Effects of intrathecal injections of melatonin analogs on capsaicin-induced secondary mechanical allodynia and hyperalgesia in rats

Melatonin, its agonists/antagonists were administered intrathecally (i.t.) before/after intradermal injection of capsaicin. Capsaicin produced an increase in the paw withdrawal frequency (PWF) in the presumed area of secondary mechanical allodynia and hyperalgesia. Melatonin agonists in the absence of a capsaicin injection decreased the PWF significantly, whereas melatonin antagonists given intrathecally alone were ineffective in the absence of a capsaicin injection. Pre-treatment with a melatonin agonist i.t. caused a reduction in the PWF after capsaicin. In contrast, the PWF increased after capsaicin with pre-administration of a melatonin antagonist i.t. Combined pre-treatment with melatonin and a melatonin antagonist i.t. prevented the change in PWF induced by melatonin alone after capsaicin. Intrathecal post-treatment with a melatonin agonist reduced the enhanced PWF that followed an injection of capsaicin, but treatment with a combination of a melatonin agonist and its antagonist did not alter the responses. The PWF was unaffected when melatonin analogs were applied i.t. at the T6 level or were injected intramuscularly adjacent to the L4 vertebra. In spinal rats, the data showed comparable effects of melatonin analogs on capsaicin-induced secondary mechanical hyperalgesia. Animal motor function tested by 'activity box' showed that motion activity was not affected by i.t. melatonin or its antagonist. These results suggest that activation of the endogenous melatonin system in the spinal cord can reduce the generation, development and maintenance of central sensitization, with a resultant inhibition of capsaicin-induced secondary mechanical allodynia and hyperalgesia.     

Long-term outcomes during treatment of chronic pain with intrathecal clonidine or clonidine/opioid combinations

To evaluate the effectiveness of intrathecal clonidine or clonidine/opioid admixture for the treatment of chronic pain states, a retrospective chart audit of 15 patients seen by the Pain Medicine and Neurosurgical Services was performed. Subjects included 9 men and 6 women aged 26-86 years. Diagnoses included complex regional pain syndrome, neuropathic pain, and cancer pain. All patients received a trial of single-shot and/or short-term infusion of clonidine. Those reporting a significant reduction in pain, or at least 50% reduction in their visual analog scale (VAS), received long-term therapy. Intrathecal clonidine as a single-shot dose, infusion, or as intrathecal polytherapy did not improve VAS scales from pre-treatment values in 5 patients. Ten patients reported significant pain relief or >50% decrease in VAS scores with the initial trial and received long-term therapy. Two received clonidine alone for 7-11 months before the therapy failed; others failed after just a few days. Seven of eight initially responded to clonidine alone (75-950 microg/day) before failing and requiring a second drug. Three received hydromorphone (200-8000 microg/day) and four morphine (0.15-15 mg/day) with clonidine. Four patients then failed 2-drug therapy (duration 6-21 months). Two continue with intrathecal clonidine/hydromorphone (duration 19-29 months) and 1 with clonidine/morphine (duration 21 months). After initiation of intrathecal clonidine, one patient reported good relief with clonidine/morphine until his death 5 months later. In this population, intrathecal clonidine was of limited utility for most patients. It may be of benefit for subset(s) of patients, but in our experience, duration of relief is typically <18 months.     

Role of epidural and intrathecal narcotics and peptides in the management of cancer pain

The spinal administration of opioids may provide analgesia of long duration to patients with bilateral or midline lower abdominal or pelvic cancer pain. However, cross-tolerance to orally and parenterally administered narcotics and the rapid development of tolerance to spinal narcotics have limited their usefulness. Opioids have extensive distribution in the CSF and plasma when administered into the epidural or intrathecal space, and delivery of drug to brain stem sites may account for many of the toxic and therapeutic effects of spinal opioids. Further clinical and pharmacokinetic studies are required to provide the information regarding: the optimal opioids for use as spinal analgesics; equieffective dose ratios of spinal opioids in comparison to parenteral or oral opioids; strategies useful to forestall the development of tolerance of spinally administered opioids; the analgesic efficacy of this therapy in opioid-tolerant patients; and the role of spinally administered nonopioid analgesics in the management of cancer pain in the tolerant patient. These questions will need resolution before this therapy can be recommended for routine use in the management of cancer pain.     

