ognizant Communication Corporation


VOLUME 4, NUMBERS 1-4, 1999

Analgesia, Vol. 4, pp. 1-7, 1999
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Involvement of Adrenergic, Serotonergic and Opioid Mechanisms in Tramadol-Induced Antinociception in Mice

H. F. Miranda, T. Pelissier, and G. Pinardi

Department of Pharmacology, Faculty of Medicine, Universidad de Chile, P.O. Box 70.000, Santiago 7, Chile

Tramadol (TRAM) is an analgesic pharmacologically different to classical opioids. In the present work, the involvement of adrenergic-, opioid-, and serotonergic-mediated pathways in the mechanism of TRAM antinociceptive action was studied. Intrathecal TRAM appeared less active than systemic, probably due to extense systemic metabolization to the active metabolite O-desmethyl-tramadol, which possess a higher affinity for m-opioid receptors than the parent compound. The IP pretreatment with the selective antagonists yohimbine (a2-adrenergic) and ondansetron (5-HT3) did not modify the effect of the ED50 of IP TRAM; however, IT administration of yohimbine increased, whereas ondansetron reduced, the antinociception of IT TRAM. Naloxonazine and naltrindole (IP and IT) reduced the effect of IP and IT TRAM. Nor-binaltorphimine administered systemically had no effect on IP TRAM, but when given IT, antagonized the ED50 of spinal TRAM. Even if these opioid antagonists are not definitive subtype discriminators, these results suggest that opioid antagonists with m preference reduce TRAM antinociception when it is administered systemically, possibly in relation with the effect of O-desmethyl-tramadol. TRAM is confirmed as an atypical opioid agent, its opioid agonist activity mainly due to its active metabolite and with its antinociception modulated by monoaminergic pathways.

Key words: Antinociception; Tramadol; Naloxonazine; Naltrindole; Nor-binaltorphimine; Yohimbine; Ondansetron; Writhing test

Address correspondence and reprint requests to H. F. Miranda. Fax: (56-2) 737-2783.

Analgesia, Vol. 4, pp. 9-17, 1999
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The Effects of Coadministration of Morphine and Naloxone on the Severity of Hypertension in SHR During Experimental Inflammation

Helena E. Makulsak-Nowak,1 Sasa Kolaric,1 Eliza Koros,1 Iwona Maszczynska,2 and Stanislaw W. Gumulka1

1Department of Pharmacodynamics and Pharmacology, Medical University, Krakowskie Przedmiescie St. 26/28, 00-927 Warsaw 64 No. 3, Poland
2Medical Research Center, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland

The aim of our study was to determine the effects of subcutaneous (SC) administration of morphine, naloxone, and the combination of the two on systems engaged in blood pressure control in spontaneously hypertensive rats (SHR) with and without chronic pain. The administration of morphine produced a marked decrease in arterial blood pressure in SHR experiencing chronic pain. The resulting effect is probably due to several opposing actions by morphine at various sites of the CNS and the periphery. Overall, in SHR with chronic pain, morphine's hypotensive effects prevail over the hypertensive effects. Naloxone decreased blood pressure in SHR with chronic pain to values similar to those for SHR experiencing no pain. We believe this to be the effect of blockade by naloxone of opioid receptors vicinal to vasomotor centers in the CNS and elimination of stimulatory effects caused by release of endogenous opioids. Morphine and naloxone administered concomitantly in SHR with chronic pain resulted in a very weak decrease in blood pressure, not comparable to that of either of these compounds administered separately. Each compound antagonizes the other's action at opioid sites in the brain, the dorsal horn of the spinal cord, and in the periphery. It would appear that the opioidergic mechanisms engaged in blood pressure control are thus not fully activated causing the overall hypotensive effect to be blunted.

Key words: Morphine; Naloxone; Hypertension; Chronic pain; Descending pain inhibitory pathways

Address correspondence and reprint requests to Helena E. Makulska-Nowak. Tel: +48 22 828 10 88; Fax: +48 22 826 13 66.

