED(50) of C:E was 1.1+/-0.98 microg a significant 6- fold leftward shift of the dose response curve, compared with clonidine alone. The antinociceptive effect of C:E (26:1) was attenuated by pre- treatment with the nAChR antagonist mecamylamine. Neostigmine dose- dependently reduced tonic pain behaviors (ED(50)=1.5+/-1.3 microg). The combination of neostigmine and epibatidine, in a ratio of 8:1, significantly shifted the dose response curve 4-fold to the left (ED(50)=0.4+/-0.3 microg). The effect is mediated in part by the activation of the nAChR and possibly by the enhanced release of ACh. These data demonstrate significant enhancement of the antinociceptive effects of spinally delivered analgesics by a nAChR agonist, suggesting that this class of compounds may have utility as adjuvants when combined with conventional therapeutics. <> Merck Research Laboratories, San Diego, 505 Coast Blvd. South, #300, La Jolla CA 92037, USA.

    • Hao S, Takahata O and Iwasaki H (2000). Intrathecal endomorphin-1 produces antinociceptive activities modulated by alpha 2-adrenoceptors in the rat tail flick, tail pressure and formalin tests. Life Sci. 66 (15): PL195-204. Summary: It is known that spinal morphine produces antinociception that is modulated by alpha 2-adrenoceptors. Endomorphin-1, a newly-isolated endogenous opioid ligand, shows the greatest selectivity and affinity for the mu-opiate receptor of any endogenous substance found to date and may serve as a natural ligand for the mu-opiate receptor. We examined the antinociceptive effects of endomorphin-1 administered intrathecally (i.t.) in the rat tail flick, tail pressure and formalin tests. Intrathecal endomorphin-1 produced dose-dependent antinociceptive effects in the three tests. ED50 (CI95) values for antinociception of i.t. endomorphin-1 in the tail flick test and tail pressure test were 1.9 (0.96-3.76) nmol and 1.8 (0.8-4.2) nmol, respectively. ED50 (CI95) values for phase 1 and phase 2 in the formalin test were 12.5 (7.9-19.8) nmol and 17.5 (10.2-30) nmol, respectively. Pretreatment with i.t. beta-funaltrexamine (a mu-opioid receptor selective antagonist) significantly antagonized the antinociceptive effects of endomorphin-1 in the three tests. Beta- funaltrexamine alone had not effects on the three tests. The antinociceptive effects of endomorphin-1 were also antagonized by i.t. yohimbine (an alpha 2-adrenoceptor selective antagonist). The combination of ineffective doses of i.t. clonidine (an alpha 2- adrenoceptor agonist) and endomorphin-1 produced a significant antinociception in the three tests. The results showed that intrathecal endomorphin-1 produced antinociception in a dose-dependent manner in the rat tail flick, tail pressure and formalin tests, which was mediated by spinal mu-opioid receptors and modulated by alpha 2- adrenoceptors. <> Department of Anesthesiology & Critical Care Medicine, Asahikawa Medical College, 078-8510 Japan.

    • Hao S, Takahata O and Iwasaki H (2001). Antinociceptive interaction between spinal clonidine and lidocaine in the rat formalin test: an isobolographic analysis. Anesth Analg. 92 (3): 733-8. Summary: Clinical and basic science studies suggest that spinal alpha-2- adrenergic receptor agonists and local anesthetics produce analgesia, but interaction between alpha-2-adrenergic receptor agonists and local anesthetics in the persistent pain model has not been examined. In the present study, using isobolographic analysis, we investigated the antinociceptive interaction of intrathecal clonidine and lidocaine in the rat formalin test. Sprague-Dawley rats were implanted with chronic lumbar intrathecal catheters, and were tested for paw flinch by formalin injection. Biphasic painful behavior was counted. Intrathecal clonidine (3-12 nmol) was administered 15 min before formalin, and intrathecal lidocaine (375-1850 nmol) was administered 5 min before formalin. To examine the interaction of intrathecal clonidine and lidocaine, an isobolographic design was used. Spinal administration of clonidine produced dose-dependent suppression of the biphasic responses in the formalin test. Spinal lidocaine resulted in dose-dependent transient motor dysfunction and the motor dysfunction recovered to normal at 10-15 min after administration. Spinal lidocaine produced dose-dependent suppression of phase-2 activity in the formalin test. Isobolographic analysis showed that the combination of intrathecal clonidine and lidocaine synergistically reduced Phase-2 activity. We conclude that intrathecal clonidine synergistically interacts with lidocaine in reducing the nociceptive response in the formalin test. IMPLICATIONS: Preformalin administration of intrathecal clonidine and lidocaine dose-dependently produced antinociception in the formalin test. The combination of clonidine and lidocaine, synergistically produced suppression of nociceptive response in the persistent pain model. <> Department of Anesthesiology & Critical Care Medicine, Asahikawa Medical College, Asahikawa, Japan.

