Regina Curry

Intrathecal, but Not Intravenous, Clonidine Reduces Experimental Thermal or Capsaicin-induced Pain and Hyperalgesia in Normal Volunteers

Clonidine is approved for intraspinal administration in the treatment of neuropathic cancer pain.Some studies have suggested an analgesic effect after systemic clonidine administration. The purpose of this study was to compare the analgesic effects of intrathecal and IV clonidine with acute noxious stimulation and with hyperalgesia from intradermal capsaicin injection in volunteers. Sixteen healthy volunteers received intradermal injections of capsaicin (100 [micro sign]g) before and after the IV or intrathecal injection of clonidine 50 or 150 [micro sign]g in a randomized, double-blind manner. Pain and areas of mechanical hyperalgesia and allodynia were determined at specified intervals. In addition, pain to noxious heat stimulation was determined. The capsaicin injection produced pain, followed by hyperalgesia and allodynia. The intrathecal, but not IV, injection of 150 [micro sign]g of clonidine reduced capsaicin-induced pain and area of hyperalgesia. Intrathecal clonidine (150 [micro sign]g) reduced pain to heat stimulation, whereas IV clonidine did not. The groups did not differ in hemodynamic or sedative effects from clonidine. These data support the value of intraspinal administration of clonidine for the treatment of acute pain and of pain states associated with hyperalgesia. Similarly, they suggest that analgesia from the systemic administration of this [alpha]2-adrenergic agonist, if any, is weak in doses that produce sedation and reduce blood pressure. Implications: To the extent that the experimental pain conditions used in this study reflect those in patients with acute and chronic pain, these data support the spinal rather than IV injection of clonidine for analgesia. (Anesth Analg 1998;87:591-6)

Spinal versus Epidural Anesthesia for Cesarean Section in Severely Preeclamptic Patients A Retrospective Survey

BACKGROUND Selection of spinal anesthesia for severely preeclamptic patients requiring cesarean section is controversial. Significant maternal hypotension is believed to be more likely with spinal compared with epidural anesthesia. The purpose of this study was to assess, in a large retrospective clinical series, the blood pressure effects of spinal and epidural anesthesia in severely preeclamptic patients requiring cesarean section. METHODS The computerized medical records database was reviewed for all preeclamptic patients having cesarean section between January 1, 1989 and December 31, 1996. All nonlaboring severely preeclamptic patients receiving either spinal or epidural anesthesia for cesarean section were included for analysis. The lowest recorded blood pressures were compared for the 20-min period before induction of regional anesthesia, the period from induction of regional anesthesia to delivery, and the period from delivery to the end of operation. RESULTS Study groups included 103 women receiving spinal anesthesia and 35 receiving epidural anesthesia. Changes in the lowest mean blood pressure were similar after epidural or spinal anesthesia. Intraoperative ephedrine use was similar for both groups. Intraoperative crystalloid administration was statistically greater for patients receiving spinal versus epidural anesthesia (1780 +/- 838 vs. 1359 +/- 674 ml, respectively). Neonatal Apgar scores and incidence of maternal intensive care unit admission or postoperative pulmonary edema were also similar. CONCLUSION Although we cannot exclude the possibility that the spinal and epidural anesthesia groups were dissimilar, the magnitudes of maternal blood pressure declines were similar after spinal or epidural anesthesia in this series of severely preeclamptic patients receiving cesarean section. Maternal and fetal outcomes also were similar.

Analgesia from a peripherally active κ-opioid receptor agonist in patients with chronic pancreatitis