比较鞘内和硬膜外吗啡预镇痛对硬膜外自控镇痛患者效果的影响

目的为探寻术后镇痛最佳方案,观察并比较鞘内和硬膜外吗啡预镇痛对术后病人自控镇痛效果的影响。方法选择美国麻醉医师协会分级标准(ASA)I～II级择期在腰麻-硬膜外联合阻滞麻醉下行剖宫产的产妇40例。随机数字法分为鞘内吗啡预镇痛组和硬膜外吗啡预镇痛组,每组20例。腰麻用药均为5g/L布比卡因7.5mg。鞘内吗啡预镇痛组于腰麻药中加0.2mg吗啡,硬膜外吗啡预镇痛组则于硬膜外腔注入2mg吗啡。术后接病人自控镇痛(patientcontrolledanalgesia,PCA)泵行病人硬膜外自控镇痛。记录胎儿取出后1min及5min时的Apgar新生儿评分。观察并记录术后6,12,24,48h的视觉模拟疼痛评分(VAS)、Ramesay镇静评分、PCA总需要量、总体满意度及并发症情况。结果鞘内吗啡预镇痛组术后12,24h的VAS评分显著低于硬膜外吗啡预镇痛组(t=2.578,t=3.584,P<0.05);Ramesay镇静评分显著高于硬膜外吗啡预镇痛组(t=2.629,t=6.201,P<0.05)。鞘内吗啡预镇痛组术后总体满意度显著高于硬膜外吗啡预镇痛组(χ2=4.800,P<0.05),且鞘内吗啡预镇痛组的PCA总需要量明显少于硬膜外吗啡预镇痛组(t=11.260,P<0.01)。两组均无呼吸抑制发生,恶心、呕吐及皮肤瘙痒的发生率差异无显著性意义(χ2=0.114～0.440,P>0.05)。结论在采用术后镇痛时,鞘内吗啡预镇痛效果优于     

Antiallodynic effects of loperamide and fentanyl against topical capsaicin-induced allodynia in unanesthetized primates

Capsaicin produces thermal allodynia in animals and humans by acting as an agonist at vanilloid receptor subtype 1 [VR1; also known as transient receptor potential vanilloid type 1 (TRPV1)]. VR1 receptors are widely distributed in the periphery (e.g., on primary afferent neurons). These studies examined the ability of loperamide (0.1-1 mg/kg s.c.; a micro-opioid agonist that is peripherally selective after systemic administration), in preventing and reversing thermal allodynia caused by topical capsaicin (0.004 M) in rhesus monkeys, within a tail withdrawal assay (n = 4; 38 degrees C and 42 degrees C; normally non-noxious thermal stimuli). The effects of loperamide were compared with those of the centrally penetrating micro-agonist, fentanyl (0.0032-0.032 mg/kg s.c.). We also characterized the allodynic effects of the endogenous VR1 agonist ("endovanilloid"), N-oleoyldopamine (OLDA; 0.0013-0.004 M). In this model, loperamide and fentanyl produced dose-dependent prevention of capsaicin-induced allodynia, whereas only fentanyl produced robust reversal of ongoing allodynia. Antagonism experiments with naltrexone (0.1 mg/kg s.c.) or its analog, methylnaltrexone (0.32 mg/kg s.c.), which does not readily cross the blood-brain barrier, suggest that the antiallodynic effects of loperamide and fentanyl were predominantly mediated by peripherally and centrally located micro-receptors, respectively. Loperamide and fentanyl (1 mg/kg and 0.032 mg/kg, respectively) also prevented OLDA (0.004 M)-induced allodynia. Up to the largest dose studied, loperamide was devoid of thermal antinociceptive effects at 48 degrees C (a noxious thermal stimulus, in the absence of capsaicin). By contrast, fentanyl (0.01-0.032 mg/kg) caused dose-dependent antinociception in this sensitive thermal antinociceptive assay (a presumed centrally mediated effect). These studies show that loperamide, acting as a peripherally selective micro-agonist after systemic administration, can prevent capsaicin-induced thermal allodynia in primates in vivo, in the absence of thermal antinociceptive effects.     