    • Kumar K, Kelly M and Pirlot T (2001). Continuous intrathecal morphine treatment for chronic pain of nonmalignant etiology: long-term benefits and efficacy. Surg Neurol. 55 (2): 79-86; discussion 86-8. Summary: BACKGROUND: To analyze, prospectively, the long-term effects of continuous intrathecal morphine infusion therapy in 16 patients with chronic nonmalignant pain syndromes.METHODS: Twenty-five patients with severe, chronic, nonmalignant pain that had proven refractory to conservative management were considered candidates for trial of intrathecal spinal morphine. Sixteen patients achieved more than 50% pain relief after a trial period of intrathecal morphine infusion. They were implanted with fully implantable and programmable pumps through which morphine was delivered intrathecally on a continuous basis. These patients were followed prospectively and underwent careful evaluation of their functional and mental status, and pain intensity measurements using standardized techniques before treatment and every 6 months thereafter in the follow-up period. The follow-up period ranged from 13 months to 49 months (mean 29.14 months +/- 12.44 months) for the patients who had implanted morphine pumps.RESULTS: The mean morphine dosage initially administered was 1.11 mg/day (range 0.2--6.5 mg/day); after 6 months, it was 3.1 mg/day (range 0.4--8.75 mg/day). In long- term observation, no patient had a constant dosage history. The patients who received intrathecal morphine for longer than 2 years all showed an increase in morphine dosage to more than 10 mg/day. The best long-term results were seen with deafferentation pain and mixed pain, with 75% and 61% pain reduction (visual analog scale), respectively. Nociceptive pain patients had best pain relief initially (78% pain reduction) but it tended to decrease over the follow-up period to 57% pain reduction at final follow-up. The average pain reduction for all groups after 6 months was 67.5% and at last follow-up, it was 57.5%. Ten patients were satisfied with the delivery system and eleven reported improvement in their quality of life. In two patients, morphine was not able to adequately control the pain without producing undesirable side effects requiring the addition of clonidine to their infusion medication. In this series, 12 patients were considered successes and 4 patients were considered failures. In two patients, the intrathecal opioid therapy was unable to produce satisfactory pain relief and in the other two patients the pumps had to be explanted because of intolerable side effects.CONCLUSIONS: In our experience, the administration of intrathecal opioid medications for nonmalignant pain is justified in carefully selected patients. <> Department of Surgery, Section of Neurosurgery, Regina General Hospital, University of Saskatchewan, Regina, Saskatchewan, Canada.