&NA; Preclinical studies suggest that visceral afferents constitutively express &kgr;‐opioid receptors (KORs) and that noxious visceral stimuli can be inhibited at a peripheral site by KOR activation. To test the relevance of these observations to humans, we infused, in a randomized, double blind manner, a peripherally selective KOR agonist (ADL 10‐0101) or placebo into six patients with chronic pancreatitis and ongoing abdominal pain despite &mgr;‐opioid agonist therapy. Pain was assessed using a pain magnitude estimate, an open ended scale of each patients choosing and compared to their rating of pain from a 1.6 cm2 thermode applied to the skin and heated to 49°C for 5 s. Normalizing pain scores to this rating as 100, pain prior to study drug treatment was 40 70, and was unaffected by placebo infusion in the two individuals receiving this therapy. In contrast, ADL 10‐0101 infusion reduced pain score from 63±7.6 (mean±SE) prior to infusion to 23±15 4 h after infusion (P<0.05 vs. baseline). One patient receiving placebo and one receiving ADL 10‐0101 experienced a mild headache during the study. One patient receiving ADL 10‐0101 experienced restlessness and another had assymptomatic transient dysrhythmia upon standing after the 4 h study. Neither of the treatments affected blood pressure, heart rate, respiratory rate, or oxyhemoglobin saturation, and no patient experienced nausea during the study. These limited data support the hypothesis that human visceral afferents express KOR and that peripherally restricted KOR agonists produce analgesia in patients with chronic visceral pain.

Intrathecal, but not intravenous adenosine reduces allodynia in patients with neuropathic pain

Intrathecal adenosine reduces allodynia from intradermal capsaicin in human volunteers, and reduces hypersensitivity to mechanical stimuli in animals with nerve injury. Although both intrathecal and intravenous adenosine have been reported to relieve pain in patients with neuropathic pain, there are no controlled trials of this therapy. In order to determine the effect of adenosine, seven patients with chronic neuropathic pain and stable areas of mechanical hyperalgesia and allodynia were recruited. Using a double‐blind, cross‐over design, patients were studied on two occasions – once with intrathecal adenosine, 2 mg and once with intravenous adenosine, 2 mg, using saline by the alternate route. Areas of hyperalgesia and allodynia and pain from von Frey stimulation in the area of allodynia were determined up to 24 h after drug injection. Intrathecal, but not intravenous adenosine reduced area of allodynia by approximately 25% (P<0.05) from 2 to 24 h after injection. Intrathecal adenosine reduced pain from von Frey filament stimulation in the area of allodynia by approximately 20% (P<0.05). Ongoing pain was unaffected by adenosine by either route. Intrathecal, but not intravenous adenosine, caused backache in five of seven patients, lasting 6 h. These results indicate that intrathecal adenosine reduces allodynia and pain from stimulation in the area of allodynia, whereas the same dose of adenosine intravenously was ineffective. Given the modest effect and common side effects, the role for intrathecal adenosine as a sole agent for the treatment of neuropathic pain may be limited.

Preliminary Efficacy Assessment of Intrathecal Injection of an American Formulation of Adenosine in Humans

Background Preclinical studies of intrathecal adenosine suggest it may be effective in the treatment of acute and chronic pain in humans, and preliminary studies in volunteers and patients with a Swedish formulation of adenosine suggests it may be effective in hypersensitivity states but not with acute noxious stimulation. The purpose of this study was to screen for efficacy of a different formulation of adenosine marketed in the US, using both acute noxious stimulation and capsaicin-evoked mechanical hypersensitivity. Methods Following Food and Drug Administration and institutional review board approval and written informed consent, 65 volunteers were studied in two trials: an open-label, dose-escalating trial with intrathecal adenosine doses of 0.25–2.0 mg and a double-blind, placebo-controlled trial of adenosine, 2 mg. Cerebrospinal fluid was obtained for pharmacokinetic analysis, and pain ratings in response to acute heat stimuli and areas of mechanical hyperalgesia and allodynia after intradermal capsaicin injection were determined. Results Adenosine produced no effect on pain report to acute noxious thermal or chemical stimulation but reduced mechanical hyperalgesia and allodynia from intradermal capsaicin injection for at least 24 h. In contrast, residence time of adenosine in cerebrospinal fluid was short (< 4 h). Conclusions These results show selective inhibition by intrathecal adenosine of hypersensitivity, presumed to reflect central sensitization in humans after peripheral capsaicin injection. The long-lasting effect is consistent with that observed in preliminary reports of patients with chronic neuropathic pain and is not due to prolonged residence of adenosine in cerebrospinal fluid.

