Randall P. Brewer

Contemporary Management of Neuropathic Pain for the Primary Care Physician

Neuropathic pain (NP), caused by a primary lesion or dysfunction in the nervous system, affects approximately 4 million people in the United States each year. It is associated with many diseases, including diabetic peripheral neuropathy, postherpetic neuralgia, human immunodeficiency virus-related disorders, and chronic radiculopathy. Major pathophysiological mechanisms include peripheral sensitization, sympathetic activation, disinhibition, and central sensitization. Unlike most acute pain conditions, NP is extremely difficult to treat successfully with conventional analgesics. This article introduces a contemporary management approach, that is, one that incorporates nonpharmacological, pharmacological, and interventional strategies. Some nonpharmacological management strategies include patient education, physical rehabilitation, psychological techniques, and complementary medicine. Pharmacological strategies include the use of first-line agents that have been supported by randomized controlled trials. Finally, referral to a pain specialist may be indicated for additional assessment, interventional techniques, and rehabilitation. Integrating a comprehensive approach to NP gives the primary care physician and patient the greatest chance for success.

Analysis of the brain bioavailability of peripherally administered magnesium sulfate: A study in humans with acute brain injury undergoing prolonged induced hypermagnesemia

Objective:Based on preclinical investigations, magnesium sulfate (MgSO4) has gained interest as a neuroprotective agent. However, the ability of peripherally administered MgSO4 to penetrate the blood-brain barrier is limited in normal brain. The current study measured the passage of intravenously administered Mg2+ into cerebrospinal fluid in patients with brain injury requiring ventricular drainage. Design:A prospective evaluation of the cerebrospinal fluid total and ionized magnesium concentration, [Mg2+], during sustained hypermagnesemia was performed. Setting:Neurosciences intensive care unit at a major teaching institution. Patients:Thirty patients with acute brain injury secondary to subarachnoid hemorrhage, traumatic brain injury, primary intracerebral hemorrhage, subdural hematoma, brain tumor, central nervous system infection, or ischemic stroke were studied. Interventions:Patients underwent 24 hrs of induced hypermagnesemia during which total and ionized cerebrospinal fluid [Mg2+] was measured. Serum [Mg2+] was adjusted to 2.1–2.5 mmol/L. Cerebrospinal fluid [Mg2+] was measured at baseline, at 12 and 24 hrs after onset of infusion, and at 12 hrs following infusion termination. Measurements and Main Results:At baseline, total (1.25 ± 0.14 mmol/L) and ionized (0.80 ± 0.10 mmol/L) cerebrospinal fluid [Mg2+] was greater than serum total (0.92 ± 0.18 mmol/L) and ionized (0.63 ± 0.07 mmol/L) [Mg2+] (p < .05). Total (1.43 ± 0.13 mmol/L) and ionized (0.89 ± 0.12 mmol/L) cerebrospinal fluid [Mg2+] was maximally increased by 15% and 11% relative to baseline, respectively, during induced hypermagnesemia (p < .05). Conclusions:Hypermagnesemia produced only marginal increases in total and ionized cerebrospinal fluid [Mg2+]. Regulation of cerebrospinal fluid [Mg2+] is largely maintained following acute brain injury and limits the brain bioavailability of MgSO4.

Magnesium neuroprotection is limited in humans with acute brain injury

Based on the results of preclinical models, magnesium sulfate (MgSO4) has gained attention as a putative neuroprotective agent. The negative results of a large-scale, randomized clinical trial using MgSO4 in acute stroke have tempered the initial enthusiasm for a neuroprotective benefit of the ion. Additional, large-scale clinical trials in stroke and other forms of brain injury are underway. This article reviews the central nervous system (CNS) physiology of Mg++, disordered Mg++ homeostasis in acute brain injury, preclinical and preliminary clinical foundations of current clinical trials, and the data regarding the CNS bio-availability of MgSO4—an important requisite for neuroprotective therapy. Although human studies have confirmed that moderate hypermagnesemia is well-tolerated and feasible, only modest elevation of cerebrospinal fluid (CSF) [Mg++] occurs. This modest increment of CSF [Mg++] in brain-injured humans occurs in the range of 10 to 19%. However, experimental evidence has yet to establish whether this modest elevation is sufficient for neuroprotection. Because of the limited CNS passage of the ion, further experimental work is needed to define the neuroprotective threshold of [Mg++] in the injured brain.

