Preliminary results from a randomized, controlled, cross-over trial of intrathecal oxytocin for neuropathic pain.

OBJECTIVE: Compare intrathecal oxytocin, 100 µg to placebo on ongoing neuropathic pain and mechanical hyperalgesia and allodynia. STUDY DESIGN: Randomized, controlled, double-blind cross-over. SETTING: Clinical research unit. SUBJECTS: Individuals aged 18 to 70 years with neuropathic pain for at least 6 months. METHODS: Individuals received intrathecal injections of oxytocin and saline, separated by at least 7 days, and ongoing pain in neuropathic area (VAS [visual analog scale]) and areas of hypersensitivity to von Frey filament and cotton wisp brushing were measured for 4 hours. Primary outcome was VAS pain in the first 4 hours after injection, analyzed by linear mixed effects model. Secondary outcomes were verbal pain intensity scores at daily intervals for 7 days and areas of hypersensitivity and elicited pain for 4 hours after injections. RESULTS: The study was stopped early after completion of 5 of 40 subjects planned due to slow recruitment and funding limitations. Pain intensity prior to injection was 4.75 ± 0.99 and modeled pain intensity decreased more after oxytocin than placebo to 1.61 ± 0.87 and 2.49 ± 0.87, respectively (P = .003). Daily pain scores were lower in the week following injection of oxytocin than saline (2.53 ± 0.89 vs 3.66 ± 0.89; P = .001). Allodynic area decreased by 11%, but hyperalgesic area increased by 18% after oxytocin compared to placebo. There were no study drug related adverse effects. CONCLUSION: Although limited by the small number of subjects studied, oxytocin reduced pain more than placebo in all subjects. Further study of spinal oxytocin in this population is warranted. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov on 03/27/2014 (NCT02100956). The first subject was studied on 06/25/2014.

Phase 1 safety assessment of intrathecal oxytocin.

BACKGROUND: Preclinical data suggest that oxytocin reduces hypersensitivity by actions in the spinal cord, but whether it produces antinociception to acute stimuli is unclear. In this article, the authors examined the safety of intrathecal oxytocin and screened its effects on acute noxious stimuli. METHODS: After institutional review board and Food and Drug Administration approval, healthy adult volunteers received 5, 15, 50, or 150 µg intrathecal oxytocin in a dose-escalating manner in cohorts of five subjects. Hemodynamic and neurologic assessments were performed for 4 h after injections and 24 h later, at which time serum sodium was also measured. Cerebrospinal fluid was obtained 60 min after injection, and responses to noxious heat stimuli in arm and leg as well as temporal summation to repeated application of a von Frey filament were obtained. RESULTS: One subject receiving the highest dose experienced transient hypotension and bradycardia as well as subjective numbness in a lumbo-sacral distribution. No other subject experienced subjective or objective neurologic symptoms. Overall, blood pressure and heart rate increased 1 to 4 h after injection by less than 15% with no dose dependency. There was no effect on serum sodium, and cerebrospinal fluid oxytocin increased in a dose-dependent manner after injection. Pain scores to noxious heat stimuli were unaffected by oxytocin, and the temporal summation protocol failed to show summation before or after drug treatment. CONCLUSION: This small study supports further investigation on oxytocin for analgesia for hypersensitivity states, with continued systematic surveillance for possible effects on blood pressure, heart rate, and neurologic function.

Intrathecal ketorolac does not improve acute or chronic pain after hip arthroplasty: a randomized controlled trial.

Hypersensitivity to mechanical stimuli following surgery has been reported in patients who subsequently develop chronic pain after surgery. In animals, peripheral injury increases prostaglandin production in the spinal cord, and spinal cyclooxygenase inhibitors reduce hypersensitivity after injury. We therefore tested the hypothesis that spinal ketorolac reduces hypersensitivity and acute and chronic pain after hip arthroplasty ( www.clinicaltrials.gov NCT 00621530). Sixty-two patients undergoing total hip arthroplasty with spinal anesthesia were randomized to receive 13.5 mg hyperbaric bupivacaine with spinal saline or 13.5 mg hyperbaric bupivacaine with 2 mg preservative-free ketorolac. The primary outcome was area of hypersensitivity surrounding the wound 48 h after surgery, but this only occurred in 4 patients, precluding assessment of this outcome. The groups did not differ in acute pain, acute opioid use, or pain incidence or severity at 2 and 6 months after surgery. There were no serious adverse events. Our results suggest that a single spinal dose of ketorolac does not substantially reduce acute surgical pain and is thus unlikely to reduce the risk of persistent incisional pain.