Spinal cord lesion after long-term intrathecal clonidine and bupivacaine treatment for the management of intractable pain

Long-term intrathecal drug administration using implanted pumps is increasingly used in the treatment of chronic refractory pain [Anderson and Burchiel 1999, Neurosurgery 44 (1999) 289; Krames 2002, Best Pract Res Clin Anaesthesiol 16 (2002) 619; Wallace 2002, Neurology 59 (2002) S18]. Extensive clinical experience over the last 15 years suggests that in selected cases the technique is safe, although infections, system malfunction and drug-related complications have been reported. In most cases, drug-related spinal cord injuries have resulted from the compression of a spinal inflammatory mass or abcess rather than from a direct neurotoxic effect. We report on a case of toxic spinal cord lesion occurring after more than 3 years of uneventful continuous infusion of a mixture of bupivacaine and clonidine.     

Synergy between the antinociceptive effects of intrathecal clonidine and systemic morphine in the rat

These experiments tested the hypothesis that intrathecal alpha 2-adrenergic antinociception could be potentiated by the concurrent administration of systemic morphine. Thirty-four male rats, implanted with chronic indwelling intrathecal catheters, received a subcutaneous injection of either morphine sulfate or an equal volume of saline, followed by an intrathecal injection of clonidine HCl or an equal volume of vehicle. Antinociception was assessed using the tail-flick test. Tail-flick latencies following subcutaneous morphine plus intrathecal vehicle, or subcutaneous saline plus intrathecal clonidine were not significantly different from baseline. However, the combination of subcutaneous morphine plus intrathecal clonidine produced a significant antinociceptive effect. Such potentiation may prove to be a useful clinical strategy to help maximize analgesia, minimize side effects and attenuate the development of tolerance.     

Relative potency of levo-alpha-acetylmethadol and methadone in humans under acute dosing conditions

levo-alpha-Acetylmethadol (LAAM) and methadone are full mu-opioid agonists used to treat opioid dependence. Current labeling indicates that LAAM is less potent than methadone. Clinical studies have not determined the relative potency of these drugs. This study compared the effects of acute doses of LAAM and methadone and also examined the ability of naloxone to reverse their effects. Five occasional opioid users received once weekly doses of either placebo, LAAM, or methadone (15, 30, or 60 mg/70 kg p.o.) in agonist exposure sessions and then received naloxone (1.0 mg/70 kg i.m.) 24, 72, and 144 h after agonist exposure. Subject-rated, observer-rated, and physiological measures were assessed regularly. Comparisons of physiological and subjective measures collected in agonist exposure sessions indicate that LAAM is not less potent than methadone under acute dosing conditions. For some measures, LAAM was significantly more potent. Three subjects who entered the study were withdrawn for safety reasons due to greater than anticipated and clinically relevant respiratory depression after receiving 60 mg of LAAM. Naloxone did not fully reverse the pupil constriction produced by 60 mg of LAAM. Acute agonist effects suggest that LAAM may be more potent than methadone and more potent than current labeling indicates. An accurate LAAM:methadone relative potency estimate will aid determination of adequate doses for opioid-dependent patients inducted onto LAAM and for methadone maintenance patients who choose to switch to more convenient thrice-weekly LAAM.     

Successful treatment of erythromelalgia with intrathecal hydromorphone and clonidine

OBJECTIVE: The objective of this study was to determine if intractable pain from erythromelalgia could be successfully treated with intrathecal hydromorphone and clonidine. DESIGN: A single case of pain from erythromelalgia refractory to multiple treatment modalities was examined and treated. SETTING: The setting is an outpatient pain clinic at a major university teaching hospital. PATIENT: Our patient is an 82-year-old woman with hypertension and peripheral vascular disease. INTERVENTION: Intrathecal opioid and an alpha2-agonist were administered. OUTCOME MEASURES: Outcome was determined by means of patient self-report during office follow-up visits. RESULTS AND CONCLUSIONS: Administration of intrathecal opioid and an alpha2-agonist can be effective in the treatment of the pain of erythromelalgia and offers an alternative pain treatment modality for patients with unremitting pain refractory to more conservative therapy.     