Intravenous magnesium sulfate does not increase ventricular CSF ionized Magnesium concentration of patients with intracranial hypertension

Magnesium sulfate has attracted interest as a potential neuroprotectant but passage of magnesium ion into the central nervous system has not been well documented. For this study, we quantified plasma and cerebrospinal fluid (CSF) ionized magnesium concentration after systemic magnesium sulfate infusion in patients with intracranial hypertension. Patients (N = 9) received an intravenous infusion of 5 g/20 mmol magnesium sulfate (125 mL of a 4% wt/vol solution) over 30 minutes. Before and after dosing, CSF (from an indwelling ventricular catheter) and blood samples were collected at hourly intervals. Ionized magnesium concentration in all samples was determined using an electrolyte analyzer. Baseline plasma and CSF ionized magnesium concentrations were 0.58 ± 0.05 and 0.82 ± 0.06 mmol/L, respectively. Intravenous magnesium sulfate infusion significantly increased plasma ionized magnesium concentration (peak, 0.89 ± 0.11 mmol/L), but CSF magnesium levels did not change during the 4-hour study. Systemic administration of magnesium sulfate failed to increase CSF ionized magnesium concentration in patients with intracranial hypertension despite increasing plasma magnesium levels by >50%.

Severe phantom leg pain in an amputee after lumbar plexus block.

12. Capdevila X, Biboulet P, Morau D, Bernard N, Descholt J, Lopez S, d’Athis F. Continuous three-in-one blocks for postoperative pain control after lower limb orthopedic surgery: Where do catheters go? Anesth Analg 2002;94:1001-1006. 13. Ganapathy S, Wasserman RA, Watson JT, Bennet J, Armstrong K, Stockall C, Chess D, MacDonald C. Modified continuous femoral three-in-one block for postoperative pain control after total knee arthoplasty. Anesth Analg 1999;89: 1197-1202.Objectives: To describe the onset of phantom leg pain in an amputee with the performance of a lumbar plexus block and the subsequent alleviation after the performance of a sciatic nerve block. Case Report: A 72‐year‐old American Society of Anesthesiologists physical status III woman presented for left total hip arthroplasty. Her history was significant for a left below the knee amputation. Since the amputation she had suffered from intermittent phantom leg pain. A lumbar plexus block was performed for postoperative pain management. After the lumbar plexus block, the patient experienced severe pain radiating to the left phantom foot. Because of the severity of the phantom pain, a sciatic nerve block was performed. The phantom leg pain resolved within 5 minutes. The intraoperative care under general anesthesia was uneventful. After surgery the patient had continued blockade in both nerve distributions with excellent analgesia. Full recovery of the lumbar plexus and sciatic nerve function was present on the first postoperative day. Conclusion: The temporal relationship between the onset of the phantom leg pain and the lumbar plexus block suggests a causal relationship. In this case, it appears that ongoing peripheral input from the lumbar plexus may have been sufficient for the tonic inhibition of phantom pain in the sciatic distribution. The immediate reactivation of the phantom pain and its subsequent relief suggests dynamic processing of peripheral inputs by central neurons, which apparently is rapid and reversible in some cases of phantom pain.

Long-Term Safety and Efficacy of Lubiprostone in Opioid-induced Constipation in Patients with Chronic Noncancer Pain.

Chronic opioid analgesic use often causes opioid‐induced constipation (OIC). This open‐label extension study evaluated the safety and efficacy of lubiprostone, a chloride channel (ClC‐2) activator, for treatment of OIC in patients with chronic noncancer pain.

Opioid titration and conversion in patients receiving morphine sulfate and naltrexone hydrochloride extended release capsules.