Analgesia, Vol. 4, pp. 19-26, 1999
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Human Pharmacology and Abuse Potential of an Enkephalin-Like Pentapeptide: BW942C

Rolley E. Johnson,1* Hendrée E. Jones,1 and Donald R. Jasinski2

1Behavioral Pharmacology Research Unit, The Department of Psychiatry and Behavioral Sciences and 2Clinical Pharmacology Research Unit, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD

Background: The concept of using synthetic pentapeptides resembling the enkephalins for pharmacotherapies has been given much scientific attention. BW942C, a chemically novel enkephalin-like pentapeptide, exhibits a wide separation between therapeutic dosages and dosages producing adverse consequences; however, BW942C exhibits naloxone-reversible opioid activity in animal models.
Purpose: Because BW942C is a synthetic pentapeptide and appears to have some opioid-like effects in animals, the present study assessed BW942C for morphine-like subjective effects, miosis, and physiological effects.
Methods: Comparisons of physiological and subjective effects were made between intramuscularly administered morphine (7.5, 15, and 30 mg), BW942C (0.5, 1.0, and 2.0 mg), and placebo in nine opioid abusers using a double-blind, randomized, crossover design.
Results: Morphine and BW942C constricted pupils and increased scores on the "Feel Drug" psychoactivity measure; however, only morphine produced these effects in a dose-related manner. BW942C was not identified as an opiate and did not increase drug "Liking" or MBG (euphoria) scale scores. BW942C did increase LSD (dysphoria) and PCAG (sedation) scale scores. BW942C decreased body temperature and blood pressure.
Conclusion: The results indicate that BW942C is not a morphine-like drug. The profile of effects is consistent with mixed m- and k-opioid agonists and appears more similar to cyclazocine and ketocyclazine than morphine. The abuse potential of BW942C should be low and is less than that of a m agonist.

Key words: Abuse potential; Abuse liability; BW942C; Enkephalin; Pentapeptide; Opioid; Morphine; Subjective effects

Address correspondence and reprint requests to Rolley E. Johnson, Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences, Behavioral Pharmacology Research Unit, 5510 Nathan Shock Dr., Baltimore, MD 21224-6823. Tel: (410) 550-2796; Fax: (410) 550-0030.

Analgesia, Vol. 4, pp. 27-32, 1999
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Opioid Peptide Receptor Studies. 13. Characterization of Opioid Antagonists With the [35S]GTP-g -S Binding Assay

John S. Partilla,1 F. Ivy Carroll,2 James B. Thomas,2 Kenner C. Rice,3 Dennis M. Zimmerman,4 and Richard B. Rothman1

1Clinical Psychopharmacology Section, Division of Intramural Research, NIDA, NIH, 5500 Nathan Shock Drive, Baltimore, MD 21224
2Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, NC 27709
3Laboratory of Medicinal Chemistry, NIDDK, NIH, Bethesda, MD 20892
4Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285

The major purpose of this study was to develop and validate assay conditions suitable for determining the apparent functional Ki values of opioid antagonists at m, d, and k1 receptors using the [35S]GTP-g-S binding assay. The apparent Ki values of selected opioid antagonists were determined by measuring their inhibition of DAMGO (m)-, SNC80 (d)-, and U69,593 (k1)-stimulated [35S]GTP-g-S binding using guinea pig caudate membranes. The k1-selective antagonist, nor-BNI, had high affinity for the k1 receptor (Ki = 0.038 nM) and was 440- and 268-fold selective for the k1 receptor relative to the m and d receptors, respectively. The d -selective antagonist, naltrindole, had high affinity for the d receptor (Ki = 0.062 nM) and was 52- and 143-fold selective for the d receptor relative to the m and k1 receptors, respectively. The peptidic m-selective antagonist CTAP had moderate affinity for the m receptor (Ki = 65.7 nM) and was about 100-fold selective for the m receptor relative to the d and k1 receptors. The phenylpiperdine antagonist RTI-5989-25 was the most potent m antagonist tested (Ki = 0.013 nM) and was about 13- and 25-fold m selective relative to the d and k1 receptors, respectively. Oxymorphindole, which has d agonist activity in vivo, tested as an antagonist in this system, having Ki values of 1583, 23.1, and 1514 nM at the m , d , and k1 receptors, respectively. These results indicate that the [35S]GTP-g -S binding assay can be used to functionally characterize opioid antagonists in vitro.