Randomized controlled trial of intrathecal oxytocin on speed of recovery after hip arthroplasty.

ABSTRACT: Recovery from surgery is quicker in the postpartum period, and this may reflect oxytocin action in the spinal cord. We hypothesized that intrathecal injection of oxytocin would speed recovery from pain and disability after major surgery. Ninety-eight individuals undergoing elective total hip arthroplasty were randomized to receive either intrathecal oxytocin (100 µg) or saline. Participants completed diaries assessing pain and opioid use daily and disability weekly, and they wore an accelerometer beginning 2 weeks before surgery until 8 weeks after. Groups were compared using modelled, adjusted trajectories of these measures. The study was stopped early due to the lack of funding. Ninety patients received intrathecal oxytocin (n = 44) or saline (n = 46) and were included in the analysis. There were no study drug-related adverse effects. Modelled pain trajectory, the primary analysis, did not differ between the groups, either in pain on day of hospital discharge (intercept: -0.1 [95% CI: -0.8 to 0.6], P = 0.746) or in reductions over time (slope: 0.1 pain units per log of time [95% CI: 0-0.2], P = 0.057). In planned secondary analyses, postoperative opioid use ended earlier in the oxytocin group and oxytocin-treated patients walked nearly 1000 more steps daily at 8 weeks ( P < 0.001) and exhibited a clinically meaningful reduction in disability for the first 21 postoperative days ( P = 0.007) compared with saline placebo. Intrathecal oxytocin before hip replacement surgery does not speed recovery from worst daily pain. Secondary analyses suggest that further study of intrathecal oxytocin to speed functional recovery without worsening pain after surgery is warranted.

Role of spinal cyclooxygenase in human postoperative and chronic pain.

BACKGROUND: Nonsteroidal antiinflammatory drugs are commonly used to treat postoperative and chronic pain. Animal studies suggest that these drugs act, in part, by blocking prostaglandin production in the spinal cord. The authors tested intrathecal ketorolac in patients with chronic or postoperative pain. METHODS: After approval of the institutional review board and the Food and Drug Administration, three clinical studies were performed. First, 15 patients receiving chronic intrathecal morphine received 0.5-2.0 mg of intrathecal ketorolac. Second, 12 patients receiving chronic intrathecal morphine received, in a double-blinded, randomized, cross-over design, intrathecal saline or 2.0 mg of ketorolac, with pain intensity as the primary outcome measure. Third, 30 patients undergoing total vaginal hysterectomy received, in a double-blinded, randomized, controlled design, intrathecal saline or 2.0 mg of ketorolac, with bupivacaine with time to first morphine dose after surgery as the primary outcome measure. RESULTS: Patients with chronic pain had many symptoms before intrathecal injection, without worsening of these symptoms from ketorolac. Pain intensity was reduced by intrathecal ketorolac, but this did not differ from placebo. In the first study, pain was reduced by intrathecal ketorolac in patients with high cerebrospinal fluid prostaglandin E2 concentrations but not in those with normal concentrations. Intrathecal ketorolac did not alter time to first morphine after surgery. CONCLUSIONS: Intrathecal ketorolac did not relieve chronic pain or extend anesthesia or analgesia from intrathecal bupivacaine administered at the beginning of surgery. Under the conditions of these studies, it seems that spinal cylcooxygenase activity does not contribute to chronic or postoperative pain.

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.

Patterns of recovery from pain after cesarean delivery.

We know very little about the change in pain in the first 2 months after surgery. To address this gap, we studied 530 women scheduled for elective cesarean delivery who completed daily pain diaries for 2 months after surgery through text messaging. Over 82% of subjects missed fewer than 10 diary entries and were included in the analysis. Completers were more likely to be Caucasian, nonsmokers, and with fewer previous pregnancies than noncompleters. Daily worst pain intensity ratings for the previous 24 hours were fit to a log(time) function and allowed to change to a different function up to 3 times according to a Bayesian criterion. All women had at least one change point, occurring 22 ± 9 days postoperatively, and 81% of women had only one change, most commonly to a linear function at 0 pain. Approximately 9% of women were predicted to have pain 2 months after surgery, similar to previous observations. Cluster analysis revealed 6 trajectories of recovery from pain. Predictors of cluster membership included severity of acute pain, perceived stress, surgical factors, and smoking status. These data demonstrate feasibility but considerable challenges to this approach to data acquisition. The form of the initial process of recovery from pain is common to all women, with divergence of patterns at 2 to 4 weeks after cesarean delivery. The change-point model accurately predicts recovery from pain; its parameters can be used to assess predictors of speed of recovery; and it may be useful for future observational, forecasting, and interventional trials.

