John R. Grothusen

Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: A double-blind placebo controlled study

ABSTRACT Complex regional pain syndrome (CRPS) is a severe chronic pain condition that most often develops following trauma. The pathophysiology of CRPS is not known but both clinical and experimental evidence demonstrate the important of the NMDA receptor and glial activation in its induction and maintenance. Ketamine is the most potent clinically available safe NMDA antagonist that has a well established role in the treatment of acute and chronic pain. This randomized double‐blind placebo controlled trial was designed to evaluate the effectiveness of intravenous ketamine in the treatment of CRPS. Before treatment, after informed consent was obtained, each subject was randomized into a ketamine or a placebo infusion group. Study subjects were evaluated for at least 2 weeks prior to treatment and for 3 months following treatment. All subjects were infused intravenously with normal saline with or without ketamine for 4 h (25 ml/h) daily for 10 days. The maximum ketamine infusion rate was 0.35 mg/kg/h, not to exceed 25 mg/h over a 4 h period. Subjects in both the ketamine and placebo groups were administered clonidine and versed. This study showed that intravenous ketamine administered in an outpatient setting resulted in statistically significant (p < 0.05) reductions in many pain parameters. It also showed that subjects in our placebo group demonstrated no treatment effect in any parameter. The results of this study warrant a larger randomized placebo controlled trial using higher doses of ketamine and a longer follow‐up period.

Efficacy of Ketamine in Anesthetic Dosage for the Treatment of Refractory Complex Regional Pain Syndrome: An Open‐Label Phase II Study

OBJECTIVEnAdvanced complex regional pain syndrome (CRPS) remains very difficult to treat. While subanesthetic low-dose ketamine has shown promise in early localized CRPS, its use in advanced CRPS has not been as effective. Since ketamines analgesic potency and duration of effect in neuropathic pain are directly dose-dependant, we investigated the efficacy of ketamine in anesthetic dosage in refractory CRPS patients that had failed available standard therapies.nnnMETHODSnTwenty ASA I-III patients suffering from refractory CRPS received ketamine in anesthetic dosage over 5 days. Outcome criteria were pain relief, effect on the movement disorder, quality of life, and ability to work at baseline and up to 6 months following treatment.nnnRESULTSnSignificant pain relief was observed at 1, 3, and 6 months following treatment (93.5 +/- 11.1%, 89.4 +/- 17.0%, 79.3 +/- 25.3%; P < 0.001). Complete remission from CRPS was observed at 1 month in all patients, at 3 months in 17, and at 6 months in 16 patients. If relapse occurred, significant pain relief was still attained at 3 and 6 months (59.0 +/- 14.7%, P < 0.004; 50.2 +/- 10.6%, P < 0.002). Quality of life, the associated movement disorder, and the ability to work significantly improved in the majority of patients at 3 and 6 months.nnnCONCLUSIONSnThis open-label trial suggests benefit in pain reduction, associated CRPS symptoms, improved quality of life and ability to work following anesthetic ketamine in previously refractory CRPS patients. However, a randomized controlled trial will be necessary to prove its efficacy.

Pathophysiology of complex regional pain syndrome

Complex regional pain syndrome (CRPS) most often follows injury to peripheral nerves or their endings in soft tissue. A combination of prostanoids, kinins and cytokines cause peripheral nociceptive sensitization. In time, the Mg2+ block of the N-methyl-D-aspartate receptor is removed, pain transmission neurons (PTN) are altered by an influx of Ca2+ that activates kinases for excitation and phosphatases for depression, activity-dependent plasticity that alters the firing of PTN. In time, these neurons undergo central sensitization that lead to a major physiological change of the autonomic, pain and motor systems. The role of the immune system and the sickness response is becoming clearer as microglia are activated following injury and can induce central sensitization while astrocytes may maintain the process.

Gyroxin, a toxin from the venom of Crotalus durissus terrificus, is a thrombin-like enzyme

We report a simple method for the isolation of gyroxin, a protein from the venom of the South American rattlesnake Crotalus durissus terrificus. The intravenous injection of gyroxin into mice produces temporary episodes characterized by opisthotonos and rotations around the long axis of the animal. We found gyroxin to be a glycoprotein with thrombin-like and esterase activities. Gyroxin loses its ability to produce the gyroxin syndrome, its thrombin-like activity and its esterase activity with heat, dithiothreitol, phenylmethylsulfonyl fluoride or diisopropylfluorophosphate. We also report that three other thrombin-like enzymes, crotalase from the eastern diamondback rattlesnake (Crotalus adamanteus), ancrod from the Malayan pit viper (Agkistrodon rhodostoma) and a thrombin-like enzyme from the Central American rattlesnake (Crotalus durissus durissus), produce the gyroxin syndrome in mice. These enzymes may work by releasing neuroactive peptides from endogenous precursors.