Key words: Opioid receptors; Opioid antagonists; GTP; Ligand binding

Address correspondence and reprint requests to Richard B. Rothman, CPS, DIR, NIDA, NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224. Tel: (410) 550-1487; Fax: (410) 550-2997; E-mail: rrothman@intra.nida.nih.gov

Analgesia, Vol. 4, pp. 173-179, 1999
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The Novel Anticonvulsant Topiramate is Antiallodynic in a Rat Model of Neuropathic Pain

Annette M. Shadiack,1* Lory J. Molino,1 Susan K. Yagel,1 Richard P. Shank,1 Kathryn E. Rogers,1 Ellen E. Codd,1 Robert B. Rafa,2 and Kenneth D. Wild1

1Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477
2Department of Pharmaceutical Sciences, Temple University School of Pharmacy and Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140

Background: Neuropathic pain is a difficult clinical challenge because one of its defining characteristics - allodynia - is resistant to treatment using conventional analgesic drugs, even morphine. Recent reports suggest that some anticonvulsant drugs are antiallodynic in preclinical models or clinical conditions of neuropathic pain. However, it is unclear whether the antiallodynic effect is due to some common mechanism of action or whether it is due to anticonvulsant activity independent of any particular shared mechanism.
Purpose: Topiramate is a recently approved anticonvulsant with a novel mechanism of action and, therefore, offers the opportunity to address this issue. This study examined the tactile antiallodynic potential of topiramate in a rat model of neuropathic pain.
Methods: Topiramate (3, 10, 30 mg/kg, PO) was tested in the "Kim and Chung" model of neuropathic pain in rats (tight ligation of L5 and L6 spinal nerves). Tactile allodynia was assessed by paw-withdrawal latency to mechanical stimulation by von Frey filaments. Tramadol was the positive control. Acute and multiple dosing of topiramate were tested.
Results: Single oral administration of topiramate at 30 mg/kg produced an inhibition of tactile allodynia (41% decrease in sensitivity of the affected paw at 1 h) that was long-lasting (24% and 19% reduction in sensitivity at 8 h and 24 h after administration, respectively). By comparison, oral administration of tramadol at 60 mg/kg produced 58% and 8% decreased sensitivity 2 h and 8 h after dosing, respectively. Multiple dosing of topiramate (2 times a day for 5 days) at 30 mg/kg produced near-maximal inhibition of tactile allodynia (92% and 83% at 2 h and 5 h, respectively) by the third day. Sensitivity returned to baseline by 3 d after cessation of topiramate dosing.
Conclusions: These results demonstrate that (i) multiple anticonvulsant mechanisms can contribute to antiallodynic activity and, (ii) topiramate is highly effective in this model of neuropathic pain after repeated dosing, suggesting that topiramate might be effective in treating some types of neuropathic pain in humans.

Key words: Neuropathic pain; Allodynia; Analgesia; Topiramate; Anticonvulsant; Chung model

Address correspondence and reprint requests to Kenneth D. Wild at his present address: Department of Neuroscience, Amgen Inc., One Amgen Center Drive, MS 29-2-B, Thousand Oaks, CA 91320-1799. Tel: (805) 447-4783; Fax: (805) 480-1347; E-mail: kwild@amgen.com

*current address: Palatin Technologies, Edison, NJ 08837

Analgesia, Vol. 4, pp. 181-186, 1999
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Analgesic Effect of Ketoprofen Is Mainly Associated to its R-Enantiomer: Role of Cytokine Modulation