Pupil responses and pain ratings to heat stimuli: Reliability and effects of expectations and a conditioning pain stimulus.

BACKGROUND: The locus coeruleus (LC) signals salience to sensory stimuli and these responses can modulate the experience of pain stimuli. The pupil dilation response (PDR) to noxious stimuli is thought to be a surrogate for LC responses, but PDR response to Peltier-controlled noxious heat stimuli, the most commonly used method in experimental pain research, has not been described. NEW METHOD: Healthy volunteers were presented with randomly presented heat stimuli of 5 sec duration and provided pain intensity ratings to each stimulus. Pupillometry was performed and a method developed to quantify the PDR relevant to these stimuli. The stimulus response, reliability, and effect of commonly used manipulations on pain experience were explored. RESULTS: A method of artifact removal and adjusting for lag from stimulus initiation to PDR response was developed, resulting in a close correlation between pain intensity rating and PDR across a large range of heat stimuli. A reliable assessment of PDR within an individual was achieved with fewer presentations as heat stimulus intensity increased. The correlation between pain rating and PDR was disrupted when cognitive load is increased by manipulating expectations or presenting a second pain stimulus. COMPARISON WITH EXISTING METHODS: The PDR began later after skin heating than electrical stimuli and this is the first examination of the PDR using standard nociceptive testing and manipulations of expectations and competing noxious stimulation. CONCLUSIONS: A method is described applying PDR to standard heat nociceptive testing, demonstrating stimulus response, reliability, and disruption by cognitive manipulation.

Day-to-day experience in resolution of pain after surgery.

We know little about the individual pain experience of patients recovering from surgery in the first weeks after hospital discharge. Here, we examine individual differences in the day-to-day experience after 2 major surgeries: lower limb total major joint arthroplasty (TJA) and cesarean delivery (CD). Fifty-five TJA patients and 157 CD patients were recruited to complete questionnaires and record their daily pain experiences after surgery. After hospital discharge, patients recorded their pain intensity once daily for 60 days (CD) or twice daily for 2 weeks, once daily for 2 weeks, weekly for 8 weeks, and monthly for 3 months (TJA). Pain scores were modeled using growth curve and Bayesian change-point models. Individual differences in the model fits were examined for evidence of day-to-day differences in pain. A log time model was the simplest model that fit the data, but examination of the residuals revealed high autocorrelation representing misspecification. A change-point model fit the data better and revealed that the form of recovery fundamentally changed between days 10 and 21 after surgery. These data add meaningfully to our understanding of recovery from pain after surgery by extending the period of frequent observations a few days after surgery to a 2-month period. These high time resolution data suggest that there is a typical experience of pain resolution after surgery, but that meaningful subpopulations of experience may exist. They also indicate that a transition occurs within 1 month after surgery from 1 pattern of change in pain over time to another.

Failure of intrathecal ketorolac to reduce remifentanil-induced postinfusion hyperalgesia in humans.

In rodents, acute exposure to opioids results in transient antinociception followed by longer lasting hypersensitivity to tactile or thermal stimuli, a phenomenon termed opioid-induced hyperalgesia. This hypersensitivity can be blocked or reversed by intrathecally administered cyclooxygenase inhibitors, including ketorolac, suggesting a role for spinal prostaglandins. In surgical patients, the dose of intraoperative opioid, particularly the short-acting drug, remifentanil, is directly related to increased pain and opioid requirements for many hours postoperatively. In addition, experimentally induced tactile hypersensitivity in humans is exaggerated after cessation of remifentanil infusions. The degree of this experimental opioid-induced hyperalgesia is reduced by systemic treatment with cyclooxygenase inhibitors, and investigators have speculated that this reduction reflects the actions in the central nervous system, most likely in the spinal cord. To test this hypothesis, we measured cerebrospinal fluid prostaglandin E2 concentrations during and after remifentanil infusion in 30 volunteers. These volunteers received intrathecal ketorolac or saline in a random, blinded manner during intravenous remifentanil infusion after generation of hypersensitivity by topical capsaicin. Remifentanil reduced pain to noxious heat stimuli and reduced areas of capsaicin-induced hypersensitivity similarly in those receiving intrathecal ketorolac or saline. The primary outcome measure, area of capsaicin-induced hypersensitivity after stopping remifentanil, showed a similar increase in those receiving ketorolac as in those receiving saline. Cerebrospinal fluid prostaglandin E2 concentrations did not increase during postinfusion hyperalgesia compared with those during infusion, and they were not increased during infusion compared with those in historical controls. These data fail to support the hypothesis that acute opioid-induced hyperalgesia reflects spinal cyclooxygenase activation causing central sensitization.