Alfentanil, but Not Amitriptyline, Reduces Pain, Hyperalgesia, and Allodynia from Intradermal Injection of Capsaicin in Humans

Background: Intradermal injection of capsaicin produces brief pain followed by hyperalgesia and allodynia in humans, and the latter effects are mediated by spinal N‐methyl‐D‐aspartate mechanisms. Amitriptyline recently was shown to antagonize N‐methyl‐D‐aspartate receptors, and in this study, the authors sought to determine the effect of amitriptyline alone and with the opioid alfentanil on hyperalgesia and allodynia produced by intradermal injection of capsaicin. Methods: Forty‐six healthy volunteers in the general clinical research center received repeated intradermal injections of capsaicin (100 micro gram) alone or before and after systemic injection of 4 mg midazolam, 25 mg amitriptyline, alfentanil by computer‐controlled infusion, or amitriptyline plus alfentanil. Acute pain and areas of mechanical hyperalgesia and allodynia were determined at specified intervals. Blood was obtained for alfentanil and amitriptyline assay. Results: Capsaicin injection produced acute pain followed by hyperalgesia and allodynia. Alfentanil reduced these pain responses in a plasma‐concentration‐dependent manner, and reduction in hyperalgesia and allodynia correlated with reduction in acute pain. Amitriptyline alone had no effect and did not potentiate alfentanil. Alfentanil produced concentration‐dependent nausea, an effect diminished by amitriptyline. Discussion: These data correspond with previous studies in volunteers demonstrating reduction in hyperalgesia and allodynia after intradermal injection of capsaicin by systemically administered opioids, and they suggest that this reduction may be secondary to reduced nociceptive input by acute analgesia. These data do not support the use of acute systemic administration of amitriptyline for acute pain, hyperalgesia, and allodynia, although the roles of chronic treatment and spinal administration are being investigated.

Phase I human safety assessment of intrathecal neostigmine containing methyl- and propylparabens.

Intrathecal (IT) neostigmine produces analgesia in humans with acute experimental, postoperative, and chronic pain.The sole manufacturer of the preservative-free neostigmine solution used in the initial clinical studies no longer markets this preparation. Although solutions containing preservatives are generally avoided for IT injection, methyl- and propylparabens have not been demonstrated to be toxic. After preclinical toxicity screening in animals and Food and Drug Administration approval, 12 volunteers received IT neostigmine 10, 30, or 100 micro g, containing these preservatives and glucose. This preparation produced dose-dependent analgesia, nausea, weakness, and sedation similar to the preservative-free preparation. IT neostigmine increased acetylcholine but not norepinephrine concentrations in cerebrospinal fluid. Although nitric oxide synthesis has been implicated in analgesia from IT neostigmine injection in animals, cerebrospinal fluid concentrations of nitrite as a measure of nitric oxide were not increased by IT neostigmine in these volunteers. These data support the investigational application of IT neostigmine containing methyl- and propylparabens in the concentrations studied. Implications: Because intrathecal injection of neostigmine may be a useful analgesic, we performed a Phase I tolerability and safety study of the commercially available neostigmine formulation in human volunteers and found no evidence of toxicity. These data are important to the clinical use of this new therapy. (Anesth Analg 1997;85:842-6)

Relative potency of epidural to intrathecal clonidine differs between acute thermal pain and capsaicin-induced allodynia.