Riccardo Bertini and Gianfranco Caselli

Department of Pharmacology, Dompé S.p.A. Research Center, L'Aquila, Italy

Although it is commonly accepted that the anti-inflammatory effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is mainly associated to their ability to inhibit the cyclooxygenase (COX) enzyme system, several results indicate that the analgesic action of these drugs could be independent of their efficacy in inhibiting prostaglandin (PGs) synthesis. A unique opportunity to better dissociate the inhibition of peripheral PG synthesis from the analgesic properties of NSAIDs is constituted by R- and S-isomers of 2-arylpropionic acids (e.g., ketoprofen and flurbiprofen), with the S-isomers being 100-1000 times more potent than R-isomers on COX inhibition. Therefore, if COX inhibition was the main mechanism of action of arylpropionic NSAIDs, R-isomers should be devoid of relevant pharmacological actions. On the contrary, although the anti-inflammatory effect of ketoprofen and flurbiprofen, as well as their gastric toxicity, is mainly associated with the S-isomers, R-ketoprofen and R-flurbiprofen play a major role in analgesia. The mechanism underlying this activity is not clarified. While a significant component of NSAID analgesic effect could be centrally mediated, there has been no convincing experimental data to support the hypothesis that there is a selective inhibition of PG synthesis in the CNS. The present review will focus on recent data that delineate a possible role for cytokine regulation in the non-COX-dependent effects of NSAIDs. For instance, S-ketoprofen is responsible for ketoprofen-mediated cytokine upregulation in vitro and in vivo. The effect of S-ketoprofen is particularly evident on tumor necrosis factor (TNF) production, which represents the main component of carrageenan nociception. The fact that S-ketoprofen, unlike the R-isomer, amplifies cytokine production could contribute to its reduced analgesic effect and exacerbate its gastric toxicity.

Key words: Ketoprofen; Cytokine modulation; Cyclooxygenase enzyme system

Address correspondence and reprint requests to Dr. Riccardo Bertini, Dompé S.p.A., Via Campo di Pile, 67100 L'Aquila, Italy. Tel: +39-0862-338371; Fax: +39-0862-338219; E-mail: bertini@dompe.it

Analgesia, Vol. 4, pp. 187-195, 1999
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Decreased Spinal Morphine/Clonidine Antinociceptive Synergism in Clonidine-Tolerant Mice

Sandra C. Roerig, Timothy Busch, and Yaohui Li

Department of Pharmacology, Louisiana State University Medical Center, Shreveport, LA

Both clinical and animal studies show potentiation of analgesia when opioids and a2 adrenergic agonists such as clonidine are administered together either peripherally or spinally. In animals tolerant to morphine, the spinal morphine/clonidine synergism decreases to an additive interaction, an event that may be a mechanism underlying development of opioid tolerance. The mechanism for opioid/a2 synergism is not understood, but may also be altered with development of tolerance to clondine. In the present studies, mice were treated for 4 days with SC clonidine or saline and tail flick antinociception was measured after intrathecal (IT) morphine, clonidine, or morphine plus clonidine combinations. In animals tolerant to SC clonidine, no tolerance was shown to IT clonidine and no cross-tolerance developed to morphine. In the saline-pretreated animals the morphine/clonidine interaction was synergistic, while in the clonidine-tolerant mice the interaction between IT morphine and clonidine was additive. When considered with previous studies, these results indicate that spinal morphine/clonidine synergism can be decreased to additivity after chronic treatment with either agonist. The decreased spinal morphine/clonidine synergism despite unaltered sensitivity to IT agonists and lack of cross-tolerance between SC agonists suggests that the decreased opioid/a2 synergism is probably not a result of changes in the relevant receptors, but rather may occur at the level of receptor-induced signal transduction.

Key words: Clonidine; Tolerance; Morphine; Spinal; Antinociception

Address correspondence and reprint requests to Sandra C. Roerig, Ph.D., Department of Pharmacology, Louisiana State University Medical Center, 1501 Kings Highway, Shreveport, LA 71130. Tel: (318) 675-7877; Fax: (318) 675-7857; E-mail: sroeri@lsumc.edu

Analgesia, Vol. 4, pp. 377-395, 1999
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Assessing Persistent Pain in Older Adults: Practicalities and Pitfalls

Debra K. Weiner

Division of Geriatric Medicine, Department of Medicine, Department of Psychiatry, and Pain Evaluation and Treatment Institute, University of Pittsburgh Medical Center, Pittsburgh, PA

