Percutaneous Neuromodulation of the Brachial Plexus and Sciatic Nerve for the Treatment of Acute Pain Following Surgery: Secondary Outcomes From a Multicenter, Randomized, Controlled Pilot Study.

OBJECTIVES: We recently reported that percutaneous peripheral nerve stimulation (PNS or "neuromodulation") decreased pain and opioid consumption within the first two weeks following ambulatory surgery. However, the anatomic lead locations were combined for the analysis, and benefits for each location remain unknown. We therefore now report the effects of percutaneous PNS for brachial plexus and sciatic nerve leads separately. MATERIALS AND METHODS: Before surgery, leads were implanted percutaneously to target the brachial plexus (N = 21) for rotator cuff repair or sciatic nerve (N = 40) for foot/ankle surgery, followed by a single injection of local anesthetic. Postoperatively, subjects were randomized in a double masked fashion to 14 days of electrical stimulation (N = 30) or sham/placebo (N = 31) using an external pulse generator. The primary outcome of interest was opioid consumption and pain scores evaluated jointly. Thus, stimulation was deemed effective if superior on either outcome and at least noninferior on the other. RESULTS: For brachial plexus leads, during the first seven postoperative days pain measured with the numeric rating scale in participants given active stimulation was a median [interquartile range] of 0.8 [0.5, 1.6] versus 3.2 [2.7, 3.5] in patients given sham (p < 0.001). For this same group, opioid consumption in participants given active stimulation was 10 mg [5, 20] versus 71 mg [35, 125] in patients given sham (p = 0.043). For sciatic nerve leads, pain scores for the active treatment group were 0.7 [0, 1.4] versus 2.8 [1.6, 4.6] in patients given sham (p < 0.001). During this same period, participants given active stimulation consumed 5 mg [0, 30] of opioids versus 40 mg [20, 105] in patients given sham (p = 0.004). Treatment effects did not differ statistically between the two locations. CONCLUSIONS: Ambulatory percutaneous PNS of both the brachial plexus and sciatic nerve is an effective treatment for acute pain free of systemic side effects following painful orthopedic surgery.

Percutaneous Peripheral Nerve Stimulation (Neuromodulation) for Postoperative Pain: A Randomized, Sham-controlled Pilot Study.

BACKGROUND: Percutaneous peripheral nerve stimulation is an analgesic technique involving the percutaneous implantation of a lead followed by the delivery of electric current using an external pulse generator. Percutaneous peripheral nerve stimulation has been used extensively for chronic pain, but only uncontrolled series have been published for acute postoperative pain. The current multicenter study was undertaken to (1) determine the feasibility and optimize the protocol for a subsequent clinical trial and (2) estimate the treatment effect of percutaneous peripheral nerve stimulation on postoperative pain and opioid consumption. METHODS: Preoperatively, an electrical lead was percutaneously implanted to target the sciatic nerve for major foot/ankle surgery (e.g., hallux valgus correction), the femoral nerve for anterior cruciate ligament reconstruction, or the brachial plexus for rotator cuff repair, followed by a single injection of long-acting local anesthetic along the same nerve/plexus. Postoperatively, participants were randomized to 14 days of either electrical stimulation (n = 32) or sham stimulation (n = 34) using an external pulse generator in a double-masked fashion. The dual primary treatment effect outcome measures were (1) cumulative opioid consumption (in oral morphine equivalents) and (2) mean values of the "average" daily pain scores measured on the 0 to 10 Numeric Rating Scale within the first 7 postoperative days. RESULTS: During the first 7 postoperative days, opioid consumption in participants given active stimulation was a median (interquartile range) of 5 mg (0 to 30) versus 48 mg (25 to 90) in patients given sham treatment (ratio of geometric means, 0.20 [97.5% CI, 0.07 to 0.57]; P < 0.001). During this same period, the average pain intensity in patients given active stimulation was a mean ± SD of 1.1 ± 1.1 versus 3.1 ± 1.7 in those given sham (difference, -1.8 [97.5% CI, -2.6 to -0.9]; P < 0.001). CONCLUSIONS: Percutaneous peripheral nerve stimulation reduced pain scores and opioid requirements free of systemic side effects during at least the initial week after ambulatory orthopedic surgery.

Ultrasound-Guided Percutaneous Peripheral Nerve Stimulation: A Pragmatic Effectiveness Trial of a Nonpharmacologic Alternative for the Treatment of Postoperative Pain.