Abstract Objective: To determine the number of steps and identify characteristics associated with attaining a stable dose of morphine sulfate and sequestered naltrexone extended release capsules (MS-sNT). Patients and Methods: Data from an open-label, long-term multicenter study designed to assess the safety of MS-sNT for managing chronic (≥ 3 m), moderate-to-severe pain were analyzed post hoc. Initial MS-sNT dose was 20 mg twice daily (BID) for opioid-naïve patients and 50% to 75% of current daily opioid dose for opioid-experienced patients. Dose adjustments upward/downward were allowed throughout the study with ≥ 3 days between increases; opioid-experienced patients could increase ≥ 24 hours after initial drug dispensing. Nonopioid analgesics were permitted as rescue medication. Stable dose was defined post hoc as one maintained for 2 consecutive study visits. Results: Overall, 69% of patients (n = 319/465) achieved a stable dose; 85% (n = 272) achieved a stable dose in ≤ 2 titration dose adjustments or “steps,” and 96% (n = 305) achieved a stable dose in ≤ 4 steps. The mean time to stable dose was 28.9 days (standard deviation [SD], 34.1 days); the median was 12 days. A stable dose was achieved in 70% (118/168) of opioid-naïve patients (mean, 24.2 days [SD, 33.4 days]; median, 8 days) and 68% (201/297) of opioid-experienced patients (mean, 31.7 days [SD, 34.3 days]; median, 25 days). A stable dose was achieved by 79% (19/24) of patients who previously used morphine, 64% (27/42) who used oxycodone, 59% (47/79) who used hydrocodone, and 71% (83/117) who used multiple opioids. Baseline pain scores were similar between patients who did and did not achieve a stable dose. At the time of stable dose achievement, average, least, worst, and current pain were all decreased from baseline. Conclusions: The study provides information about anticipated rates of achieving stable opioid dose in patients who received MS-sNT for up to 1 year to manage chronic, moderate-to-severe pain. Both opioid-naïve and opioid-experienced patients achieved a stable dose of MS-sNT, generally in ≤ 2 steps. Opioid experience and previous opioid use may influence ability to achieve a stable dose and number of steps required. More studies are needed on the anticipated experience of opioid titration/conversion to help physicians and patients set expectations for initiation of and conversion between opioid therapies.

Neurogenic pulmonary edema during intracranial endovascular therapy

Neurogenic pulmonary edema (NPE) is a well-known complication of acute brain injury. Neurogenic stunned myocardium (NSM) occurs clinically in a significant subset of patients with NPE. A 49-year-old woman developed refractory cerebral vasospasm requiring angioplasty following a subarachnoid hemorrhage. During angioplasty, NPE with NSM manifested as acute pulmonary edema associated with elevated pulmonary artery occlusion pressure and reduced cardiac output. Evaluations disclosed a right insular infarction, cardiac wall motion abnormalities, and electrocardiographic characteristics of NSM. The NSM completely resolved, and the neurological outcome was good. A 56-year-old woman developed NPE during complicated coil embolization of an internal carotid artery aneurysm. Cardiac function was normal, and the NPE resolved with a brief period of mechanical ventilation and diuresis. The delayed appearance of NSM and NPE during endovascular therapy in these patients implies a degree of risk for sympathetically mediated cardiopulmonary dysfunction during complex intracranial endovascular procedures.

Lubiprostone for Opioid-Induced Constipation Does Not Interfere with Opioid Analgesia in Patients with Chronic Noncancer Pain.

To determine whether lubiprostone 24 μg twice daily (BID), administered to relieve opioid‐induced constipation (OIC), affects opioid analgesia in patients with chronic noncancer pain.

Efficacy of Lubiprostone for the Treatment of Opioid-Induced Constipation, Analyzed by Opioid Class

Objectives To examine the efficacy and safety of lubiprostone for the treatment of opioid-induced constipation (OIC) in patients by opioid class received. Design Data were pooled from three phase III, randomized, double-blind, placebo-controlled studies. Subjects/Setting Adults with chronic noncancer pain receiving opioid therapy for 30 or more days and diagnosed with OIC. Methods Overall mean change from baseline in spontaneous bowel movement (SBM) frequency, overall treatment response (≥1 SBM/week improvement over baseline SBM frequency in all treatment weeks with available data and ≥3 SBMs/week for ≥9 of the 12 weeks of treatment), and OIC-related symptoms were examined in patients taking opioids. Data were pooled and analyzed by opioid group. Results In patients receiving phenanthrene opioids (e.g., oxycodone; N = 1,159), lubiprostone significantly increased overall mean changes in SBM frequency from baseline (P = 0.0001), increased overall response rate (P = 0.0024), and improved OIC symptoms (P ≤ 0.0229) vs placebo. Patients receiving phenylpiperidine opioids (e.g., fentanyl; N = 137) had significant improvement in SBM frequency (P = 0.0129) and favorable trends in response rates (21.4% vs 9.8%; P = 0.0723) and OIC symptoms vs placebo. Efficacy was not observed in overall analyses of patients receiving diphenylheptane opioids (e.g., methadone), although an increase in SBM frequency was observed in patients who received a morphine-equivalent daily dose of 200 or fewer mg, suggesting a dose-dependent negative interference of this opioid class on lubiprostone effects. For all groups, the lubiprostone adverse event profile was similar; the most common treatment-emergent adverse events were nausea and diarrhea. Conclusions In patients using commonly prescribed opioids, lubiprostone is effective and generally well tolerated for the treatment of OIC.