Objective: To provide an evaluative framework for clinicians who care for community-dwelling and/or institutionalized older adults with persistent pain, and for investigators who study these individuals.
Data Sources: Relevant papers on pain in older adults limited to the English language obtained through MEDLINE, CINAHL, and PSYCH ABSTRACTS searches for the years 1985 through 1999 were reviewed. Abstracts and in press publications describing the author's original research were also included.
Data Synthesis: Evaluating pain in older adults is challenging because of the wide range of cognitive function and physical abilities that exist in these individuals. Even when individuals are cognitively intact, traditional pain assessment instruments, particularly those that require the ability to think abstractly (e.g., the 0 to 10 scale), may be problematic. The pain thermometer and pain maps have been used successfully even in those with substantial cognitive impairment. Observation of pain behavior may be useful in both cognitively intact and demented individuals. Evaluation directed at pain-related functional impairment is critical, as is the evaluation of important psychosocial consequences and modifiers of persistent pain such as depression, sleep disturbance, and fear.
Conclusions: Persistent pain in older adults is underrecognized and undertreated. Clinicians must become more adept at recognizing and evaluating its consequences. Knowledge of the strengths and weaknesses of existing assessment tools will allow physicians to evaluate, manage, and investigate persistent pain in older adults more effectively.

Key words: Persistent pain; Older adults; Pain assessment; Assessment tools

Address correspondence and reprint requests to Debra K. Weiner, M.D., University of Pittsburgh Medical Center, Division of Geriatric Medicine, Keystone Building - Suite 300, 3520 Fifth Avenue, Pittsburgh, PA 15213-3313. Tel: (412) 624-4018; Fax: (412) 383-1972; E-mail: dweiner+@pitt.edu

Analgesia, Vol. 4, pp. 397-404, 1999
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Comparison of Antinociceptive Effects Induced by Kappa Opioid Agonists in Male and Female Mice

Corinne A. Patrick,* M. C. Holden Ko, And James H. Woods

Department of Pharmacology, University of Michigan, Medical School, Ann Arbor, MI 48109

A recent clinical report suggested that kappa opioids such as nalbuphine and butorphanol produced greater pain relief in women than in men. However, both compounds have been characterized as partial agonists with mixed mu/kappa opioid actions in animal studies. The aim of this study was to evaluate whether there is a sex difference in antinociception caused by nalbuphine and butorphanol as well as more selective kappa opioid agonists including U50,488 and CI-977 in mice. In the acid-induced writhing assay, all compounds (U50,488: 1-10 mg/kg; CI-977: 0.01-0.1 mg/kg; nalbuphine: 1-320 mg/kg; butorphanol: 0.032-0.32 mg/kg) dose-dependently inhibited writhing, but there were no sex-related differences found when comparing ED50 values in male and female mice. In the warm water (48°C) tail withdrawal assay, U50,488 (10-100 mg/kg) and CI-977 (0.1-3.2 mg/kg) also dose-dependently produced antinociception, although there were no sex-related differences observed. Nalbuphine (10-320 mg/kg) did not have antinociceptive effects under this condition. On the other hand, butorphanol (0.32-32 mg/kg) produced greater antinociception in male (50% MPE) than female mice (20% MPE). Further antagonist studies revealed that butorphanol is a mixed mu/kappa opioid with low efficacy. In summary, there were no sex-related differences in response to more selective kappa opioid agonists on antinociception in mice under these conditions.

Key words: Kappa opioids; Antinociception; Sex difference; Visceral pain; Somatic pain

Address correspondence and reprint requests to M. C. Holden Ko, Ph.D., Department of Pharmacology, University of Michigan, Medical School, 1301 MSRB III, Ann Arbor, MI 48109-0632. Tel: (734) 647-3119; Fax: (734) 764-7118; E-mail: mko@umich.edu

*This study partially fulfills the requirements for the Doctor of Pharmacy degree from College of Pharmacy, University of Michigan.