The epidural and intrathecal administration of ketamine

An overview of the spinal administration of ketamine is presented. Ketamine acts as a noncompetitive antagonist of the NMDA receptor Ca++ channel pore. This effect provides interesting possibilities in pain therapy. However, there are still contrasting results that seem to be due to a lack of comparative controlled studies. The presence of systemic and neurotoxic effects presently limits clinical use.     

Mechanical allodynia and thermal hyperalgesia upon acute opioid withdrawal in the neonatal rat

Upon withdrawal from opioids many patients experience a heightened sensitivity to stimuli and an exaggerated pain response. We present evidence that neonatal rats exhibit allodynia and hyperalgesia on acute opiate withdrawal. Postnatal 7 and 21 day rats were used to approximately model a full term human infant and a human child, respectively. The opiate antagonist naloxone was used to precipitate withdrawal at 30 or 120 min after a single acute administration of morphine. Alternatively, rats were allowed to undergo spontaneous withdrawal. Behavioral manifestations of withdrawal syndrome were not observed when naloxone was administered at 30 min post-morphine, but were present when withdrawal was precipitated at 120 min. Spontaneous and precipitated withdrawal from a single acute administration of morphine produced mechanical allodynia and thermal hyperalgesia in postnatal day 7 rats and mechanical allodynia in postnatal day 21 rats. A higher dose of morphine was required to produce mechanical allodynia in postnatal day 21 versus 7 rats but this increase was independent of the analgesic efficacy of morphine at these two ages. The present work illustrates the need to examine the phenomenon of hypersensitivity upon opioid withdrawal in the human pediatric population.     

Effects of stress and relaxation on capsaicin-induced pain.

A sizable body of research has been devoted to understanding the relationship between pain sensitivity and the psychological state of the individual. Considerable disagreement as to the direction of the association still exists. This study examines the effects of 2 experimental manipulations, cognitive/emotional stress and relaxation, on capsaicin-induced pain. Subjects were pretrained in relaxation and then randomized to experimental stress produced by a 20-minute Stroop test, relaxation (tape), or a control condition (neutral video), followed by a capsaicin injection in the forearm. Cardiovascular measures were taken at regular intervals, and cortisol, norepinephrine (NE), and self-reports of arousal (relaxation index) were taken immediately before and after the experimental task. The manipulation significantly interacted with sex to predict capsaicin-induced maximum pain. Women in the stress condition reported greater pain than both men in the stress condition and women in the relaxation condition. Pain was correlated negatively with task-induced changes in NE and cortisol and positively with self-reported arousal (decreased relaxation). However, separate analyses showed that some physiologic indexes of heightened arousal (increased blood pressure and NE) predicted lower pain only in men, whereas subjective increases in arousal predicted higher pain only in women. Multiple hierarchical regression analyses confirmed that physiologic and self-reported arousal predicted pain independently and in opposite directions, and a model including both accounted for 56% of the overall variance. These findings suggest that a unidimensional model of arousal may be insufficient to explain the effects of stress on pain and that these effects operate differently in men and women.     

可乐定减少硬膜外分娩镇痛中突破性疼痛的临床观察

目的观察可乐定联合罗哌卡因及芬太尼减少硬膜外分娩镇痛中突破性疼痛的临床疗效。方法 100例拟行无痛分娩的初产妇,随机分为可乐定组(n=50)和对照组(n=50)。可乐定组和对照组硬膜外腔分别注射0.1%罗哌卡因,2μg/ml芬太尼及5μg/ml的可乐定混合液和0.1%罗哌卡因及2μg/ml芬太尼混合液10~15 ml作为负荷剂量,维持镇痛药物两组均为0.1%罗哌卡因及2μg/ml芬太尼混合液,背景剂量6 ml,病人自控单次给药剂量(PCEA)6ml,锁定时间15 min,比较两组突破性疼痛的数量、产程时间、罗哌卡因用量和分娩方式。结果两组产程时间和分娩方式差异无统计学意义(P0.05)。对照组产妇发生突破性疼痛的例数高于可乐定组,两组比较差异有统计学意义(P0.05)。对照组患者罗哌卡因用量大于可乐定组,两组比较差异有统计学意义(P0.05)。结论可乐定联合罗哌卡因及芬太尼用于硬膜外分娩镇痛可减少产妇的突破性疼痛,并降低罗哌卡因的用量。     

Effects of gender and acute dental pain on thermal pain responses.