Changes in brain catecholamines and dopamine uptake sites at different stages of MPTP parkinsonism in monkeys.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to produce parkinsonism in primates. We have studied the changes in brain catecholamines and the distribution of desipramine insensitive mazindol binding sites in MPTP parkinsonian primates at different levels of parkinsonism. Thirty-seven monkeys (Macaca fascicularis) were utilized in this study. Twelve naive animals received no treatment and served as controls. Twenty-five animals were rendered parkinsonian with serial injections of MPTP. All animals were given scored neurologic examinations throughout the study. Their movement was quantitated in an activity box. The animals were sacrificed 30-360 days after their last MPTP injection. The clinical exam of the MPTP parkinsonian monkeys demonstrated mildly to severely affected animals. There was an exponential decrease in brain catecholamine levels with increased clinical parkinsonism. The MPTP parkinsonian animals showed the greatest decrease (67-99.8%) in tissue dopamine levels in the caudate nucleus. The putamen followed closely in severity (48-99.8%) and the nucleus accumbens was much less affected (0-40%). The percent reduction of norepinephrine in the anterior pole of the frontal cortex (0-48%) was similar in degree to the decreased dopamine levels in the nucleus accumbens. Mazindol binding was decreased 30-98% in the caudate nucleus, 20-97% in the putamen, 0-26% in the nucleus accumbens, 80-96% in the substantia nigra pars compacta and 49-94% in the ventral tegmental area. In the striatum, the decreased mazindol binding was more pronounced laterally and posteriorly. In each animal, there was good correlation between tissue dopamine levels and the number of mazindol binding sites.

Changes in brain dopamine receptors in MPTP parkinsonian monkeys followingL-dopa treatment

Twenty-two monkeys (Macaca fascicularis) were utilized in this study. Ten animals were rendered parkinsonian with serial injections of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Five of these parkinsonian monkeys received L-dopa/carbidopa treatment, and five animals did not. The remaining twelve animals did not receive MPTP. Eight of these animals received no L-dopa treatment, two animals were treated chronically with L-dopa/carbidopa and two animals received L-dopa/carbidopa only on the day of sacrifice. All animals were given weekly scored neurologic examinations throughout the study. Their movement was quantitated in an activity box. All animals were sacrificed by an overdose of sodium pentobarbital. The parkinsonian animals were sacrificed 107-355 days after their last MPTP injection. The brains were removed and frozen. Punch samples were taken from the caudate and putamen for tissue dopamine determination. Selected areas of the basal ganglia were cut into 20 microns sections for quantitative receptor autoradiography. The density of D1 and D2 receptors was evaluated in the basal ganglia of these animals at the level of the anterior commissure. For the D2 assay, total binding was determined using various concentrations of [3H]spiperone in buffer containing 300 nm mianserin. For the D1 assay, total binding was determined using various concentrations of [3H]SCH-23390. Tissue isotope concentration was determined from the autoradiographs. The MPTP parkinsonian monkeys showed a mean striatal dopamine depletion of 93.5% and a mean clinical score of 9.0. The untreated parkinsonian monkeys demonstrated an increase in the number of D2 sites as compared to controls. This increase was greatest in the lateral putamen.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopamine receptor changes in untreated and (+)-PHNO-treated MPTP parkinsonian primates.

Fifteen monkeys (Macaca fascicularis) were utilized in this study. Seven naive animals received no treatment and served as controls. Eight animals were rendered parkinsonian with serial injections of MPTP. Three of the parkinsonian monkeys were treated with (+)-4-propyl-9-hydroxynaphthoxasine [(+)-PHNO], a selective dopamine D2 agonist. (+)-PHNO (2-5 micrograms/kg/h) was administered continuously using subcutaneous osmotic pumps. All animals were given weekly scored neurologic examinations throughout the study. Their movement was quantitated in an activity box. The animals were sacrificed 30-120 days after their last MPTP injection by an overdose of sodium pentobarbital. The brains were removed, frozen and cut into 20-microns sections. The density of D1 and D2 receptors was studied in the basal ganglia of these animals at the level of the anterior commissure. For the D2 assay, total binding was determined using various concentrations of [3H]spiperone in buffer containing 300 nm mianserine. For the D1 assay, total binding was determined using various concentrations of [3H]SCH-23390. Tissue isotope concentration was determined from the autoradiographs. The parkinsonian animals demonstrated 90-97% dopamine depletion in the striatum. There was a 75-90% decrease in free movement in the untreated parkinsonian monkeys and their composite clinical score was 8.9 on a scale of 0-16 (zero being normal). Control monkey scores averaged 0.6. The untreated parkinsonian monkeys demonstrated an increase in the number of D2 sites as compared to controls. This increase was greatest at the lateral putamen. The (+)-PHNO-treated monkeys demonstrated increased activity, a neurologic score of 3.4, and a 40-70% decreased in D2 sites in both caudate and putamen. There was no change in the number of D1 binding sites in both the untreated and the (+)-PHNO-treated parkinsonian monkeys as compared to controls.