Analgesia, Vol. 4, pp. 405-407, 1999
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PAG-Microinjected Dipyrone Prevents the Late Response of Spinal Nociceptive Neurons to Subcutaneous Formalin in Rats

Enrique Vásquez, Dilia Hernández-Matheus, Víctor Tortorici, and Horacio Vanegas

Instituto Venezolano de Investigaciones Científicas (IVIC), Apartado 21827, Caracas 1020A, Venezuela

Background: The late phase of the response to SC formalin injection is a model of central sensitization (i.e., of enhanced responsiveness of nociceptive neurons). Nonopioid analgesics such as dipyrone produce antinociception when microinjected into the periaqueductal gray (PAG).
Purpose: To study whether PAG microinjection of dipyrone prevents central sensitization.
Methods: In rats, the responses of spinal nociceptive neurons to SC formalin injection into a hindpaw were recorded extracellularly. Dipyrone (100 mg/0.5 ml) was microinjected into PAG 30 min before the formalin injection.
Results: Dipyrone in PAG prevented the late phase of the formalin response.
Conclusion: Dipyrone, a commonly used analgesic, prevents central sensitization, as inferred from prevention of the late phase response to SC formalin, by acting upon the PAG.

Key words: Dipyrone; Spinal neurons; Periaqueductal gray; Formalin response; Central sensitization

Address correspondence and reprint requests to Prof. Dr. Horacio Vanegas at his current address: Institut für Physiologie, Teichgraben 8, 07740 Jena, Germany. Tel: (49) (3641) 938864; Fax: (49) (3641) 938812; E-mail: hvanegas@mti-n.uni-jena.de

Analgesia, Vol. 4, pp. 461-466, 1999
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Interaction Between Intrathecal Neostigmine and MK-801 in Rats With Nerve Ligation Injury

Jai-Hyun Hwang, Cheong Lee, Pyung-Hwan Park, Sung-Min Han, and Dong-Myung Lee

Department of Anesthesiology, Asan Medical Center, University of Ulsan, Seoul, Korea

Background: Nerve ligation injury may generate a syndrome including spontaneous pain, hyperalgesia, and allodynia. Spinally administered MK-801 as well as neostigmine has shown to have actions attenuating allodynia in a rat model. This study examines the tactile allodynic interaction between neostigmine and MK-801 in a rat model of neuropathic pain.
Methods: Male SD rats were prepared with tight ligation of left L5-6 spinal nerves and chronic intrathecal catheter implantation. Tactile allodynia was measured by application of von Frey hairs to the hindpaw ipsilateral to the nerve ligation. Neostigmine (0.3, 1, 3, and 10 mg) and MK-801 (1, 3, 10, and 30 mg) were administered intrathecally to obtain dose-response curves and the ED50 for each agent. Fractions of ED50 (1/2, 1/4, 1/8, and 1/16) of drug combination were administered intrathecally to establish the ED50. Using both isobolographic and fractional methods, analysis for the drug interaction was carried out.
Results: Intrathecal neostigmine and MK-801 alone produced dose-dependent reduction of tactile allodynia. Neostigmine/MK-801 combination produced a dose-dependent increase in withdrawal threshold of the lesioned hindpaw with reduced side effects. Both analyses revealed a synergistic interaction after the coadministration of these agents.
Conclusions: These experiments suggest that the antiallodynic action of neostigmine/MK-801 combination is synergistic at the spinal level when coadministered intrathecally. Such combination might be useful in potentiating the antiallodynic effect in this abnormal pain state and in reducing the side effects of each agent.

Key Words: Neostigmine; MK-801; Nerve ligation injury; Allodynic interaction

Address correspondence and reprint requests to Jai-Hyun Hwang, M.D., Department of Anesthesiology, Asan Medical Center, University of Ulsan, 388-1 Pungnap-Dong, Songpa-Ku, Seoul 138-736, Korea. Tel: 82 2 2224 3859; Fax: 82 2 470 1363; E-mail: jhhwang@www.amc.seoul.kr

Analgesia, Vol. 4, pp. 467-473, 1999
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Pharmacokinetics of Epidurally Administered Buprenorphine and Postoperative Analgesia: A Comparison of Two Dosages

Yasuko Miwa,1 Hajime Toyoda,2 Rie Kubota,3 Takako Komiyama,3 and Noriko Shibuya3

1Department of Anaesthesia and 2Department of Surgery, The Kitasato Institute Hospital, Tokyo, Japan
3Center for Clinical Pharmacology, School of Pharmacy, Kitasato University, Tokyo, Japan