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

Preclinical studies suggest that visceral afferents constitutively express kappa-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 mu-opioid agonist therapy. Pain was assessed using a pain magnitude estimate, an open ended scale of each patient's choosing and compared to their rating of pain from a 1.6 cm(2) thermode applied to the skin and heated to 49 degrees C for 5s. Normalizing pain scores to this rating as 100, pain prior to study drug treatment was 4070, 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 4h 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 4h 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.

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

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 micrograms) or epidural clonidine (150, 300, or 600 micrograms) 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. Clonidine's 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.

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 2mg (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 24h 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.

Cystatin C in cerebrospinal fluid is not a diagnostic test for pain in humans.

A recent subtractive cDNA cloning study in rats demonstrated an unexpected increase in expression of the proteinase inhibitor, cystatin C in the spinal cord during acute peripheral inflammation, suggesting this protein may be involved in the pathogenesis of persistent pain. A subsequent study of 10 women suggested that prolonged labor pain resulted in increased cystatin C concentrations in cerebrospinal fluid, and that this could be used as a biomarker for pain. To confirm and extend these observations, we measured cystatin C concentrations in cerebrospinal fluid in 131 subjects: 30 normal volunteers without pain, 25 women at elective cesarean section without pain, 60 women in labor with severe pain, and 16 patients with chronic neuropathic pain and tactile allodynia. The median cystatin C concentration in normal volunteers, 2.2 microg/ml, was similar to that previously reported by multiple investigators, and cystatin C concentrations were increased in women in labor (3.9 microg/ml). However, contrary to the previous report, cystatin C concentrations in laboring women with pain did not differ from those of pregnant women without pain (3.7 microg/ml). There was no relationship between duration of painful labor and cystatin C concentration. Patients with neuropathic pain had similar cystatin C concentrations (2.4 microg/ml) to controls. Logistic regression analysis indicated that cystatin C concentrations could not be used to reliably predict the presence of pain in either acute or chronic settings. These data suggest that cystatin C concentration in cerebrospinal fluid is an unreliable diagnostic marker for pain in humans.

Intrathecal but not intravenous opioids release adenosine from the spinal cord.

UNLABELLED: Opioids increase spinal release of adenosine in rats, and analgesia from systemic and intrathecal morphine is reduced in animals by adenosine receptor antagonists. We performed 3 studies to determine whether opioid administration also induces adenosine release in humans. To determine the effect of intrathecal opioid exposure, 15 women received intrathecal fentanyl, 50 microg, or saline, and cerebrospinal fluid was sampled at 2-minute intervals for 6 minutes before surgery. In a second study, 8 healthy volunteers received intrathecal morphine, 50 microg, plus fentanyl, 50 microg, with cerebrospinal fluid sampled 20 and 60 minutes later. To determine the effect of intravenous opioid exposure, 9 healthy volunteers received intravenous remifentanil for 60 minutes, and cerebrospinal fluid was sampled before and at the end of the infusion. Adenosine concentrations were similar in the 3 studies before opioid administration. Intrathecal fentanyl or saline did not affect adenosine concentrations during the 6 minutes in the first study. Adenosine concentrations increased significantly 20 and 60 minutes after intrathecal morphine plus fentanyl was administered. In contrast, adenosine concentrations were unaffected by intravenous remifentanil. These results suggest that intrathecal but not systemic opioid analgesia in humans is associated with spinal release of adenosine. PERSPECTIVE: Although the role of adenosine release in the spinal cord for opioid receptor activation in subsequent analgesia from opioids is controversial in laboratory studies, these clinical data suggest that local opioid receptor stimulation in the spinal cord of humans does release adenosine. Whether adenosine participates in analgesia from spinal opioids in humans is not known, but spinal adenosine itself is analgesic in humans, consistent with an opioid-adenosine role in analgesia.