    • Nishiyama T, Gyermek L, Lee C, Kawasaki-Yatsugi S, Yamaguchi T and Hanaoka K (2001). The analgesic interaction between intrathecal clonidine and glutamate receptor antagonists on thermal and formalin-induced pain in rats. Anesth Analg. 92 (3): 725-32. Summary: Clonidine, an alpha(2) adrenergic receptor agonist, inhibits glutamate release from the spinal cord. We studied the interaction of intrathecally administered clonidine and glutamate receptor antagonists on acute thermal or formalin induced nociception. Sprague-Dawley rats with lumbar intrathecal catheters were tested for their tail withdrawal response by the tail flick test and paw flinches produced by formalin injection after intrathecal administration of saline, clonidine, AP-5 (a N-methyl-D-aspartate receptor antagonist), or YM872 (an alpha-amino- 3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist). The combinations of clonidine and the other two agents were also tested by isobolographic analyses. Motor disturbance and behavioral changes were observed as side effects. The ED(50) values of clonidine decreased from 0.26 microg (tail flick), 0.12 microg (Phase 1) and 0.13 microg (Phase 2) to 0.036 microg, 0.006 microg, and 0.013 microg with AP-5, and 0.039 microg, 0.057 microg, and 0.133 microg with YM872, respectively. Side effects were attenuated in both combinations. In conclusion, spinally administered clonidine and AP-5 or YM872 exhibited potent synergistic analgesia on acute thermal and formalin-induced nociception with decreased side effects in rats. IMPLICATIONS: Combinations of a spinally administered alpha(2) adrenergic receptor agonist and an a N- methyl-D-aspartate receptor antagonist or an alpha-amino-3-hydroxy-5- methylisoxazole-4-propionic acid receptor antagonist exhibited potent synergistic analgesia in acute thermal and inflammatory-induced nociception with decreased side effects. <> Department of Anesthesiology, Harbor-University of California, Los Angeles Medical Center, Torrance, California, USA. nishiyam@ims.u-

    • Osenbach RK and Harvey S (2001). Neuraxial infusion in patients with chronic intractable cancer and noncancer pain. Curr Pain Headache Rep. 5 (3): 241-9. Summary: Ever since the application in 1980 of morphine for spinal analgesia in patients with refractory cancer pain, spinal infusion therapy has become one of the cornerstones for the management of chronic, medically intractable pain. Initially, spinal infusion therapy was indicated only for patients with cancer pain that could not be adequately controlled with systemic narcotics. However, over the past decade, there has been a significant increase in the number of pumps implanted for the treatment of nonmalignant pain. Indeed, "benign" pain syndromes, particularly failed back surgery syndrome, are the most common indication for intrathecal opiates. As we have gained more experience with this therapy, it has become apparent that even intrathecal opiates, when administered in the long term, can be associated with problems such as tolerance, hyperalgesia, and other side effects. Consequently, long-term efficacy has not been as significant as had been hoped. Because of the difficulties associated with long-term intrathecal opiate therapy, much of the research, both basic and clinical, has focused on developing alternative nonopioid agents to be used either alone or in combination with opiates. Clinical trials have been and continue to be conducted to evaluate drugs such as clonidine, SNX-111, local anesthetics, baclofen, and many other less common agents to determine their efficacy and potential toxicity for intrathecal therapy. This article reviews the agents developed as alternatives to intrathecal opiates. <> Department of Neurological Surgery, 48 CSB, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425-2272, USA.

    • Paqueron X, Li X, Bantel C, Tobin JR, Voytko ML and Eisenach JC (2001). An obligatory role for spinal cholinergic neurons in the antiallodynic effects of clonidine after peripheral nerve injury. Anesthesiology. 94 (6): 1074-81. Summary: BACKGROUND: Indirect evidence supports a role of spinal cholinergic neurons in tonically reducing response to noxious mechanical stimulation and in effecting analgesia from alpha2-adrenergic agonists. This study directly assessed the role of cholinergic neurons in regulating the level of mechanical allodynia and in participating in the antiallodynic effect of the clinically used alpha2-adrenergic agonist, clonidine, in an animal model of neuropathic pain. METHODS: Allodynia was produced in rats by ligation of the left L5 and L6 spinal nerves. Rats received a single intrathecal injection of saline or one of three different doses of the cholinergic neurotoxin, ethylcholine mustard aziridinium ion (AF64-A; 2, 5, and 15 nmol). Seven days later, allodynia was assessed before and after intrathecal injection of 15 microg clonidine. The spinal cord was removed, and spinal cord acetylcholine content, cholinergic neuron number and distribution, and alpha2-adrenergic receptor expression were determined. RESULTS: AF64-A administration reduced both the number of cholinergic cells and the acetylcholine content of the lumbar dorsal spinal cord by 20-50% but did not affect level of mechanical allodynia. AF64-A did, however, completely block the anti-allodynic effect of clonidine. AF64-A did not reduce alpha2-adrenergic ligand binding in dorsal lumbar cord. CONCLUSIONS: These data suggest that spinal cholinergic tone does not affect the level of mechanical allodynia after peripheral nerve injury. There is a quantitative reliance on spinal cholinergic neurons in the allodynia relieving properties of intrathecal clonidine, and this reliance does not depend on alpha2-adrenergic receptors colocalized on spinal cholinergic interneurons. <> Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