BACKGROUND: Percutaneous peripheral nerve stimulation (PNS) is an analgesic modality involving the insertion of a lead through an introducer needle followed by the delivery of electric current after needle withdrawal. This modality has been used extensively to treat chronic pain, but only small series have been published involving postoperative pain. The ultimate objective of this study is to determine the postoperative effects of percutaneous PNS following moderately to severely painful ambulatory surgery within a real-world clinical practice setting. The primary hypothesis is that surgical pain and opioid consumption during the initial 7 days after surgery will be reduced by percutaneous PNS compared with usual and customary analgesia (dual primary outcome measures). DESIGN: A multicenter pragmatic effectiveness trial. We are randomizing participants having painful orthopedic surgical procedures of the upper and lower extremity to receive 14 days of either 1) electrical stimulation or 2) sham in a double-masked fashion. End points are being assessed at various time points over 12 postoperative months. SUMMARY: The postoperative experience will be much improved if percutaneous PNS provides potent analgesia while concurrently decreasing opioid requirements following painful surgery. Because this modality can be administered for up to 60 days at home, it may provide postoperative analgesia that outlasts surgical pain yet has relatively few risks and, unlike opioids, has no systemic side effects or potential for abuse, addiction, and overdose. Percutaneous PNS has the potential to revolutionize postoperative analgesia as it has been practiced for the past century. This study will inform key stakeholders regarding an evidence-based nonpharmacologic approach to the management of postoperative pain.

Mindfulness-Meditation-Based Pain Relief Is Not Mediated by Endogenous Opioids.

Mindfulness meditation, a cognitive practice premised on sustaining nonjudgmental awareness of arising sensory events, reliably attenuates pain. Mindfulness meditation activates multiple brain regions that contain a high expression of opioid receptors. However, it is unknown whether mindfulness-meditation-based analgesia is mediated by endogenous opioids. The present double-blind, randomized study examined behavioral pain responses in healthy human volunteers during mindfulness meditation and a nonmanipulation control condition in response to noxious heat and intravenous administration of the opioid antagonist naloxone (0.15 mg/kg bolus + 0.1 mg/kg/h infusion) or saline placebo. Meditation during saline infusion significantly reduced pain intensity and unpleasantness ratings when compared to the control + saline group. However, naloxone infusion failed to reverse meditation-induced analgesia. There were no significant differences in pain intensity or pain unpleasantness reductions between the meditation + naloxone and the meditation + saline groups. Furthermore, mindfulness meditation during naloxone produced significantly greater reductions in pain intensity and unpleasantness than the control groups. These findings demonstrate that mindfulness meditation does not rely on endogenous opioidergic mechanisms to reduce pain. SIGNIFICANCE STATEMENT: Endogenous opioids have been repeatedly shown to be involved in the cognitive inhibition of pain. Mindfulness meditation, a practice premised on directing nonjudgmental attention to arising sensory events, reduces pain by engaging mechanisms supporting the cognitive control of pain. However, it remains unknown if mindfulness-meditation-based analgesia is mediated by opioids, an important consideration for using meditation to treat chronic pain. To address this question, the present study examined pain reports during meditation in response to noxious heat and administration of the opioid antagonist naloxone and placebo saline. The results demonstrate that meditation-based pain relief does not require endogenous opioids. Therefore, the treatment of chronic pain may be more effective with meditation due to a lack of cross-tolerance with opiate-based medications.

Preclinical toxicity screening of intrathecal oxytocin in rats and dogs.

BACKGROUND: Anatomic, physiologic, and behavioral studies in animals suggest that spinally released oxytocin should produce analgesia in humans and may also protect from chronic pain after injury. In this article, the authors report preclinical toxicity screening of oxytocin for intrathecal delivery. METHODS: Intrathecal oxytocin, 11 µg (6 U) or vehicle, was injected intrathecally in 24 rats, followed by frequent behavioral assessment and histologic examination of spinal contents 2 or 14 days after injection. In three dogs, a range of intrathecal oxytocin doses (18 to 550 µg in 0.5 ml) was injected followed by physiologic, biochemical, and behavioral assessments. Ten dogs were then randomized to receive five daily injections of intrathecal oxytocin, 550 µg in 0.5 ml, or vehicle with similar assessments and, necropsy and histologic analysis were conducted 2 days later. RESULTS: In rats, intrathecal oxytocin resulted in transient scratching and itching behaviors, without other differences from vehicle. There was no behavioral, gross anatomic, or histologic evidence of neurotoxicity. Dose ranging in dogs suggested mild effects on motor tone, blood pressure, and heart rate at the 550 µg dose. Repeated boluses in dogs did not produce behavioral, biochemical, neurological, gross anatomic, or histologic evidence of neurotoxicity. CONCLUSIONS: Substances, including natural neurotransmitters, may be toxic when administered in pharmacologic doses in the spinal cord. This preclinical toxicity screen in two species suggests that bolus injections of oxytocin in concentrations up to 1,100 µg/ml are unlikely to cause neurotoxicity. The authors also support cautious clinical application of intrathecal oxytocin under regulatory supervision.

Predicting acute pain after cesarean delivery using three simple questions.