OBJECTIVE: Considerable research suggests that females exhibit greater sensitivity to laboratory pain procedures than do males; however, whether the presence of acute clinical pain influences this sex difference in pain sensitivity has not been investigated. The present experiment investigated the effects of sex and acute dental pain on laboratory pain responses. DESIGN: Thermal pain onset and tolerance were determined in 46 dental patients (15 male, 31 female) experiencing pain due to acute irreversible pulpitis and in 33 healthy controls (13 male, 20 female). In addition, measures of mood and coping were obtained in all participants. All subjects participated in two experimental sessions. The first session took place immediately before the patients underwent endodontic treatment for relief of pulpal pain. The second session took place approximately 1-2 weeks later, when pulpitis patients were pain free after treatment. During each session, thermal pain onset and tolerance were assessed with a 1-cm2 contact thermode applied to the right volar forearm using an ascending method of limits. RESULTS: During both sessions, thermal pain onset and tolerance were lower in control females than in control males; however, male and female pulpitis patients did not differ in their thermal pain responses during either session. Pulpitis patients also showed greater affective distress than controls. CONCLUSIONS: These data suggest that the sex difference in thermal pain sensitivity frequently reported in pain-free subjects appears to be absent in patients presenting with acute dental pain. However, this effect cannot be explained solely based on the presence of clinical pain because the effect on pain threshold and tolerance persisted into session 2, when pulpitis patients were pain free. Potential explanations for these results are discussed.     

Care and management of intrathecal and epidural catheters.

Epidural and intrathecal catheters have increasingly become a part of acute and chronic pain management over the past 25 years. Externalized systems include temporary, permanent exteriorized, and permanent port systems for use over weeks to months of expected therapy. Implanted, completely internalized systems are available for conditions expected to require many months or years of therapy. Expert care includes routine management as well as advanced troubleshooting. Prevention of infection is a key priority for nurses managing these devices.     

Effects of intrathecal lidocaine on hyperalgesia and allodynia following chronic constriction injury in rats

The present study investigated the effects of different doses of intrathecal lidocaine on established thermal hyperalgesia and tactile allodynia in the chronic constriction injury model of neuropathic pain, defined the effective drug dose range, the duration of pain‐relief effects, and the influence of this treatment on the body and tissues. Male Sprague–Dawley rats were divided into five groups and received intrathecal saline or lidocaine (2, 6.5, 15, and 35mg/kg) 7 days after loose sciatic ligation. Respiratory depression and hemodynamic instability were found to become more severe as doses of lidocaine increased during intrathecal therapy. Two animals in the group receiving 35mg/kg lidocaine developed pulmonary oedema and died. Behavioral tests indicated that 6.5, 15, and 35mg/kg intrathecal lidocaine showed different degrees of reversal of thermal hyperalgesia, and lasted for 2–8 days, while 2mg/kg lidocaine did not. The inhibition of tactile allodynia was only observed in rats receiving 15 and 35mg/kg lidocaine, and the anti‐allodynic effects were identical in these two groups. Histopathologic examinations on the spinal cords revealed mild changes in rats receiving 2–15mg/kg lidocaine. However, lesions were severe after administration of 35mg/kg lidocaine. These findings indicate that intrathecal lidocaine has prolonged therapeutic effects on established neuropathic pain. The balance between sympathetic and parasympathetic nervous activities could be well preserved in most cases, except for 35mg/kg. Considering the ratio between useful effects and side effects, doses of 15mg/kg are suitable for intrathecal injection for relief of neuropathic pain.     