    • Rainov NG, Heidecke V and Burkert W (2001). Long-term intrathecal infusion of drug combinations for chronic back and leg pain. J Pain Symptom Manage. 22 (4): 862-71. Summary: Continuous intrathecal infusion of analgesic drugs by implantable pumps is recognized as an established treatment option for patients with chronic pain resistant to oral or parenteral medication. Polyanalgesia, the simultaneous use of more than one intrathecal analgesic drug, is practiced relatively often, but there are only a few published clinical studies on intrathecal polyanalgesia for chronic nonmalignant pain. This pilot study represents a long-term evaluation of a treatment regimen consisting of intrathecal morphine admixed with bupivacaine, clonidine, or midazolam in patients with chronic nonmalignant back and leg pain due to degenerative lumbar spinal disease. Twenty-six adult patients have been treated by intrathecal programmable pump-controlled infusion of analgesic drugs and followed for up to 3.5 years (27 +/- 11 months). Combination of morphine with a second drug was used in 10 cases, morphine with 2 additional drugs in 12 cases, and morphine with 3 additional drugs in 4 cases. Mean daily doses at 24 months after pump implantation were 6.2 +/- 2.8 mg for morphine, 2.5 +/- 1.5 mg for bupivacaine, 0.06 +/- 0.03 mg for clonidine, and 0.8 +/- 0.4 mg for midazolam. Nineteen patients reported excellent or good long-term treatment results, 6 patients had sufficient results, and only 1 patient complained of poor therapeutic efficacy. No long-term clinical side effects of intrathecal polyanalgesia were noted. Mean morphine dose had to be increased from 1.2 mg at baseline to 5.1 mg at 24 months due to tolerance development and disease progression. This experience suggests that intrathecal polyanalgesia employing morphine combined with additional nonopioid drugs can have a favorable analgesic efficacy in patients with complex chronic pain of spinal origin, and lacks major drug-related complications. <> Department of Neurological Science, University of Liverpool, Liverpool, United Kingdom

    • Siddall PJ, Molloy AR, Walker S, Mather LE, Rutkowski SB and Cousins MJ (2000). The efficacy of intrathecal morphine and clonidine in the treatment of pain after spinal cord injury. Anesth Analg. 91 (6): 1493-8. Summary: We performed a double-blinded, randomized, controlled trial in 15 patients to determine the efficacy of intrathecal morphine or clonidine, alone or combined, in the treatment of neuropathic pain after spinal cord injury. The combination of morphine and clonidine produced significantly more pain relief than placebo 4 h after administration; either morphine or clonidine alone did not produce as much pain relief. In addition, lumbar and cervical cerebrospinal fluid (CSF) concentrations, sampled at these levels at different times after administration were examined for a relationship between pain relief and CSF drug concentration. Lumbar CSF drug concentrations were initially several orders of magnitude larger than those in cervical CSF. After 1- 2 h, the concentrations of morphine in cervical CSF markedly exceeded those of clonidine. The concentration of morphine in the cervical CSF and the degree of pain relief correlated significantly. We conclude that intrathecal administration of a mixture of clonidine and morphine is more effective than either drug administered alone and is related to the CSF-borne drug concentration above the level of spinal cord injury. If there is pathology that may restrict CSF flow, consideration should be given to intrathecal administration above the level of spinal cord damage to provide an adequate drug concentration in this region. <> Pain Management and Research Center, University of Sydney, and Spinal Injuries Unit, Royal North Shore Hospital, St. Leonards, NSW, Australia.