BACKGROUND: Interindividual variability in postoperative pain presents a clinical challenge. Preoperative quantitative sensory testing is useful but time consuming in predicting postoperative pain intensity. The current study was conducted to develop and validate a predictive model of acute postcesarean pain using a simple three-item preoperative questionnaire. METHODS: A total of 200 women scheduled for elective cesarean delivery under subarachnoid anesthesia were enrolled (192 subjects analyzed). Patients were asked to rate the intensity of loudness of audio tones, their level of anxiety and anticipated pain, and analgesic need from surgery. Postoperatively, patients reported the intensity of evoked pain. Regression analysis was performed to generate a predictive model for pain from these measures. A validation cohort of 151 women was enrolled to test the reliability of the model (131 subjects analyzed). RESULTS: Responses from each of the three preoperative questions correlated moderately with 24-h evoked pain intensity (r = 0.24-0.33, P < 0.001). Audio tone rating added uniquely, but minimally, to the model and was not included in the predictive model. The multiple regression analysis yielded a statistically significant model (R = 0.20, P < 0.001), whereas the validation cohort showed reliably a very similar regression line (R = 0.18). In predicting the upper 20th percentile of evoked pain scores, the optimal cut point was 46.9 (z =0.24) such that sensitivity of 0.68 and specificity of 0.67 were as balanced as possible. CONCLUSIONS: This simple three-item questionnaire is useful to help predict postcesarean evoked pain intensity, and could be applied to further research and clinical application to tailor analgesic therapy to those who need it most.

Clonidine reduces hypersensitivity and alters the balance of pro- and anti-inflammatory leukocytes after local injection at the site of inflammatory neuritis.

Perineural alpha2-adrenoceptor activation relieves hypersensitivity induced by peripheral nerve injury or sciatic inflammatory neuritis. This effect is associated with a reduction in pro-inflammatory cytokines, as well as a reduction in local leukocyte number and their capacity to produce pro-inflammatory cytokines. Curiously, clonidine's antinociceptive effect appears with a 2-3-day delay after injection. Previous observations have shown that alpha-adrenoceptor activation induces apoptosis in leukocytes, which would reduce leukocyte number. Additionally, macrophage scavenging of apoptotic cells results in a shift to an anti-inflammatory phenotype, with expression of transforming growth factor (TGF)-beta1. We therefore examined the effects of perineural clonidine 24 h and 3 days after its injection on apoptosis, TGF-beta1 expression and lymphocyte and macrophage phenotype in acute sciatic inflammatory neuritis. Perineural clonidine reduced ipsilateral neuritis-induced hypersensitivity in a delayed manner (3 days after treatment), along with a reduction at this time in lymphocyte number and an increase in caspase-3 and TGF-beta1 expressing cells and macrophages co-expressing TGF-beta1 in the sciatic nerve. One day after injection clonidine treatment was associated with a reduction in lymphocytes and pro-inflammatory Th-1 cells as well as increased numbers of caspase-3 and TGF-beta1 expressing cells and macrophages co-expressing TGF-beta1 in sciatic nerve. Clonidine's effects were prevented by co-administration of an alpha2-adrenoceptor antagonist. These data suggest that alpha2-adrenoceptor activation in sciatic inflammatory neuritis increases local apoptosis and anti-inflammatory products early after treatment. This early effect likely underlies the delayed anti-inflammatory and anti-hypersensitivity effects of perineural clonidine in this setting.

Dose response of intrathecal adenosine in experimental pain and allodynia.

BACKGROUND: Intrathecal adenosine reduces areas of mechanical hypersensitivity and provides analgesia in patients with neuropathic pain. Adenosine also causes side effects, yet its dose response for either efficacy or side effects has not been examined in double blind studies. We studied two doses of intrathecal adenosine in humans with experimental hypersensitivity and the ability of the adenosine receptor antagonist, aminophylline, to reverse adenosine's effects. METHODS: Following Internal Review Board approval and written informed consent, 35 volunteers were studied. Five volunteers were studied to confirm the stability of a new method of inducing hypersensitivity with capsaicin. The remaining 30 volunteers received, in a randomized, double-blind manner, saline, or adenosine, 0.5 or 2.0 mg, by intrathecal injection 40 min after areas of allodynia and hyperalgesia were established from capsaicin. Two hr later, volunteers were randomized to receive intravenous saline or aminophylline, 5 mg/kg. RESULTS: Topical capsaicin with intermittent heating resulted in stable areas of allodynia and hyperalgesia. Intrathecal adenosine, but not saline, reduced areas of allodynia and hyperalgesia from capsaicin, with no differences between doses. Side effects occurred in 1, 2, and 6 volunteers receiving saline, 0.5 mg and 2.0 mg adenosine, respectively. Aminophylline failed to reverse adenosine's effects. CONCLUSIONS: There is no difference in efficacy to experimental hypersensitivity between the largest approved dose of intrathecal adenosine and a dose 25% this size, but side effects are more common with the larger dose. Failure of aminophylline to reverse adenosine's effects could reflect inadequate concentrations at receptors in the spinal cord after intravenous injection.

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.