The use of epidural and intrathecal analgesia in palliative care

Oral analgesics and adjunctive medicines will be used to meet the needs of most palliative care patients in terms of pain relief. However, for a small number of patients, this will not be adequate for satisfactory relief from pain, resulting in a lower quality of life. For such patients, using some of the more 'technical approaches' to pain relief, e.g. epidural or intrathecal analgesia, can prove beneficial. Taking the anatomy of the spinal space into consideration, this article will present the indications and contraindications for spinal analgesia, as well as drugs used and the most appropriate methods of drug administration.     

Relationships between pain, cognitive activity and epidural analgesia during labor

This study examined the dynamic interplay between subjective pain, pain behavior and cognitive activity during the latent (less than or equal to 3 cm), mid-active (5-7 cm) and transition (greater than or equal to 8 cm) phases of labor in 115 nulliparous women. Subjects received no analgesia during the latent phase and either no analgesia or epidural analgesia during the active and/or transition phase. Data were analyzed according to phase and analgesic condition. For subjects with no epidural analgesia, both the Present Pain Intensity (PPI) and the Present Behavioral Intensity (PBI) scores were correlated within and between phases. In contrast, Coping/Distress scores were weakly correlated between the latent and active labor phases and were unrelated between the active and transition phases. PPI and Coping/Distress scores were highly correlated within the latent phase but were independent within the active and transition phases of labor. PBI and Coping/Distress scores were moderately correlated within the latent and active phases and were unrelated during the transition phase. Epidural techniques reduced subjective pain and pain behavior significantly but had no apparent effect on the coping or distress-related cognitive activity characteristic of active labor. We concluded that coping and distress-related cognitive activity in labor may follow a phase-specific pattern which is relatively independent of pain or pain relief after labor has become active.     

Endogenous opioid peptides contribute to antinociceptive potency of intrathecal [Dmt1]DALDA

[Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH(2); Dmt = 2',6'-dimethyltyrosine) is a dermorphin analog that shows high affinity and selectivity for the mu opioid receptor. The intrathecal potency of [Dmt(1)]DALDA far exceeded its affinity at mu receptors and suggests that other mechanisms must be involved in its action in the spinal cord. The affinity and selectivity of [Dmt(1)]DALDA was determined using cell membranes expressing cloned human mu, delta, and kappa opioid receptors. Competitive displacement binding with [(3)H][Dmt(1)]DALDA, [(3)H]DPDPE (H-Tyr-d-Pen-Gly-Phe-d-Pen), and [(3)H]U69,593 [(5alpha,7alpha,8beta)-(+)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec-8-yl)-benzeneacetamide] revealed K(i) of 156 +/- 26 pM for mu opioid receptor (MOR), 1.67 +/- 0.04 microM for delta opioid receptor (DOR), and K(i) of 4.4 +/- 1.7 nM for kappa opioid receptor (KOR), respectively. [Dmt(1)]DALDA increased guanosine 5'-O-(3-[(35)S]thiotriphosphate) binding in MOR, DOR, and KOR membranes, with EC(50) being 17 (8.8-33) nM, 2 (1.2-3.2) microM, and 124 (15-1000) nM, respectively. Intrathecal [Dmt(1)]DALDA inhibited the tail-flick response in mice with ED(50) = 1.22 (0.59-2.34) pmol. Intrathecal administration of an antiserum against dynorphin A(1-17) or [Met(5)]enkephalin significantly attenuated the response to i.t. [Dmt(1)]DALDA, resulting in ED(50) of 6.2 (3.6-12.6) pmol and 6.6 (3.5-19.6) pmol, respectively. Neither antisera had any effect on the response to i.t. morphine. Intracerebroventricular (i.c.v.) [Dmt(1)]DALDA was not affected by previous i.c.v. administration of anti-Dyn or anti-ME. Pretreatment with norbinaltorphimine or naltriben also attenuated the antinociceptive response to i.t., but not i.c.v., [Dmt(1)]DALDA. These data suggest that i.t. [Dmt(1)]DALDA causes the release of dynorphin and [Met(5)]enkephalin-like substances that act at kappa and delta receptors, respectively, to contribute to the extraordinary potency of [Dmt(1)]DALDA.