Background: Twelve patients undergoing lower abdominal surgery and orthopedic surgery were divided into two groups depending on the dosage: group A (4 mg/kg buprenorphine with 1% mepivacaine 5 ml) and group B (8 mg/kg buprenorphine with 1% mepivacaine 5 ml).
Purpose: The effect on the postoperative analgesia of preemptively administered epidural buprenorphine was evaluated in terms of the pharmacokinetic aspects.
Method: The serum concentration of buprenorphine was determined by high performance liquid chromatography (HPLC) at control, 5, 10, 30, 60, 180, and 300 min. The pharmacokinetic parameters were examined by nonlinear regression analysis with a two-compartment method. Postoperative analgesia was assessed by the dosage of pentazocine required for the 48 h after the surgery, and the view of the visual analog scale (VAS).
Results: The peak of the serum concentration was 2.28 ± 1.34 ng/ml (mean ± SD) in group A and 7.75 ± 2.22 ng/ml in group B. The time to the peak of the concentration was within 5 min in both groups. Two patients in group A required pentazocine, while one required it in group B. The VAS was under 4 in all patients; there seemed a remarkable reduction in group B.
Conclusion: The serum concentration of buprenorphine seemed to be a good indicator to determine the minimum effective dosage.

Key Words: Buprenorphine; Pharmacokinetic; Epidural; Postoperative analgesia; Preemptive analgesia

Address correspondence and reprint requests to Yasuak Miwa, M.D., Department of Anaesthesia, The Kitasato Institute Hospital, 5-9-1 Shirogane, Minatoku, Tokyo 108-8642, Japan. Tel: 81-3-3444-6161; Fax: 81-3-3448-0553; E-mail: miwa-y@kitasato.or.jp

Analgesia, Vol. 4, pp. 475-478, 1999
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Time Span Between Nociceptive Stimulus and Denervation Modifies Autotomy Behavior in the Rat*

Alberto López-Avila,1,2 Francisco Sotres-Bayón,1 Rosendo Del Angel,1 and Francisco Pellicer1

1Departamento de Neurofisioloá, División de Neurociencias, Instituto Mexicano de Psiquiatría, México D.F.
2Facultad Mexicana de Medicina, Universidad La Salle, México D.F.

Thermal nociceptive stimulus prior to denervation increases the intensity of autotomy behavior. However, experimental evidence provided by formalin infiltration as a chemonociceptive stimulus previous to denervation shows contradictory results in autotomy behavior. Based on this framework, we explored the effect of a peripheral nociceptive inflammatory process [carrageenan (CAR) 250 ml at 1%, intraplantar] induced 30 min (CAR 30) or 24 h (CAR 24) before denervation, on the development of autotomy behavior. Male adult Wistar rats were used. The control group (CON) was only denervated. The results showed a significant enhancement of autotomy score in the CAR 30 group and a decreased autotomy score in the CAR 24 group when compared with the CON group. These results show that the time span between a noxious stimulation and denervation is an important factor in determining the intensity of autotomy.

Key Words: Autotomy; Denervation; Inflammation; Nociception; Carrageenan; Rat

Address correspondence and reprint requests to Francisco Pellicer, Instituto Mexicano de Psiquiatría, Camino a Xochimilco 101, San Lorenzo Huipulco, Tlalpan, México D.F., CP 14370. Fax: +655 99 80; E-mail: pellicer@neuroserver.imp-neuro.edu.mx

*A preliminary report of the data was presented at the Annual Meeting for Neuroscience, Miami Beach, 1999.