Changes in Plasma Cytokines and Their Soluble Receptors in Complex Regional Pain Syndrome

UNLABELLEDnComplex Regional Pain Syndrome (CRPS) is a chronic and often disabling pain disorder. There is evidence demonstrating that neurogenic inflammation and activation of the immune system play a significant role in the pathophysiology of CRPS. This study evaluated the plasma levels of cytokines, chemokines, and their soluble receptors in 148 subjects afflicted with CRPS and in 60 gender- and age-matched healthy controls. Significant changes in plasma cytokines, chemokines, and their soluble receptors were found in subjects with CRPS as compared with healthy controls. For most analytes, these changes resulted from a distinct subset of the CRPS subjects. When the plasma data from the CRPS subjects was subjected to cluster analysis, it revealed 2 clusters within the CRPS population. The category identified as most important for cluster separation by the clustering algorithm was TNFα. Cluster 1 consisted of 64% of CRPS subjects and demonstrated analyte values similar to the healthy control individuals. Cluster 2 consisted of 36% of the CRPS subjects and demonstrated significantly elevated levels of most analytes and in addition, it showed that the increased plasma analyte levels in this cluster were correlated with disease duration and severity.nnnPERSPECTIVEnThe identification of biomarkers that define disease subgroups can be of great value in the design of specific therapies and of great benefit to the design of clinical trials. It may also aid in advancing our understanding of the mechanisms involved in the pathophysiology of CRPS, which may lead to novel treatments for this very severe condition.

Efficacy of 5-Day Continuous Lidocaine Infusion for the Treatment of Refractory Complex Regional Pain Syndrome

OBJECTIVEnChronic regional pain syndrome (CRPS) is a severe pain condition that usually results from an injury or surgical procedure. The pain in CRPS often spreads from the site of injury, and with time becomes refractory to conventional therapy. The present study was undertaken to evaluate the effects of 5-day continuous intravenous lidocaine treatment in patients afflicted with CRPS.nnnMETHODSnIntravenous lidocaine was administered in an escalating dose schedule to 49 severely affected CRPS patients in a monitored setting over 5 days. Evaluation of pain parameters and other signs and symptoms of CRPS were obtained during the infusion and at 1, 3, and 6 months following therapy.nnnRESULTSnThe majority of patients demonstrated a significant decrease in pain parameters and other symptoms and signs of CRPS. The pain reduction lasted an average of 3 months. Lidocaine may be particularly effective for thermal and mechanical allodynia. Less clinically significant effects were documented on the motor aspects of the syndrome.nnnDISCUSSIONnIntravenous lidocaine administration titrated to 5 mg/L demonstrated: 1) a significant decrease in mechanical and thermal allodynia for three months, 2) lessened associated inflammatory components of CRPS, and 3) only minimal side effects and no severe complications.

A Pilot Open-Label Study of the Efficacy of Subanesthetic Isomeric S( + )-Ketamine in Refractory CRPS Patients

OBJECTIVEnComplex regional pain syndrome (CRPS) is a severe neuropathic pain state that is often disproportionate to the initial trauma. Associated features are autonomic dysregulation, swelling, motor dysfunction, and trophic changes to varying degrees. Despite a multitude of treatment modalities, a subgroup of CRPS patients remain refractory to all standard therapies. In these patients, the disease may spread extraterritorially, which results in severe disability. A critical involvement of N-methyl-D-aspartate receptors (NMDARs) has been demonstrated both clinically and by animal experimentation. NMDA antagonists may be effective in many neuropathic pain states. In long-standing, generalized CRPS, we investigated the effects of S(+)-ketamine on pain relief and somatosensory features, assessed by quantitative sensory testing (QST).nnnMETHODSnFour refractory CRPS patients received continous S(+)-ketamine-infusions, gradually titrated (50 mg/day-500 mg/day) over a 10-day period. Pain intensities (average, peak, and least pain) and side effects were rated on visual analogue scales, during a 4-day baseline, over 10 treatment days, and 2 days following treatment. QST (thermo-, mechanical detection, and pain thresholds) was analyzed at baseline and following treatment.nnnRESULTSnSubanesthetic S(+)-ketamine showed no reduction of pain and effected no change in thermo- and mechanical detection or pain thresholds. This procedure caused no relevant side effects. The lack of therapeutic response in the first four patients led to termination of this pilot study.nnnCONCLUSIONnS(+)-ketamine can be gradually titrated to large doses (500 mg/day) without clinically relevant side effects. There was no pain relief or change in QST measurements in this series of long-standing severe CRPS patients.