Abstract Clonidine is approved in the US for epidural administration in the treatment of intractable neuropathic cancer pain, but is also administered intrathecally for this indication and both epidurally and intrathecally in the treatment of acute, postoperative pain. The purpose of the current study was to estimate the relative potency of clonidine by epidural and intrathecal routes in the treatment of capsaicin‐induced hyperalgesia and allodynia as a model of central hypersensitivity and of noxious heat as a model of acute pain. Twenty‐four healthy volunteers were randomized to receive either intrathecal clonidine (75, 150, or 300 &mgr;g) or epidural clonidine (150, 300, or 600 &mgr;g) and rated pain from a Peltier‐controlled thermode at a lumbar, thoracic, and cervical dermatomal site before and after drug administration. In addition, they rated pain from intradermal capsaicin injections at a lumbar dermatome before and 60 min after clonidine injection and described areas of hyperalgesia and allodynia to mechanical stimuli. Clonidines effect differed with route of administration and modality of sensory testing. For acute thermal pain, intrathecal clonidine produced a dose‐dependent analgesia with a lumbar>thoracic>cervical gradient, whereas only one dose of epidural clonidine reduced thermal pain and this was at the thoracic testing site. In contrast, the potency of clonidine to reduce capsaicin‐induced allodynia was similar between the two routes of injection, and, for hyperalgesia, clonidine was only slightly more potent after intrathecal than epidural injection. These data support clinical studies from non‐comparative trials and suggest there is a >6‐fold potency ratio of intrathecal: epidural administration of clonidine for acute pain, but a <2‐fold potency ratio for these routes for mechanical hypersensitivity.

Phase I safety assessment of intrathecal ketorolac

&NA; Spinal prostaglandin synthesis has been implicated in acute pain processes and in generation and maintenance of central sensitization, and intrathecal injection of cyclo‐oxygenase (COX) inhibitors produce antinociception and reduce hypersensitivity in animals. We herein report a Phase I safety assessment of intrathecal injection of the COX inhibitor, ketorolac, in healthy volunteers, and demonstrate no serious side effects. Preclinical studies suggest a major site of action of COX inhibitors for analgesia lies in the central nervous system, especially the spinal cord. For example, COX isoenzymes are expressed in the spinal cord, acute noxious stimuli and inflammation increase spinal prostaglandin production, and spinally administered prostaglandins excite dorsal horn projection neurons, induce release of excitatory neurotransmitters, and cause nociceptive behavior. Intrathecal injection of COX inhibitors increases thermal and mechanical withdrawal threshold in animals with inflammation or nerve injury at doses several 100‐fold less than those required systemically. Following pre‐clinical neurotoxicity screening and regulatory agency approval, we examined the safety of intrathecal injection of a preservative‐free formulation of the COX inhibitor, ketorolac. In an open label, dose‐escalating design, 20 healthy volunteers received intrathecal ketorolac, 0.25, 0.5, 1, or 2 mg (n=5 per group). Ketorolac did not alter blood pressure, although there was small (10–12%), dose‐independent reduction in heart rate for the first hour after injection when data from all subjects were pooled. Ketorolac did not affect sensory or motor function or deep tendon reflexes, and there were no subjective sensations, neurologic or otherwise, reported by the volunteers. Ketorolac did not reduce pain report to heat stimuli applied to the lateral calf. One subject had a mild headache 24 h after study, resolving the next day. There were no long‐term side effects 6 months after study. These data suggest that intrathecal ketorolac does not produce a high incidence of serious adverse events, and they support further investigation for analgesia.

Effects of intrathecal ketorolac on human experimental pain.

Background:Nonsteroidal antiinflammatory drugs, the most commonly used analgesics, reduce pain not only by inhibiting cyclooxygenase at peripheral sites of inflammation but also by potentially inhibiting cyclooxygenase in the central nervous system, especially the spinal cord. Animal studies suggest that products of cyclooxygenase in the spinal cord do not alter pain responses to acute noxious stimuli but reduce pain and sensitization after peripheral inflammation. We used a spinal injection of small doses of the cyclooxygenase inhibitor ketorolac to survey the role of spinal cyclooxygenase in human experimental pain and hypersensitivity states. Methods:After regulatory agency approval and informed consent, we examined the effect of 2.0 mg intrathecal ketorolac in 41 healthy volunteers to acute noxious thermal stimuli in normal skin and to mechanical stimuli in skin sensitized by topical capsaicin or ultraviolet burn. We also examined the effect of intravenous ketorolac. Results:Intrathecal ketorolac reduced hypersensitivity when it was induced by a combination of ultraviolet burn plus intermittent heat and, according to one of the two analytical strategies, when it was induced by ultraviolet burn alone. Conclusions:These data suggest a more limited role for spinal cord cyclooxygenase in human pain states than predicted by studies in animals.