Analgesia, Vol. 4, pp. 479-482, 1999
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Intramuscular Fosphenytoin Reduces Neuropathic Pain: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study

Gary McCleane

Pain Clinic, Craigavon Area Hospital, Craigavon, N. Ireland

Objective: To determine if the antiepileptic drug fosphenytoin has an analgesic effect in neuropathic pain when administered as a single intramuscular injection.
Design: This is a randomized, double-blind, placebo-controlled, crossover study with washout period.
Subjects: Fifty adult patients with chronic neuropathic pain of mixed etiology.
Interventions: Patients received fosphenytoin 500 PE IM or an equal volume of saline IM. When they returned 1 week later those who had fosphenytoin received placebo and those who got placebo received fosphenytoin.
Outcome measures: Age, duration of pain, and clinical diagnosis were recorded. Overall pain, shooting pain, paresthesia, burning pain, numbness, and sensitivity were recorded every 12 h for 1 week after each injection using a 0-10 scale. Side effects and perceived efficacy of treatment were also recorded.
Results: Forty-eight patients provided results for both phases. Reduction in pain scores were seen for 48 h after fosphenytoin injection and not after placebo injection. Overall pain scores for the first 48 h after fosphenytoin injection fell from 7.49 ± 0.34 (95% CI) to 6.75 ± 0.39 (95% CI) (p = 0.01.) Twenty-eight patients perceived no benefit with either treatment (nonresponders) while 20 perceived relief with fosphenytoin (responders). No patient experienced relief with placebo. In the responder group overall pain scores in the first 48 h were 7.44 ± 0.49 (95% CI) after placebo and 5.02 ± 0.55 (95% CI) after fosphenytoin. Forty-six side effects were seen in 25 patients after fosphenytoin and nine side effects seen in seven patients in the placebo phase. More side effects were injection related rather than systemic in nature.
Conclusion: Intramuscular injection of 500 PE fosphenytoin produces significant pain relief in a proportion of patients with neuropathic pain of mixed etiology.

Key Words: Neuropathic pain; Anticonvulsants; Fosphenytoin

Address correspondence and reprint requests to Gary McCleane, Consultant Anaesthetist, Pain Clinic, Craigavon Area Hospital, 58 Lurgan Road, Craigavon BT63 5QQ, N. Ireland. Tel: 02838 612613; Fax: 02838 612746; E-mail: gary@mccleane.freeserve.co.uk

Analgesia, Vol. 4, pp. 483-504, 1999
1071-569X/99 $10.00 + .00
Copyright © 1999 Cognizant Comm. Corp.
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Challenges and Progress in Managing Chronic Pain

Warren A. Katz,1 David J. Bjorkman,2 Mark A. Fendrick,3 Allen W. Hauser,4 Alan H. Heaton,5 Donald C. Manning,6 James G. Morgan,7 George A. Porter,8 Robert B. Raffa,9 and Gurkirpal Singh10

1Chief, Division of Rheumatology, Director, Physician Strategic Planning and Development,Presbyterian Medical Center/University of Pennsylvania Health System,Clinical Professor of Medicine,University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
2Associate Professor of Medicine, Associate Chief, Division of Gastroenterology,University of Utah School of Medicine, Salt Lake City, Utah
3Assistant Professor, Internal Medicine/Health Management and Policy CoDirector, Consortium for Health Outcomes, Innovation, and Cost-Effectiveness Studies (CHOICES), University of Michigan, Ann Arbor, Michigan
4Professor of Neurology and Public Health, Associate Director, Sergievsky Center, Columbia University, New York, New York
5Senior Director, Pharmacoeconomics and Outcomes Research, Pharmacy Gold, Inc, St. Paul, Minnesota
6Novartis Pharmaceuticals, East Hanover, NJ
7Associate Professor of Medicine, Department of Rheumatology,Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
8Professor of Medicine, Division of Nephrology, Hypertension, and Clinical Pharmacology, Oregon Health Sciences University, Portland, Oregon
9Professor of Pharmacology, School of Pharmacy, and Research Associate Professor, School of Medicine, Temple University,Philadelphia, Pennsylvania
10Clinical Instructor in Medicine, Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, California

Abstract: This manuscript has been designed to provide an overview of contemporary issues facing the practitioner in managing chronic pain. It is intended to encourage recognition of the multiple needs of patients with chronic pain states, increase awareness of the value of a comprehensive, multidisciplinary approach to pain management, and outline economic considerations involved in the total cost of providing care to such a patient.

Keywords: Pain; Chronic Pain; Opioids; Nsaids; Tramadol; Drug Approaches; Non-Drug Approaches; Economics