    • von Heijne M, Hao JX, Sollevi A and Xu XJ (2001). Effects of intrathecal morphine, baclofen, clonidine and R-PIA on the acute allodynia-like behaviours after spinal cord ischaemia in rats. Eur J Pain. 5 (1): 1-10. Summary: The present study assessed the efficacy and potency of intrathecal (i.t.) administration of the opiate morphine, the gamma-aminobutyric acid-B (GABA(B)) receptor agonist baclofen, the alpha2-adrenoceptor agonist clonidine and the adenosine A1-receptor agonist R- phenylisopropyl-adenosine (R-PIA) on the acute allodynia-like behaviour after photochemically induced spinal cord injury (SCI) in rats. Rats displaying allodynia-like behaviours to brushing, von Frey hairs and cold stimulation 1-2 days after photochemically induced SCI were studied. In a cumulative dose regime, morphine (0.1-10 micrcog), baclofen (0.1-1 microg), clonidine (0.1-10 microg) and R-PIA (0.01-10 nmol) were administered i.t. through an implanted catheter at the lumbar spinal cord. All tested drugs dose-dependently reduced the brushing, von Frey hairs and cold stimulation-induced allodynia-like behaviour. No increase in adverse effects such as motor deficits was found for morphine, clonidine and R-PIA. There was a slight increase in motor impairments at the highest dose of baclofen. For the mechanical allodynia, morphine appeared to be most effective, whereas baclofen, clonidine and R-PIA only provided a partial alleviation. For the cold allodynia, morphine and baclofen were more effective than clonidine and R-PIA. In relieving acute mechanical and cold allodynia-like behaviours in rats 1-2 days after SCI, i.t. morphine and baclofen were superior to clonidine and R-PIA. Copyright 2001 European Federation of Chapters of the International Association for the Study of Pain. <> Karolinska Institutet, Pediatric Anesthesia and Intensive Care, Astrid Lindgren Children's Hospital, Karolinska Hospital, Stockholm, Sweden.

    • Yoon MH, Yoo KY and Jeong CY (2001). Synergistic effects between intrathecal clonidine and neostigmine in the formalin test. J Korean Med Sci. 16 (4): 498-504. Summary: Spinal alpha-2 adrenoceptors and cholinergic receptors are involved in the regulation of acute nociception and the facilitated processing. The aim of this study was to examine the pharmacological effect of an intrathecal alpha-2 agonist and a cholinesterase inhibitor on the facilitated pain model induced by formalin injection and to determine the nature of drug interaction using an isobolographic analysis. Both intrathecal clonidine and neostigmine dose-dependently suppressed the flinching during phase 1 and phase 2. Intrathecal pretreatment with atropine reversed the antinociceptive effects of clonidine and neostigmine in both phases. Pretreatment with intrathecal yohimbine attenuated the effect of clonidine. The antinociception of clonidine and neostigmine was not reversed by mecamylamine. Isobolographic analysis showed that intrathecal clonidine and neostigmine acted synergistically in both phase 1 and 2. Intrathecal pretreatment with atropine and yohimbine antagonized the effect of the mixture of clonidine and neostigmine in both phases, but no antagonism was observed with mecamylamine pretreatment. These data indicate that spinal clonidine and neostigmine are effective to counteract the facilitated state evoked formalin stimulus, and these two drugs interact in a synergistic fashion. In addition, the analgesic action of intrathecal clonidine is mediated by spinal muscarinic receptors as well as alpha-2 adrenoceptors. <> Department of Anesthesiology, Chonnam National University, Medical School, Kwangju, Korea.