Gabapentin activates spinal noradrenergic activity in rats and humans and reduces hypersensitivity after surgery.

BACKGROUND: Gabapentin has been reported to inhibit various acute and chronic pain conditions in animals and humans. Although the efficacy of gabapentin depends on the alpha2delta subunit of voltage-gated calcium channels, its analgesic mechanisms in vivo are still unknown. Here, the authors tested the role of spinal noradrenergic inhibition in gabapentin's analgesia for postoperative pain. METHODS: Gabapentin was administered orally and intracerebroventricularly to rats on the day after paw incision, and withdrawal threshold to paw pressure was measured. The authors also measured cerebrospinal fluid concentration of norepinephrine and postoperative morphine use after surgery in patients who received oral placebo or gabapentin. RESULTS: Both oral and intracerebroventricular gabapentin attenuated postoperative hypersensitivity in rats in a dose-dependent manner. This effect of gabapentin was blocked by intrathecal administration of the alpha2-adrenergic receptor antagonist idazoxan and the G protein-coupled inwardly rectifying potassium channel antagonist tertiapin-Q, but not by atropine. In humans, preoperative gabapentin, 1,200 mg, significantly increased norepinephrine concentration in cerebrospinal fluid and decreased morphine requirements. CONCLUSIONS: These data suggest that gabapentin activates the descending noradrenergic system and induces spinal norepinephrine release, which produces analgesia via spinal alpha2-adrenoceptor stimulation, followed by activation of G protein-coupled inwardly rectifying potassium channels. The authors' clinical data suggest that gabapentin activates the descending noradrenergic system after preoperative oral administration at the time of surgery. These data support a central mechanism of oral gabapentin to reduce postoperative pain and suggest that this effect could be magnified by treatments that augment the effect of norepinephrine release.

Phase I safety 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. A phase I safety trial of the intrathecal injection of a mannitol-containing formulation of adenosine in Sweden showed a considerable incidence of backache. We performed a phase I safety trial of intrathecal injection of the American formulation of adenosine, which lacks mannitol. METHODS: Following US 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 (25 subjects) and a double-blind, placebo-controlled trial of adenosine, 2 mg (40 subjects). Blood pressure, heart rate, end-tidal carbon dioxide, and sensory, motor, and reflex neurologic functions were systematically examined for 24 h after injection, and volunteers were contacted by telephone at times up to 6 months after injection. RESULTS: Intrathecal adenosine did not affect blood pressure, heart rate, end-tidal carbon dioxide, or neurologic function. Headache was reported by 10 and back pain was reported by 8 of 30 subjects exposed to adenosine in the second double-blind trial, whereas none of these symptoms was reported by the 10 saline-treated subjects. CONCLUSION: These data support further investigation of intrathecal adenosine for analgesia in humans and suggest that this agent does not produce a high incidence of severe side effects.

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.

Intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia.

Opioids administered during surgery may be beneficial by preempting postoperative pain or detrimental by causing acute tolerance. We used a stable model of hyperalgesia in volunteers to test whether acute opioid exposure also results in such pain sensitization over a period of hours in humans. Ten healthy volunteers were studied. Areas of mechanical hyperalgesia and allodynia were induced by topical capsaicin application plus intermittent heating. Computer-controlled IV remifentanil infusion was titrated to a targeted plasma concentration that reduced pain report to noxious heat by 70% and was maintained at this level for 60-100 min. Areas of hyperalgesia and allodynia were measured during and after remifentanil infusion. Remifentanil (targeted concentration of 3.1 +/- 1.2 ng/mL) reduced areas of hyperalgesia and allodynia by 33% +/- 31% and 65% +/- 28%, respectively, during infusion (P < 0.05). Areas of hyperalgesia and allodynia continuously enlarged 4 h after remifentanil was stopped, to 180% +/- 47% and 180% +/- 86%, respectively. This study demonstrates that acute opioid exposure enhances hypersensitivity for hours after exposure. If applicable to the surgical setting, this could increase the dose of opioid required for postoperative analgesia and enhance, rather than inhibit, postoperative pain.